A Review on Sulfonamide Complexes with Metals: Their Pharmacological Potential as Anticancer Drugs

Abstract

Sulfonamides represent a versatile class of biologically active compounds, best known for their antibacterial activity, but increasingly investigated for their potential in oncology. Free sulfonamides themselves display cytotoxic properties; however, coordination with metal ions often enhances both selectivity and potency, while also introducing new mechanisms of action. Although numerous studies have reported sulfonamide–metal complexes with anticancer activity, a systematic overview linking biological properties to the central metal atom has been lacking. This review summarizes current research on sulfonamide complexes with transition metals and selected main-group elements, focusing on their pharmacological potential as anticancer agents. The compounds discussed include complexes of titanium, chromium, manganese, rhenium, ruthenium, osmium, iridium, palladium, platinum, copper, silver, gold, iron, cobalt, nickel, uranium, calcium, magnesium and bismuth. For each group, representative structures are presented along with cytotoxicity data against cancer cell lines, comparisons with reference drugs such as for example cisplatin, and where relevant, studies on carbonic anhydrase inhibition. The survey of available data demonstrates that many sulfonamide–metal complexes show cytotoxic activity comparable to or greater than existing chemotherapeutic agents, while in some cases exhibiting reduced toxicity toward non-cancerous cells. These findings highlight the promise of sulfonamide–metal complexes as a fertile area for anticancer drug development and provide a framework for future design strategies. This review covers the research on anti-cancer activity of sulfonamide complexes during the years 2007–2025.

1. Introduction

Sulfonamides are part of a broader class of biologically active compounds. Their prominence emerged from their invaluable antibacterial properties, which, during the Second World War, played a crucial role in saving countless lives. The biological activity of sulfonamides is closely linked to their molecular structure, characterized by sulfonamide and amine substituents, as well as a variety of aromatic and heteroaromatic frameworks. As of 24 August 2025, the DrugBank database lists 175 compounds classified as sulfonamides. Of these, 110 structures are either approved or in clinical trials, with 80 approved for therapeutic use. Sixty-nine structures remain under investigation, and 65 are in experimental stages. Among those approved as drugs, 16 have been withdrawn from medical practice due to health concerns. Silver salts are also present in this group as therapeutic agents; however, no records in DrugBank describe sulfonamide–metal complexes [1]. This absence does not imply a lack of such compounds in the scientific literature, where publications on the subject are in fact numerous. Despite this body of work, no comprehensive review has yet examined the biological activity of sulfonamide complexes in relation to the metal present. This article aims to address that gap by synthesizing findings from various studies and organizing them according to the type of metal forming complexes with structurally diverse sulfonamides.

Among sulfonamides with anticancer activity are sulfonamides containing various aromatic or heteroaromatic rings for example: quinazoline [2], 1,2,4-triazine [3], 1,3,5-triazine [4], thiophene [5], 3,4-dihydro-2(1H)-quinolinone [6], 1,3-oxazole [7], fluorinated pyridine [8] and many others heteroaromatic rings, as well as sulfamethoxazole-based sulfonamides [9] many chiral sulfonamides [10]. In addition, there are sulfonamide anticancer drugs that are already widely used in oncological treatment. Examples of such drugs include pazopanib [11], amsacrine (used in the treatment leukemias as well as Hodgkin’s and non-Hodgkin’s lymphomas) [12], belinostat (used in the treatment of T-cell lymphoma) [13], venetoclax (used to treat chronic lymphocytic leukemia) [14] and dabrafenib (used to treat melanoma) [15]. The sulfonamide group plays a key role in anticancer activity, but it can also act as a link between two groups that are important in increasing the activity of the compound [16].

In medicine, various organic compounds, acting in different ways, such as by intercalation, alkylation, etc., as well as some metal complexes, are used for widespread use in cancer treatment. The most popular anticancer drug currently used in medicine is cisplatin and its analogs: carboplatin, oxaliplatin, nedaplatin, lobaplatin and heptaplatin, shown in Figure 1. This figure also shows the history of the discovery of these drugs and their introduction into patient treatment.

The oldest platinum drug is cisplatin, obtained in 1845 by the Italian chemist Michele Peyrone. After 120 years, the cytotoxic properties of this compound were accidentally discovered by American biophysicist Barnett Rosenberg. Currently, this compound is most often used in multi-drug therapy. Cisplatin is an alkylating cytotoxic agent, which binds to DNA by covalent binding. Cisplatin has many side effects, e.g., action only on certain types of cancer, non-selectivity of the drug, adverse effects on: kidneys, nervous system, hearing, vomiting and fatigue, natural or acquired drug resistance of certain types of cancer during therapy. To reduce these side effects, new platinum drugs have been obtained and are widely used in medicine: carboplatin, oxaliplatin, nedaplatin, lobaplatin and heptaplatin. All these platinum drugs meet the rule of the so-called classical platinum drugs: platinum is present in the II oxidation state, they contain two labile anionic and two inert neutral ligands with cis geometry and the entire complexes are inert.

Over the years, many other platinum complexes deviating from these rules have been obtained and studied, e.g., complexes with trans geometry, platinum complexes on the IV oxidation state, platinum multicore complexes, encapsulation of platinum drugs in liposomal carriers and a number of complexes of other transition metals, e.g., titanium, ruthenium, osmium, gold, etc.—elements that differ in chemical properties related to their electron configuration. The most important features of the new compounds sought are cytotoxicity and selectivity. The chemical properties of the new complexes often determine different mechanisms of biological action than in the case of cisplatin and its derivatives. This could lead to a reduction in tumor resistance to the drug.

The design of new complexes with anticancer activity uses multiple organic ligands, complexing most often via a nitrogen or oxygen atom. Examples of such organic ligands are sulfonamides—compounds containing the functional group -SO₂NR₂. Since free sulfonamides themselves also exhibit anticancer activity [17], therefore this publication presents examples of sulfonamide complexes of d-block metals and uranium and bismuth with anti-cancer activity.

There are various mechanisms of anticancer activity of the complexes discussed. The most common mechanism is the inhibition of carbonic anhydrase IX and XII. Other mechanisms include, for example, cell cycle arrest in the S phase or G1 phase, double DNA breaks, increased levels of reactive oxygen species, interaction with proteins responsible for tumor development and high mitochondrial membrane depolarization.

The collected information on the latest sulfonamide complexes with anticancer activi-ty covers publications from the beginning of the 21st century to 2025. Databases such as Reaxys, SciFinder, and DrugBank were used for this purpose.

2. Sulfonamide Complexes with Metals

2.1. Titanium Complexes

Sulfonamides form complexes with titanium as shown in Figure 2. Antitumor sulfonamide titanium complexes include the seven-coordinated Ti(IV) complexes 1a–d [18].

The compounds 1a–d were tested for anticancer activity against cell lines: Hela S3 (a derivative of the parent HeLa cell line—cervical cancer) and Hep G2 (Hepatocellular carcinoma). The anticancer activity of Ti(IV) complexes, depending on the X substituent, is shown in

Table 1. Anticancer activity of complexes 1a–d.

Compound	IC50 (μM)
	Hela S3	Hep G2
1a	3.1 ± 0.2	9.3 ± 0.2
1b	0.9 ± 0.1	1.8 ± 0.2
1c	0.5 ± 0.1	1 ± 0.1
1d	19 ± 4	Non-toxic
Cisplatin	2.0 ± 0.3	4.8 ± 1.2

.

The highest antitumor activity against the HeLa S3 cell line is shown by compound 1c, higher than cisplatin, used as a reference compound. Compound 1c also shows the highest anti-tumor activity against the HepG2 cell line.

Another example of anticancer sulfonamide titanium complexes are the six-coordinated complexes 2 and 3 (Figure 1) [19]. The compounds were tested for anticancer activity against PC3 and HeLa cell lines (

Table 2. Anticancer activity of complexes 2 and 3.

Compound	IC50 (μM)
	PC3 (Prostate Cancer)	HeLa (Cervical Cancer)
2	32.6 ± 0.5	36.75 ± 1.0
3	>100	>100
Doxorubicin	0.912 ± 0.120	3.10 ± 0.2

). Complex 2 was significantly more active against both cell lines than complex 3, however, it was less active than doxorubicin.

2.2. Chromium(II) Complex

The sulfonamide-chromium complex with anti-cancer activity is complex 4, shown in Figure 3 [20].

The anti-cancer activity of this complex was measured by cell viability after treatment, given as a percentage (%). For the MCF-7 cell line (breast cancer), it was 45.73%, and for the HCEC cell line (human corneal epithelial cells), it was 25.40%. For the free ligand, forming this complex—the viability of MCF-7 cells was 100%, and in the case of HCEC cells was 22.97%.

2.3. Manganese Complexes

Manganese(II) sulfonamide complexes include complex 5, containing saccharin and 2,6-bis(2-benzimidazolyl)pyridine (bzimpy) as a ligands (Figure 4) [21].

This complex was tested for cytotoxic activity against four cell lines: A459 (lung cancer), HT29 (colorectal adenocarcinoma), MCF-7 (breast cancer) and MCF-10A (non-tumorigenic epithelial cell line). Antitumor activity was compared with that of the bzimpy ligand and cisplatin. (

Table 3. Anticancer activity of complex 5.

Compound	IC50 (μM)
	A549	HT29	MCF-7	MCF-10A
5	1.60 ± 0.03	89.50 ± 2.52	3.50 ± 0.20	>100
Bzimpy ligand	8.42 ± 0.37	19.22 ± 2.84	25.33 ± 0.84	>100
Cisplatin	5.21 ± 0.18	11.25 ± 1.35	10.57 ± 0.39	13.80 ± 2.36

).

It can be seen from Table 3 that complex 5 exhibits greater anti-cancer activity against cells of the A549 line and cells of the MCF-7 line, both in comparison to the Bzimpy ligand and in comparison to cisplatin. In contrast, 5 was less cytotoxic to the HT29 cell line, compared to the ligand and cisplatin. Both complex 5 and the free Bzimpy ligand were less cytotoxic against MCF-10A cell line than cisplatin.

A sulfonamide manganese(II) complex with an identical structure to complex 4 is also known (Figure 3). This compound showed a cell viability after treatment of 42.58% against the MCF-7 cell line and 79.86% against the normal HCEC cell line [20].

2.4. Rhenium Complexes

Sulfonamide rhenium complexes that exhibit anticancer activity include carbonyl complexes (Figure 5). An example of such a complex is the carbonyl complexes of rhenium 6–9, which have a tetrahedral structure and complexes through the aromatic system of the cyclopentadiene ring [22].

These compounds were tested for human carbonic anhydrase (hCA) inhibition. Carbonic anhydrase is a target for both diagnosis and anticancer therapy. The results of the activity of this complex on tumor-associated isoforms hCA IX and hCA XII are shown in

Table 4. Inhibition data of complexes 6–10 (AZA = acetazolamide).

CA Isozymes	Ki [nM]
	6	7	8	9	10	AZA
hCA IX	43	3.7	5.2	7	29.7	25
hCA XII	6.7	4.5	6.9	4.4	45.5	5.7

. Inhibition was compared with acetazolamide, used as a reference compound.

This table shows that among complexes 6–9, complex 7 shows the highest inhibition activity against hCA IX isosyme, while complex 9 shows the highest activity against hCA XII isosyme.

Another example of a sulfonamide carbonyl rhenium complex with anticancer activity is a six-coordinated complex 10, containing a primary sulfonamide group, in which the metal atom is complexed via a 4-(2-pyridyl)-1,2,3-triazole group [23]. The compound was tested for carbonic anhydrase inhibition, including hCA IX and hCA XII isoforms, in the CO2 hydrase stopped-flow assay. The activity of this compound was compared with acetazolamide (Table 4).

The activity of the complex 10 against isoform hCA IX was slightly lower than activity of acetazolamide, however, against isoform hCA XII the complex 10 showed much lower activity than acetazolamide.

Rhenium complexes 8–10 are an example of primary benzenesulfonamide complexes. The Ph-SO₂NH₂ group is one of the most potent inhibitors of carbonic anhydrase. Its mechanism of action involves the binding of zinc ions by the deprotonated form of the sulfonamide at the lower part of the active site. In addition, hydrogen bonds are formed between the sulfonamide group and the threonine residue Thr199, as well as hydrophobic interactions between the benzene ring and the leucine residue Leu198 and valine residue Val121 in the middle part of cavity (Figure 6) [24].

Among other known compounds, there are anticancer sulfonamide rhenium six-coordinated complexes (also carbonyl), in which the rhenium atom is complexed by three nitrogen atoms, including the nitrogen atom of the sulfonamide group 11a–b and 12a–b. These ligands contain a biphenyl grouping [25] (11a–b) and naphthalene rings [26] (12a–b). The complexes 11a–b and 12a–b were tested for activity against the NCI-H292 cell line (non-small cell lung cancer cells) and compared with cisplatin (

Table 5. Anticancer activities of 11a–b and 12a–b.

NCI-H292 Cell Line
Compound	IC50 [µM]
11a	97.72
11b	39.91
12a	17.33
12b	82.54
Cisplatin	88.18

).

Compound 11a shows slightly less anti-cancer activity than cisplatin, while compound 11b shows much higher anti-cancer activity than cisplatin. This table shows that both complex 12a and complex 12b are more cytotoxic against the NCI-H292 cell line than the reference compound.

Another group of sulfonamide rhenium complexes that exhibit anti-cancer activity are sulfonamide derivatives of cyclopentadienyl imines 13a–b [27]. These compounds were tested for anticancer activity against non-small cell lung cancer cell line—H1299 and compared with cisplatin (

Table 6. Antitumor activity of compounds 13a–b against the H1299 cell line.

Compound	H1299 Cell Line IC50 [μM]
13a	37.5 ± 6.6
13b	24.3 ± 8.3
Cisplatin	12.8 ± 5.6

).

Compound 13a is less active to the H1299 cell line than cisplatin. Compound 13b is more cytotoxic against the H1299 cell line than complex 13a, however, it is also less active than the reference compound.

A different example of sulfonamide anticancer rhenium complexes are benzenesulfonamide derivatives (14a–m), shown in Figure 7 [28]. The molecules of these compounds consist of a benzenesulfonamide group linked via a linker (symbol L in the Figure 7) to nitrogen tridentate ligands that bind the rhenium atom (Z group in the Figure 7). These complexes were tested for affinity to hCA-IX carbonic anhydrase and compared with acetazolamide (

Table 7. Competitive Binding of complexes 14a–m to Hypoxic CA-IX Expressing HeLa Cell.

Compound	L	Z	IC50 [nM]
Acetazolamide			7
14a	(CH2)2	Re-DPA	116
14b	(CH2)2	Re-PAMA	28
14c	(CH2)2	Re-NMI	53
14d	(CH2)2	Re-CIM	4
14e	(CH2)2	Re-CIM/TIM	3
14f	(CH2)2	Re-TIM	9
14g	(CH2)2	Re-TIM/HIM	44
14h	(CH2)2	Re-HIM	109
14i	CH2	Re-CIM	51
14j	CH2	Re-TIM	116
14k	O(CH2)4	Re-TIM	43
14l	O(CH2)4	Re-HIM	35
14m	O(CH2)6	Re-HIM	33

). The complex with the highest affinity for hCA-IX is 14e, showing higher affinity than acetazolamide. The lowest affinity for hCA IX was shown by compound 14a and 14j.

2.5. Iron, Cobalt, Nickel Complexes

Figure 8 shows sulfonamide complexes of iron, cobalt and nickel with anticancer activity. Among the anti-cancer, sulfonamide iron complexes are ferrocene complexes 15–18 [29].

The complexes 15–18 were tested for cytotoxic activity against three cancer cell lines: HCT116 (colon cancer), MCF7 (breast cancer), MDA-MB-231 (breast cancer) and against one non-cancerous BJ cell line (fibroblasts from normal foreskin). The results are shown in

Table 8. Antitumor activity of compounds 15–18.

	IC50 [μM]
Compound	Cancer Cell Lines			Non-Cancer Cell Line
	HCT116	MCF7	MDA-MB-231	BJ
15	>100	>100	>100	>100
16	55 ± 9	42 ± 7	68 ± 10	>100
17	64 ± 11	63 ± 7	27 ± 2	63 ± 6
18	56 ± 16	33 ± 4	24 ± 2	62 ± 3
Cisplatin	21 ± 3	9.5 ± 1.5	29 ± 4	25 ± 5

.

The lowest cytostatic activity, both against the cancer cell lines and against the BJ cell line, was shown by complex 15. Against the HCT116 cell line, all complexes were less active than cisplatin. The most active complex against the HCT116 cells was complex 16. All the complexes analyzed in this research were less cytotoxic against the non-cancerous BJ cell line than cisplatin. Complexes 15 and 16 were the least cytotoxic to the BJ cell line, while compounds 17 and 18 showed similar cytotoxicity against this cell line. In the case of the MCF-7 cell line, compound 18 was the most active, although it showed less cytotoxicity against this cell line than the reference compound. Complexes 17 and 18, on the other hand, showed higher antitumor activity than cisplatin against the MDA-MB-231 cell line, with reduced cytotoxicity against the normal BJ cell line.

Sulfaclozine (SCZ) forms complexes 19–20 with iron, cobalt and nickel, shown in Figure 8 [30]. The anti-cancer activity of these complexes is shown in

Table 9. Antitumor activity of 19–20.

Compound	IC50 (µg/mL)
	MCF-7	CaCo-2
SCZ ligand	215.24 ± 0.67	97.6 ± 0.45
19	54.23 ± 0.52	190.1 ± 0.30
20a	45.62 ± 0.28	106.87 ± 0.34
20b	284.25 ± 0.31	362.9 ± 0.41

and compared with sulfaclozine, as a ligand.

Among these complexes, the highest cytotoxic activity, both against MCF-7 and CaCo-2 cell lines, was shown by complex 20a. The compound was more cytotoxic than sulfaclozine in the case of the MCF-7 cell line.

A well known compound is the sulfamethoxazole complex with nickel(II) 21, and its cytotoxic activity against K562, HT-29 and MCF-7 cell lines is shown in

Table 10. Anticancer activity of 21.

Compound	IC50(µM)
	K562 (Chronic Myelogenous Leukemia)	HT-29 (Colon Adenocarcinoma)	MCF-7 (Breast Cancer)
21	51.06	44.21	42.34
Cisplatin	4.10	8.00	7.61

[31]. However, the compound was less cytotoxic against these three cell lines than cisplatin, used as a reference compound.

Sulfonamide complexes with iron, cobalt and nickel with an identical structure to chromium(II) complex 4 (Figure 3) exhibit cytotoxic activity, which is shown in

Table 11. Cytotoxic activity of analogs of complex 4 containing iron, cobalt and nickel atoms.

Compound	Cell Viability After Treatment (%)
	MCF-7	HCEC
Iron analogue of complex 4	100	100
Cobalt analogue of complex 4	52.92	41.27
Nickel analogue of complex 4	47.52	58.11

[20]. The most active of these compounds against the MCF-7 cell line was the nickel complex.

A. Salmon’s research group studied the anticancer activity of ferrocene complexes 22–33 by inhibiting the cancer-associated carbonic anhydrase enzymes IX and XII [32]. Compound 25 was the most potent inhibitor of hCA IX and hCA XII (

Table 12. CA inhibition data for compounds 22–33 against hCA IX and XII.

Compound	Ki (nM)
	CA IX	CA XII
22	85	-
23	65	-
24	33.1	18.8
25	5.9	6.8
26a	80	9.2
26b	81	8.0
26c	7.9	6.8
27a	9.6	7.9
27b	9.1	7.3
27c	8.1	7.0
28	75.5	8.7
29	136	26.2
30	76.2	9.1
31	186	31.5
32	137	21.1
33	82.3	21.4

).

Nickel complexes 34–36 are complexes of nickel with Schiff bases, containing a sulfonamide group [33]. Their anticancer activity is shown in

Table 13. Anticancer activity of nickel complexes 34–36.

Compound	IC50 (μg/mL)
	MCF-7	OEC
34	11.3 ± 1.1	62.23 ± 3.11
35	5.04 ± 0.6	33.59 ± 1.68
36	365 ± 24.6	>100
Cisplatin	5.71 ± 0.7	32.68 ± 2.74

. Complex 35 was the most active against the MCF-7 cell line (more active than cisplatin); however, it had similar cytotoxic properties to cisplatin against normal cells of the OEC line (normal oral epithelial).

Azo derivatives of sulfafurazole form complexes with iron 37, cobalt 38 and nickel 39 [34]. The data in

Table 14. Anticancer activity of 37–39.

Compound	IC50 (µg/mL)
	A-549 (Lung Cancer)	PANC-1 (Pancreatic Cancer)
37	154.73 ± 11.48	102.03 ± 5.95
38	248.38 ± 14.65	185.81 ± 9.73
39	176.48 ± 10.72	120.84 ± 6.28
Ligand	466.25 ± 17.52	360.61 ± 14.63
Vinblastine sulfate	24.6 ± 0.65	4.68 ± 0.65

show that all three complexes (37–39) exhibit greater cytostatic activity against A-549 and PANC-1 cell lines than the unbound sulfafurazole ligand, but this activity is weaker than that of vinblastine sulfate.

Azo derivatives of sulfathiazole form complexes 40 and 41 with Co(II) and Ni(II), respectively [35]. The cytotoxic activity of these complexes against the Hep-G2 and MCF-7 cell lines is shown in

Table 15. Anticancer activity of 40–41.

Compound	IC50 (µM)
	Hep-G2 (Hepatocellular Carcinoma)	MCF-7 (Breast Cancer)
Ligand	>1236.30	>1236.30
40	197.45	26.41
41	562.00	224.80
Cisplatin	40.76	-
5-fluorouracil	-	215.26

. As can be seen from this table, both complexes show greater cytotoxic activity against both cell lines than the unbound sulfathiazole ligand, while both compounds show less cytotoxic activity against the Hep-G2 cell line than cisplatin. In contrast, cobalt complex (40) is more cytotoxic active against the MCF-7 cell line than 5-fluorouracil.

2.6. Ruthenium Complexes

Among the many metals under investigation, ruthenium complexes are among a group of compounds offering hope for potential use in chemotherapy. Ru(II) and Ru(III) ions have a strong affinity for nitrogen and sulfur [36]. Three important features predispose ruthenium ions to biological studies:

(a)

chemical similarity to iron due to ruthenium’s location in the same group of the periodic table, e.g., oxidation degrees and a preferential coordination number = 6,

(b)

low redox potentials allowing for easy change of basic oxidation degrees under physiological conditions,

(c)

relatively slow ligand exchange (a rate comparable to the rate of cell division—mitosis), which means that if ruthenium binds to a selected cell component, it will remain so bound throughout the cell life cycle [37].

Examples of sulfonamide complexes with ruthenium are shown in Figure 9. Among the sulfonamide ruthenium complexes with anticancer activity are chloride hexacoordinated complexes 42–46. These complexes contain sulfonamides, commonly used in medicine, as ligands: sulfanilamide, sulfacetamide sodium, sulfadiazine, sulfamethoxazole and sulfadimidine [38]. These complexes were tested for cytotoxic activity against cells of the HCT-116 colon cancer line and compared with doxorubicin (

Table 16. Cytotoxic activities against HCT-116 cell line for the Ru(III) complexes 42–46.

Compound	IC50 [μg]
	HCT-116 Cell Line
42	>50
43	>50
44	>50
45	24.5
46	10.3
Doxorubicin	0.471

). All five tested complexes showed less cytotoxicity against the HCT-116 cell line than doxorubicin. Complexes 42–44 were the least cytotoxic, but complex 46 was the most cytotoxic.

Another group of sulfonamide anti-cancer ruthenium complexes are sulfamethoxypyridazine complexes (47–48) [39]. The antitumor activity of these complexes against chronic myelogenous leukemia cells (K562 cell line) is shown in

Table 17. Cytotoxic activities against K562 cell line for the complexes 47–48.

Compound	IC50 (μM)
	K562 Cell Line
47	3.80 ± 0.19
48	2.00 ± 0.10
cis-[RuCl2(bpy)2]	>100
cis-[RuCl2(phen)2]	>100

. Complex 48 was more active than complex 47, however both of these complexes were much more cytotoxic than the non-sulfonamide Ru complexes: cis-[RuCl₂(bpy)₂] and cis-[RuCl₂(phen)₂].

Also of interest are organometallic compounds of ruthenium (II), the general formulas of which are shown in Figure 10. These are monoarene complexes of the “piano stool” type with pseudo-tetrahedral geometry, where the individual ligands X, Y, Z both mono- and bidentate can be varied, thus modeling their chemical properties. They are either ionic or inert compounds.

An example of such a sulfonamide ruthenium complex of the “piano stool” type is complex 49, in which the arene, complexing the metal atom via six π electrons, is p-cymene [40]. The other ligands in this complex are triphenylphosphine and a sulfonamide ligand complexing through the nitrogen atom of pyridine and the sulfur atom of the thioamide group. Complex 49 was tested for cytostatic activity against SiHa cell line of cervical cancer and compared with cisplatin. This compound was more cytotoxic against SiHa cell line (IC₅₀ = 1.9 ± 0.5 μM) than cisplatin (IC₅₀ = 3.0 ± 1.1 μM).

Another example of sulfonamide ruthenium complexes of the “piano stool” type are compounds 50a–h, in which the ruthenium atom is complexed through the nitrogen atom of the sulfonamide group, the nitrogen atom of the secondary amine group, the halogen atom (chlorine or iodine) and the aromatic ring [41]. Compounds 50a–h were tested for cytotoxic activity against A2780 (ovarian cancer) and A549 (lung cancer) cell lines. The reference compound was cisplatin (

Table 18. Cytotoxic activity of complexes 50a–h.

Compound	IC50 [μM]
	A2780 Cell Line	A549 Cell Line
50a	8.32 ± 0.54	28.8 ± 2.6
50b	11.25 ± 0.08	13.5 ± 1.4
50c	18.4 ± 1.2	32.2 ± 0.7
50d	14.25 ± 0.06	16.1 ± 2.4
50e	3.57 ± 0.98	29.8 ± 1.1
50f	5.6 ± 0.5	13.7 ± 0.1
50g	>50	4.1 ± 1.3
50h	39.4 ± 3.4	38.5 ± 1.9
Cisplatin	1.2 ± 0.02	3.1 ± 0.1

).

In the case of the A2780 cell line, the greatest cytotoxic activity was exhibited by complex 50e, which was slightly less active than cisplatin. The least active complex against the A2780 cell line was compound 50g. However, compound 50g was the most cytotoxic active against the A549 cell line, slightly less active than cisplatin. The least cytotoxic compound against the A549 cell line was 50h.

Piano stool-type ruthenium sulfonamide complexes also include organometallic, chloride complexes of acetazolamide with ruthenium 51a–b (Figure 10) [42]. These complexes were tested for inhibition of the cancer-associated carbonic anhydrase isoforms hCA IX and hCA XII. The reference compound was acetazolamide (

Table 19. Inhibition of isoforms hCA IX and hCA XII by acetazolamide and 51a–b.

Compound	KI [nM]
	hCA IX	hCA XII
51a	3.8	0.52
51b	0.63	0.04
Acetazolamide	25.2	5.7

).

Both complexes 51a and 51b were better inhibitors of hCA IX and hCA XII isoforms than acetazolamide. Complex 51b was a better inhibitor of both isoforms than complex 51a. It follows that the binding of acetazolamide to the ruthenium atom enhances its ability to inhibit cancer-associated isoforms hCA IX and hCA XII. The 1,3,4-thiadiazole ring linked to a sulfonamide group also causes carbonate anhydrase inhibition by binding the zinc ion. In addition, the nitrogen atoms of the 1,3,4-thiadiazole ring form hydrogen bonds with the OH group of the T200 residue of the active site [24].

Another example of sulfonamide ruthenium complexes of the piano stool type are complexes 52a–b, containing an imidazole ring [43]. The anticancer activity of these compounds under normoxia and hypoxia against MIA PaCa-2 (human pancreas ductal adenocarcinoma) and MDA-MB-231 (breast adenocarcinoma) cancer cell lines is shown in

Table 20. Anticancer activity of 52a–b.

Compound	IC50 (μM)
	Normoxia (~12% O2)				Hypoxia (~1.5% O2)
	CHO	MDCK	MIA PaCa-2	MDA-MB-231	MDA-MB231
52a	>200	>200	22.5 ± 1.5	38.3 ± 1.5	27.9 ± 1.0
52b	>200	>200	17.1 ± 1.0	39.6 ± 3.2	17.7 ± 1.8

. The activity of these compounds was compared against non-cancerous cells: CHO (Chinese hamster ovary) and MDCK (Madin-Darby canine kidney). Both complexes were much less cytotoxic against normal cell lines than against tumor cells.

Also known are ruthenium complexes with chiral sulfonamide (N-Tosyl) ligands 53–56. Their activity against the A2780 cell line (ovarian carcinoma) is shown in

Table 21. Anticancer activity of 53–56 against A2780 cell line.

Compound	GI50 (μM)
	A2780 Cell Line
53	5.5 ± 0.5
54	13.7 ± 0.4
55	1.2 ± 0.3
56	1.8 ± 0.2
Cisplatin	2.0 ± 0.2

, which shows that compounds 55 and 56 were more cytotoxic than cisplatin [44].

Azo sulfonamides (N-tosyl and N-mesyl) form monoarene complexes with ruthenium 57–61 [45]. The cytotoxicity of these compounds against four cancer cell lines: HeLa, A549, HCT-116 and MCF-7 are shown in

Table 22. Anticancer activity of 57–61.

Compound	IC50 (µM)
	HeLa	A549	HCT-116	MCF-7
57a	10.3 ± 1.3	n.d.	n.d.	n.d.
57b	3.3 ± 0.4	n.d.	n.d.	n.d.
57c	3.1 ± 0.4	n.d.	n.d.	n.d.
57d	7.0 ± 0.5	n.d.	n.d.	n.d.
57e	4.1 ± 0.7	13.8 ± 2.0	11.2 ± 2.8	21.9 ± 2.0
57f	3.6 ± 0.5	12.6 ± 1.4	9.8 ± 0.7	9.2 ± 0.7
57g	1.7 ± 0.4	2.5 ± 0.3	1.3 ± 0.1	8.5 ± 1.8
58	>100	n.d.	n.d.	n.d.
59	9.3 ± 1.0	n.d.	n.d.	n.d.
60	13.0 ± 1.4	n.d.	n.d.	n.d.
61	>100	n.d.	n.d.	n.d.
Cisplatin	7.0 ± 1.5	11.7 ± 2.0	16.0 ± 2.3	12.5 ± 0.9

n.d. = not determined.

. As can be seen from this table, the 57g complex was the most cytostatically active against all four cell lines. It showed greater activity than cisplatin in each case.

2.7. Osmium Complexes

Sulfonamide osmium complexes with anti-cancer activity are shown in Figure 11. Examples of such compounds are 62a–b [46], 62c–d [47] and 63a–h [48] which also belong to the “piano stool” type complexes.

The compounds 62a–b showed anticancer activity against the MRC5 (lung cancer) and A2780Cis (ovarian cancer) cell lines (

Table 23. Anticancer activities of 62a–b.

Compound	IC50 [μM]
	MRC5 Cell Line	A2780Cis
62a	15.1 ± 0.5	25.9 ± 0.7
62b	9.7 ± 0.2	10.4 ± 0.5
Cisplatin	13.5 ± 0.9	11.5 ± 0.2

).

In the case of the MRC5 cell line, the 62b complex was more cytotoxic than cisplatin, used as a reference compound. Compound 62a was only slightly less cytotoxic to the MRC5 cell line than cisplatin. In the case of the A2780Cis cell line, complex 62b was also more cytotoxic than cisplatin, while complex 62a was less cytotoxic than cisplatin.

Complexes 62c and 62d were tested for cytostatic activity against 7 cell lines: A2780 (ovarian cancer), A549 (lung cancer), HCT-116 (colon cancer), MCF7 (breast cancer), MCF7−TAMR-1 (tamoxifen resistant breast cancer), MCF10-A (non-tumorigenic breast cells) and MDA−MB-231 (breast cancer). The results of cytotoxic activity of 62c–d complexes are summarized in

Table 24. Anticancer activities of 62c–d against seven cell lines (N.D. = not determined).

Compound	IC50 [μM]
	A2780	A549	HCT-116	MCF7	MCF7−TAMR-1	MCF10-A	MDA−MB-231
62c	15.5 ± 0.5	21.1 ± 0.3	37 ± 1	11.0 ± 0.3	N.D.	N.D	15 ± 1
62d	10.5 ± 0.1	14.1 ± 0.3	36.4 ± 0.2	8.1 ± 0.2	9 ± 1	30.9 ± 0.4	9.1 ± 0.9
Cisplatin	1.2 ± 0.3	3.2 ± 0.1	5.2 ± 0.3	6.6 ± 0.2	6.0 ± 0.7	6 ± 1	9.6 ± 0.4
Tamoxifen	12.4 ± 0.1	13.5 ± 0.1	19 ± 3	5.9 ± 0.4	14.5 ± 0.1	25.0 ± 0.2	12.9 ± 0.2

. The reference compounds were cisplatin and tamoxifen. Cell lines were treated for 24 h and allowed 72 h recovery time in drug-free medium.

Table 24 shows that in the case of the A2780 cell line, compound 62d showed greater cytotoxic activity than tamoxifen. In the case of A549, HCT-116 and MCF7 cell lines, both compounds showed less cytotoxic activity than the reference compounds, while in the case of tamoxifen-resistant MCF7-TAMR-1 cell line, compound 62d showed only slightly less cytotoxic activity than cisplatin. Compound 62d was also more cytotoxic against the MDA-MB-231 cell line than both reference compounds.

Table 25. Anticancer activity of 63a–h.

Compound	IC50 (μM)
	A2780 (Ovarian Cancer)	A549 (Lung Cancer)
63a	15.2 ± 0.5	21.1 ± 0.3
63b	15.5 ± 0.5	31 ± 1
63c	31 ± 2	29.5 ± 0.5
63d	27.4 ± 0.6	33 ± 0.4
63e	27.5 ± 0.8	32 ± 0.4
63f	29 ± 3	-
63g	17 ± 1	32 ± 2
63h	27 ± 2	21.1 ± 0.3

shows the cytotoxic activity of 63a–h complexes against cell lines: A2780 and A549. Compound 63a was most active against both of these cell lines.

The anticancer sulfonamide osmium complexes also include compounds 64–65, which are not “piano stool” type complexes [49]. These complexes were tested for phototoxic activity against two cell lines in normoxia and hypoxia: A549 and MDA-MB-231 and compared with protoporphyrin IX (PPIX)—

Table 26. Phototoxic activity of compounds 64 and 65 against A549 and MDA-MB-231 cell lines (in normoxia and hypoxia) at four wavelengths of radiation.

Compound	IC50 (540 nm) [μM]	IC50 (620 nm) [μM]	IC50 (670 nm) [μM]	IC50 (740 nm) [μM]
A549 cell line (Normoxia 20%)
64	8$.1\pm 1.9$	>30	26.2 $\pm$ 5.4	22.5 $\pm$ 3.8
65	4.4$\pm$0.1	10.4 $\pm$ 0.7	9.9 $\pm$ 0.9	$7.0 \pm 0$.1
PPIX	0.3 $\pm$ 0.1	2.7 $\pm$ 0.1	3.0 $\pm$ 0.1	>100
A549 cell line (Hipoxia 2%)
64	14.6$\pm$3.1	>30	>100	>100
65	>30	>30	>100	>100
PPIX	0.7 $\pm$ 0.2	2.2 $\pm$ 0.9	3.5 $\pm$ 0.3	>100
MDA-MB-231 cell line (Normoxia 20%)
64	1.2 $\pm$ $0.1$	6.2 $\pm$ 2.8.	3.9 $\pm$ 0.5	3.6 $\pm$ 0.4
65	2.2 $\pm$ 0.1	2.6 $\pm$ 0.5	3.0 $\pm$ 1.2	0.7 $\pm$ 0.2
PPIX	0.8 $\pm$ 0.4	1.0 $\pm$ 0.5	0.7 $\pm$ 0.3	-
MDA-MB-231 cell line (Hipoxia, 2%)
64	>10	9.2 $\pm$ 3.0	12.0 $\pm$ 1.0	>30
65	>30	>30	4.6 $\pm$ 0.6	>30
PPIX	0.6 $\pm$ 0.1	1.8 $\pm$ 0.4	0.4 $\pm$ 0.1	-

.

These complexes (both 64 and 65) showed greatest anti-tumor activity with 540 nm radiation. In the case of the A549 cell line in the normoxic state (at 540 nm)—complex 65 was the most active, slightly less active than protoporphyrin IX. The same cell line, being in hypoxia, was the most sensitive to Complex 64 (at 540 nm). However, this complex was less active than PPIX. Promising activity results were obtained for complex 64 at 540 nm, acting on the normoxic MDA-MB-231 cell line. This complex was only slightly less active than PPIX. For the same cell line under hypoxia, complex 64 was most active with 620 nm radiation. Complex 65, active at 670 nm, was even more active against the MDA-MB-231 cell line under hypoxia.

2.8. Iridium Complexes

An example of sulfonamide iridium(III) complexes with anti-cancer activity is cyclopentadienyl complexes 66a–c, shown in Figure 12 [50]. These compounds have been studied towards 13 human cell lines (

Table 27. Anticancer activity of sulfonamide complexes with iridium 66a–c (N.D. = not determined).

Cell Lines	IC50 (μM)
	66a	66b	66c	Cisplatin
A2780 (ovarian cancer)	20.9 ± 0.7	14 ± 2	10.2 ± 0.6	1.2 ± 0.3
A2780cis (ovarian, cisplatin-resistant)	17 ± 2	18 ± 1	6.3 ± 0.8	13.4 ± 0.3
A549 (lung cancer)	38 ± 2	25.2 ± 0.3	17 ± 3	3.2 ± 0.1
HCT116 (colorectal cancer)	40.3 ± 0.7	58.2 ± 0.9	15.0 ± 0.1	5.2 ± 0.3
HCT116-p21-/- (colorectal cancer, p21 knockout)	62.4 ± 0.3	N.D.	N.D.	9.2 ± 0.5
HCT116-p53-/- (colorectal cancer, p53 knockout)	63 ± 2	N.D.	N.D.	36.7 ± 0.3
MCF10-A (breast, non-tumorigenic)	42 ± 3	N.D.	N.D.	6 ± 1
HOF (ovarian, non-tumorigenic)	19.0 ± 0.1	26.8 ± 0.6	15.0 ± 0.7	10.2 ± 0.7
MCF7 (breast cancer)	14.6 ± 0.2	8 ± 1	3.7 ± 0.7	6.6 ± 0.4
MCF7-TAMR1 (breast, tamoxifen-resistant)	17.8 ± 0.6	N.D.	N.D.	6.0 ± 0.7
MRC5 (lung, non-tumorigenic)	17.3 ± 0.4	11.9 ± 0.9	5.9 ± 0.2	12.8 ± 0.5
OE19 (esophageal cancer)	>50	33.2 ± 0.5	12.9 ± 0.3	9 ± 1
PC3 (prostate cancer)	35.1 ± 0.6	18.8 ± 0.2	12 ± 1	4.1 ± 0.5

). For most cancer cell lines, compound 66c showed the highest activity (against A2780cis and MCF-7 cell lines, it showed higher cytotoxic activity than cisplatin).

2.9. Palladium Complexes

Sulfonamide palladium complexes (Figure 13) with anticancer activity include palladium-saccharin complexes, for example complex 67, containing Pd-Pd bond [51] and the cationic complexes 68 and 69, in which saccharin is the anion [52].

K. Kazemi’s research team examined the cytotoxic activity of complex 67 against four cell lines: HeLa (cervical cancer), A549 (lung cancer), MCF-7 (breast cancer) and NIH (normal fibroblast cells). The reference compound in this study was cisplatin, sodium saccharin and free imine ligand (

Table 28. Anticancer activities of 67.

Compound	IC50 [µM]
	HeLa	A549	MCF-7	NIH
sodium saccharin	>200	>200	>200	-
Ligand	>200	93.8 ± 4	>200	-
67	30.4 ± 2	23.1 ± 1	22.2 ± 1	165 ± 1
Cisplatin	17.6 ± 1	24.3 ± 1	26.3 ± 1	38.67 ± 4

).

Compound 67 is more cytotoxic against A549 and MCF-7 cell lines than cisplatin, imine ligand and sodium saccharin. The cytotoxicity of compound 67 against the HeLa cell line was less than that of cisplatin, however, the palladium complex tested was much less cytotoxic against the non-cancerous NIH cell line.

E. Ulukaya’s research team tested cationic palladium-saccharin complexes (68–69) against four cell lines: A549 (lung cancer), H1299 (non-small cell lung carcinoma), PC-3 (prostatic adenocarcinoma) and CHO—chinese hamster ovary lung fibroblast (

Table 29. Cytotoxic activities of 68 and 69.

Compound	IC50 [µM]
	A549	H1299	PC-3	CHO
68	2.3	8.6	9.6	5.8
69	2.1	1.8	1.8	1.9
Cisplatin	23.1	3.2	8.6	3.2

).

Compound 69 was more cytotoxic against all three cancer cell lines: A549, H1299 and PC-3 than cisplatin, but was also more cytotoxic against the non-cancer CHO cell line. Compound 68, on the other hand, was more cytotoxic than the reference compound only to the A549 cell line, while it also showed less toxicity to non-cancerous CHO cells.

The second group of sulfonamide palladium complexes with anticancer activity are complexes of p-toluenesulfonyl-L-amino acid derivatives. These include complexes with ethylenediamine (70a–e) [53] and azaheteroaromatic ligands [54]: 2,2′-bipyridyl (71a–b), 1,10-phenanthroline (72a–b) and 2,2′-biquinoline (73). All of these complexes were tested for anticancer activity against four cell lines: HL-60, BGC-823, Bel-7402 and KB (

Table 30. Cytotoxic activities of palladium complexes 70–73.

Compound	IC50 [µM]
	HL-60 (Leukemia)	BGC-823 (Gastrocarcinoma)	Bel-7402 (Liver Carcinoma)	KB (Nasopharyngeal Carcinoma)
70a	26 $\pm$ 1	48 $\pm$ 2	45 $\pm$ 1	32 $\pm$ 2
70b	23 $\pm$ 1	38 $\pm$ 2	$35.8 \pm 0$.9	$37 \pm 2$
70c	15.9 $\pm$ $0.5$	$41 \pm 1$	33.9 $\pm$ 0.6	12 $\pm$ 1
70d	12.9 $\pm$ 0.9	35.8 $\pm$ 0.8	33 $\pm$ 2	15.6 $\pm$ 0.9
70e	12 $\pm$ 1	$34 \pm 2$	28 $\pm$ $1$	11.8 $\pm$ 0.5
71a	18.66 ± 1.07	23.74 ± 1.23	44.52 ± 1.43	9.28 ± 1.07
71b	16.76 ± 1.08	25.78 ± 1.11	40.76 ± 1.45	6.54 ± 0.97
72a	9.20 ± 0.97	21.70 ± 2.08	18.01 ± 1.32	6.08 ± 0.87
72b	12.46 ± 1.05	23.45 ± 1.32	38.98 ± 2.08	5.98 ± 0.65
73	16.54 ± 1.21	30.89 ± 1.34	30.76 ± 2.07	22.54 ± 1.23
Cisplatin	2.89 ± 0.34	6.48 ± 0.81	8.12 ± 0.97	2.65 ± 0.33

).

In the case of the HL-60 cell line, the most active palladium complex was complex 72a, less active than cisplatin. This compound is also the most active against the BGC-823 and Bel-7402 cell lines (however also less active than cisplatin). In contrast, in the KB cell line, the most active palladium complex is complex 72b, which is slightly less cytotoxic than the reference compound.

Sulfamethoxazole forms a complex 74 with palladium, whose anticancer activity is shown in

Table 31. Anticancer activity of palladium complex with sulfamethoxazole (74).

Compound	IC50(µM)
	K562	HT-29	MCF-7
74	7.20	10.42	8.64
Cisplatin	4.10	8.00	7.61

. The complex showed slightly lower cytotoxic activity than cisplatin against the MCF-7 cell line [31].

2.10. Platinum Complexes

Platinum forms many complexes with sulfonamides with anti-cancer activity (Figure 14). An example of sulfonamides forming such complexes is saccharin, which forms complexes 75–81.

The earliest studied saccharin-platinum complex was complex 75 [55]. This complex has a flat, square geometry with trans isomerism. 75 was tested for cytotoxic activity against four cell lines: A549, PC3, Hep3B, C6 and compared with carboplatin (

Table 32. Cytotoxic activities of 75 against four cancer cell lines.

Cell Lines		IC50 [µM]	IC90 [µM]
A549 (lung cancer)	75	117.5	192.4
	Carboplatin	70.5	>85.1
PC3 (prostate cancer)	75	72.2	95.6
	Carboplatin	85.1	>85.1
Hep3B (liver cancer)	75	35.0	82.1
	Carboplatin	6.8	28.7
C6 (glioma)	75	38.9	90.9
	Carboplatin	7.6	42.7

).

As shown in Table 32, complex 75 was found to be more active against the PC3 cell line than carboplatin. For the other cell lines, complex 75 was less cytotoxic than the reference compound.

In 2018, V. T. Yilmaz’s research team published the results of cytotoxic activity of another complexes of platinum with saccharin 76–78 [56]. The complexes were tested for anticancer activity against: MCF-7 (breast cancer), A549 (lung cancer), DU145 (prostate cancer), HCT116 (colon cancer) cell lines and compared with cytotoxicity against normal bronchial epithelial (BEAS-2B) cells. The reference compound in these researches was cisplatin (

Table 33. Antitumor activities of 76–78.

Compound	IC50 [µM]
	MCF-7	A549	DU145	HCT116	BEAS-2B
76	8.4 ± 0.1	10.1 ± 1.7	14.5 ± 0.5	13.0 ± 0.7	8.1 ± 0.3
77	3.8 ± 0.4	4.0 ± 0.1	4.6 ± 0.1	4.8 ± 0.1	2.4 ± 0.1
78	17.0 ± 3.7	30.1 ± 1.0	37.7 ± 0.1	36.7 ± 0.2	27.7 ± 1.2
Cisplatin	24.0 ± 4.0	2.5 ± 0.9	9.8 ± 4.5	15.5 ± 2.3	4.6 ± 0.2

).

Complex 77 was the most cytostatically active against all four cancer cell lines. However, it was also the most cytotoxic against non-cancerous BEAS-2B cells (more so than cisplatin). In the case of the MCF-7 cell line, all three complexes were more cytotoxic than cisplatin. In the case of the DU145 and HCT116 cell lines, compound 77 was more cytotoxic compared to cisplatin, while compound 77’s activity against the A549 cell line was slightly less than that of cisplatin.

In 2019, Ceyd Icsel’s research team published the results of a study of the anticancer activity of two platinum-saccharin complexes: 79 and 80 [57]. The cytotoxic activity of these compounds against three cancer cell lines: A549, MCF-7, HCT-116 and one non-cancerous BEAS-2B cell line is shown in the form of three parameters in

Table 34. GI₅₀, TGI and LC₅₀ values (after 48 h) for complexes 79 and 80.

Cell Lines		79	80	Cisplatin
A549	GI50 [µM]	16.42 ± 0.85	24.56 ± 4.34	14.38 ± 0.47
	TGI [µM]	29.13 ± 1.43	>40	22.63 ± 0.38
	LC50 [µM]	>40	>40	37.77 ± 0.65
MCF-7	GI50 [µM]	7.38 ± 0.64	5.38 ± 0.03	10.88 ± 0.18
	TGI [µM]	13.40 ± 0.66	22.06 ± 0.57	15.19 ± 0.10
	LC50 [µM]	18.93 ± 0.64	38.64 ± 0.68	19.50 ± 0.01
HCT-116	GI50 [µM]	12.19 ± 0.26	12.72 ± 1.55	9.03 ± 1.46
	TGI [µM]	17.12 ± 0.23	24.39 ± 2.53	21.24 ± 1.71
	LC50 [µM]	28.18 ± 0.49	>40	34.28 ± 1.10
BEAS-2B	GI50 [µM]	8.52 ± 0.63	21.46 ± 0.76	3.85 ± 0.03
	TGI [µM]	14.06 ± 0.81	31.06 ± 0.59	6.18 ± 0.17
	LC50 [µM]	26.95 ± 2.56	>40	10.83 ± 1.24

: GI₅₀ (dose of 50% growth inhibition), TGI (dose of total growth inhibition) and LC₅₀ (dose of 50% cell death).

Complex 79 showed slightly less cytotoxic activity against the A549 cell line than cisplatin. Good results were obtained in the MCF-7 cell line, where both complexes showed greater cytotoxic activity than cisplatin. Both complex 79 and complex 80 were less cytotoxic against the normal BEAS-2B cell line than cisplatin.

In 2023, the research team of D. I. Ugwu published the results of a cytotoxicity study of complex 81 [58]. The compound showed very good cytotoxic activity against A549 and HCT-116 cell lines, better than cisplatin. The anticancer activity against the MCF-7 cell line was slightly weaker than cisplatin, while the cytotoxicity against the non-cancerous BEAS-2B cell line was comparable to that of cisplatin (

Table 35. Cytotoxic activity of 81.

Compound	IC50 [µM]
	A549	MCF-7	HCT-116	BEAS-2B
81	7.32	16.89	6.88	6.82
Cisplatin	17.23	11.68	14.69	6.29

).

Sulfonamide ligands containing an azo group can forming a stable six-membered chelate ring as in the case of compound 82 (Figure 14) [59]. This complex showed cytotoxic activity against the A2780 (ovarian cancer) and A2780CP70 (cisplatin-resistant ovarian cancer) cell lines (

Table 36. The cytotoxic activity of 82 depending on the solubilizing solvent used.

Compound	Solubilizing Solvent	IC50 [µM]
		A2780	A2870CP70
82	DMSO	1.0 ± 0.3	2.7 ± 0.6
	DMF	0.43 ± 0.05	0.8 ± 0.1
Cisplatin	PBS (Phosphate-buffered saline)	0.18 ± 0.07	5 ± 1

). 82 was more cytotoxic against the A2780 cell line when DMF was used as a solubilizing solvent than when DMSO was used. The activity was slightly weaker than cisplatin, while the activity of this compound against the A2870CP70 cell line was significantly greater than cisplatin.

Other known compounds are the six-coordinate analogs (83 and 84) of the commonly used in oncology platinum drugs: cisplatin and oxaliplatin, containing additional axial sulfonamide ligands in trans position [60]. As shown in the

Table 37. Anti-cancer activity of compounds 83 and 84 against cell lines under normoxia and hypoxia.

Cell Lines	IC50 [μM]
	83	84	Cisplatin	Oxaliplatin
Normoxia (20% O2)
MDA-MB-231 (breast cancer)	18.0 ± 1.8	27.6 ± 2.3	14.6 ± 0.8	35.4 ± 2.0
HeLa (cervical cancer)	12.6 ± 1.2	41.7 ± 2.3	15.9 ± 1.3	28.1 ± 2.6
HepG2 (hepatocellular carcinoma)	28.6 ± 0.6	30.4 ± 0.8	17.9 ± 1.9	8.1 ± 0.8
LO2 (hepatocyte cell line)	158.5 ± 3.4	>200	12.0 ± 1.5	31.0 ± 5.3
HLF (lung fibroblast)	102.6 ± 8.6	>200	10.7 ± 2.9	23.7 ± 1.9
MCF-10A ((mammary epithelial cell line)	153.7 ± 3.6	>200	17.9 ± 1.9	8.9 ± 0.4
Hipoxia (1% O2)
MDA-MB-231	1.9 ± 0.9	5.8 ± 2.1	21.9 ± 5.9	65.7 ± 5.3
HeLa	3.6 ± 0.3	15.8 ± 2.6	28.2 ± 1.7	>50
HepG2	8.3 ± 1.8	5.6 ± 1.5	20.2 ± 3.8	18.1 ± 2.1

, the compounds showed strong anticancer properties, under both normoxia and hypoxia conditions, against cancer cell lines: MDA-MB-231, HeLa and HepG2, more potent than cisplatin and oxaliplatin, while having reduced cytotoxic properties against normal cells: MCF-10A, LO2 and HLF.

Replacement of the ammonia molecules in the basic structure of cisplatin with molecules of the sulfonamide bipyridine ligand yields complexes 85–87 [61]. Compound 85 and 86 showed less cytotoxic activity against the MCF-7 breast cancer cell line than cisplatin, while complex 87 was more active against these cells (

Table 38. Antitumor activity of 85–87 complexes against MCF-7 cells.

Compound	IC50 [μM] MCF-7 Cell Line
85	529.3 ± 0.22
86	135.7 ± 0.06
87	16.1 ± 0.08
Cisplatin	97.86

).

In addition to sulfonamide-based, planar square platinum complexes of cis geometry, compound 88 of trans geometry is also known [62]. Complex 88 had similar anticancer activity against melanoma cell line SK-MEL-5 to cisplatin. This compound, however, had higher activity than cisplatin against SK-MEL-28 cell line (

Table 39. Antitumor activity of 88 against melanoma cell lines: SK-MEL-5 and SK-MEL-28.

Compound	IC50 [μM]
	SK-MEL-5	SK-MEL-28
88	3.24  ±  1.08	5.83  ±  1.06
Cisplatin	2.89  ±  1.12	10.17  ±  1.29

).

Another sulfonamide-platinum complexes described in the 2022 publication are complexes 89–90, whose cytotoxic activity against the NCl-H292 cell line is summarized in

Table 40. Antitumor activity of 89–90 and their ligands against NCl–H292 lung cancer cells after 24, 48 and 72 h.

Compound	IC50 [μg/mL]
	24 h	48 h	72 h
89	37.83	15.94	9.01
Ligand of 89	225	31.82	36.49
90	112.8	26.21	12.13
Ligand of 90	612.4	17.88	13.95

[63]. These complexes showed higher anti-cancer activity than their free ligands. The most active after 24 h was compound 89.

Sulfamethoxazole forms a complex 91 with platinum, whose anti-cancer activity is shown in

Table 41. Anticancer activity of 91.

Compound	IC50(µM)
	K562	HT-29	MCF-7
91	9.67	12.12	11.37
Cisplatin	4.10	8.00	7.61

. This compound showed less anti-cancer activity than cisplatin against three cell lines: K562, HT-29 and MCF-7 [31].

2.11. Copper Complexes

There are many sulfonamide copper complexes with anticancer activity (Figure 15). Among the sulfonamide copper complexes with anticancer activity are complexes with saccharin, 92–94.

The 2017 publication described the anticancer activity of complex 92, containing two copper atoms, against human breast cancer cell lines: MCF-7 and MDA-MB-231 [64]. This compound was more active against both of these cell lines than tamoxifen, used as the reference compound (

Table 42. Antitumor activity of 92.

Compound	IC50 [μM]
	MCF-7	MDA-MB-231
92	3.60	3.81
Tamoxifen	4.04	13.46

).

In 2021, in turn, there was a publication describing the anticancer activity of complexes 93 and 94, each containing one copper atom [65]. Compound 93 had higher activity against MCF-7 cells than unbound saccharin and cisplatin, used as a reference compound (

Table 43. Anticancer activity of 93 and 94.

Compound	IC50 [μM]
	MCF-7	HEK-293
93	5.62 ± 2.28	93.44 ± 12.17
94	18.86 ± 1.01	94.43 ± 10.18
Saccharine	46.60 ± 7.92	>100
Cisplatin	10.37 ± 3.11	>100

). However, compound 93 was also slightly more cytotoxic against the non-cancerous HEK-293 cell line than saccharin and cisplatin.

Some anticancer compounds produce reactive oxygen species (ROS) and thus induce cell death. An example of such compounds are five-coordinated complexes of copper(II) with terpyridine (95a–e) [66]. These complexes had tested their anti-breast cancer stem cell (CSC) properties. For this purpose, 95a–e were tested for cytotoxic activity against the bulk breast cancer cells (HMLER) and breast CSC-enriched cells (HMLER-shEcad) cultured in monolayers (

Table 44. IC₅₀ values of the complexes 95a–e against HMLER cells, HMLER-shEcad cells, and HMLER-shEcad mammospheres.

Compound	IC50 [μM]
	HMLER	HMLER-shEcad	HMLER-shEcad Mammospheres
95a	0.85 ± 0.04	0.69 ± 0.12	3.44 ± 0.03
95b	0.85 ± 0.14	0.83 ± 0.01	2.98 ± 0.01
95c	0.83 ± 0.06	0.73 ± 0.04	2.63 ± 0.08
95d	0.83 ± 0.19	0.78 ± 0.03	2.99 ± 0.53
95e	0.81 ± 0.02	0.79 ± 0.18	3.34 ± 0.36
Cisplatin	2.57 ± 0.02	5.65 ± 0.30	13.50 ± 2.34
Salinomycin	11.43 ± 0.42	4.23 ± 0.35	18.50 ± 1.50

). In addition, researches were conducted for cytotoxic activity against serum-free cultures of breast CSCs, which can generate three-dimensional structures called mammospheres. All complexes were more active against HMLER cells, HMLER-shEcad cells, and HMLER-shEcad mammospheres than cisplatin and salinomycin (Table 44).

Another group of sulfonamide complexes showing anti-cancer activity are five-coordinated copper complexes with 1,3,4-thiadiazole sulfonamides (96 and 97) [67]. As shown in the

Table 45. IC₅₀ values of 96, 97 and cisplatin on the HeLa, WM35, and HFL1 cell lines after 24, 48 and 72 h.

Cell Line	Compound	IC50 [μM]
		24 h	48 h	72 h
HeLa (cervical carcinoma)	96	33.18 ± 0.19	16.36 ± 0.12	6.47 ± 0.06
	97	8.79 ± 0.21	4.06 ± 0.05	1.45 ± 0.09
	Cisplatin	21.03 ± 0.14	21.03 ± 0.14	2.39 ± 0.04
MW35 (radical growth phase melanoma)	96	41.35 ± 0.19	23.87 ± 0.17	15.42 ± 0.08
	97	13.01 ± 0.15	8.11 ± 0.13	4.66 ± 0.07
	Cisplatin	26.07 ± 0.43	11.15 ± 0.09	5.98 ± 0.03
HFL1 (normal fibroblastic epithelial cell line)	96	44.67 ± 0.51	7.38 ± 0.12	3.75 ± 0.15
	97	17.99 ± 1.08	5.55 ± 0.22	2.03 ± 0.04
	Cisplatin	13.22 ± 0.89	3.99 ± 0.22	1.18 ± 0.13

, considering activity after 24 h—compound 97 had higher cytotoxic activity against HeLa and MW35 cell lines than cisplatin, while being less cytotoxic against the HFL1, than the reference compound.

The copper atom can also take the coordination number 6 in many complexes with azaheteroaromatic ligands, for example with pyrimidine sulfonamides (98–100) [68]. Compounds 98–100 were tested for cytotoxic activity against nine cancer cell lines and one non-cancer HaCat cell line and were compared with doxorubicin (

Table 46. Total Growth Inhibition (TGI) [μM] values of the copper(II) complexes 98–100.

Cell Line	TGI [μM]
	98	99	100	Doxorubicin
U251 (glioma)	1.4	<0.3	35.3	0.1
UACC-62 (melanoma)	5.1	7.8	51.2	1.4
MCF-7 (breast cancer)	15.4	46.4	217.0	46.0
NCI-ADR/RES (multidrug resistant ovarian cancer)	291.9	111.0	298.2	46.0
786–0 (renal cancer)	291.9	47.9	298.2	0.4
NCI-H460 (lung, non-small cancer cells)	7.9	7.1	64.8	46.0
OVCAR-3 (ovarian cancer)	3.3	4.7	75.9	26.5
HT29 (colon cancer)	6.3	4.9	129.3	46.0
K562 (leukemia)	35.4	32.5	298.2	11.6
HaCat (immortal keratinocyte, non-tumor human line)	14.0	46.1	298.2	46.0

).

Complex 98 was more cytotoxic against the tumor cell lines MCF-7, NCI-H460, OVCAR-3 and HT29 than doxorubicin, but was also more cytotoxic against the normal cell line HaCat. Compound 99, in turn, showed greater activity than doxorubicin against cancerous cell lines: NCI-H460, OVCAR-3 and HT29. Its activity against HaCat cells was comparable to the reference compound.

Schiff bases derived from N-tosylbenzene-1,2-diamine form four- and five-coordinate complexes with copper(II) (101–105), showing anticancer activity (Figure 15) [69].

Table 47. Cytotoxicity of copper(II) complexes 101–105 towards the SH-SY5Y, U87-MG, U373-MG and MRC-5 cell lines.

Compound	IC50 [μM]
	SH-SY5Y (Neuroblastoma)	U87-MG (Glioblastoma)	U373-MG (Glioblastoma)	MRC-5 (Mortal Human MRC5 Fibroblasts)
101	2.63 ± 0.40	20.09 ± 0.05	14.42 ± 0.96	16.85 ± 0.57
102	2.85 ± 0.43	11.83 ± 1.07	12.92 ± 1.05	19.94 ± 1.72
103	9.06 ± 1.36	26.73 ± 5.26	17.61 ± 2.27	25.39 ± 1.32
104	23.55 ± 3.53	22.25 ± 0.89	19.78 ± 2.03	24.91 ± 1.26
105	5.57 ± 0.84	25.92 ± 1.25	22.52 ± 1.35	24.92 ± 2.28
Cisplatin	27.50 ± 4.30	>100	~150	–

shows the cytotoxic activity of compounds 101–105 against the SH-SY5Y, U87-MG, U373-MG cell lines and the non-cancerous MRC-5 cell line. All these compounds showed significantly greater cytotoxic activity against the SH-SY5Y neuroblastoma cell line (compound 101 was the most active) than cisplatin, used as a reference compound. Also against the U87-MG and U373-MG glioblastoma cell lines, all tested copper(II) complexes were more cytotoxic than cisplatin (compound 102 was the most active against these two cell lines).

Another sulfonamide copper complexes with potent anti-cancer properties are four-coordinated, tetrahedral biphosphine complexes of Cu(I) 106a–b [70]. Both copper complexes showed greater cytotoxic activity after 12 h against the B16-F10 melanoma cell line than cisplatin, doxorubicin and their unbound ligands. The most active after 12 h was compound 106a (

Table 48. IC₅₀ values of 106a–b complexes, ligands, cisplatin and doxorubicin against B16-F10 melanoma cell line.

Compound	IC50 [µM] B16-F10 Cell Line
	12 h	24 h	36 h	48 h
106a	14.4 ± 2.4	13.0 ± 3.7	16.5 ± 2.4	11.6 ± 1.9
Ligand of 106a	256.1 ± 21.3	152.9 ± 13.2	62.9 ± 5.2	41.7 ± 2.0
106b	32.6 ± 3.1	22.8 ± 2.0	19.5 ± 1.9	18.4 ± 1.7
Ligand of 106b	265.0 ± 22.1	112.5 ± 9.0	58.2 ± 4.1	55.9 ± 3.4
Cisplatin	132.9 ± 10.5	58.2 ± 2.3	38.4 ± 3.2	36.7 ± 2.1
Doxorubicin	288.0 ± 10.0	10.1 ± 2.1	3.1 ± 1.3	2.2 ± 1.1

).

Sulfaclozine (SCZ) forms a complex 107 with copper, which shows stronger cytotoxic properties against MCF-7 and CaCo-2 cell lines than sulfaclozine as a free ligand (

Table 49. Anticancer activity of 107.

Compound	IC50 (µg/mL)
	MCF-7	CaCo-2
107	86.2 ± 0.64	23.84 ± 0.33
Sulfaclozine (SCZ)	215.24 ± 0.67	97.6 ± 0.45

) [30].

An example of copper complexes with primary sulfonamides is complex 108, whose activity on carbonate anhydrase inhibition of hCA IX and hCA XII is shown in

Table 50. Enzyme inhibition for 108 and reference compounds (FTES = (4-sulfamoylphenylethyl-thioureido)-fluorescein, ABS = 4-(2-aminoethyl)-benzenesulfonamide).

Compound	Ki (nM)
	CA IX	CA XII
Ligand	62	73
108	9.0	6.1
ABS	33	3.2
Acetazolamide (AZA)	25	5.7
FTES	24	-

[71]. This table shows that compound 108 is more active against hCA IX than all three reference compounds and the free ligand, while activity against hCA XII is similar to acetazolamide.

Compound 109 is an example of a complex of an azo derivative of sulfafurazole with copper [34]. 109 is more cytostatic active against the A-549 cell line than unbounded ligand and vinblastine sulfate (

Table 51. Anticancer activity of 109.

Compound	IC50 (µg/mL)
	A-549 (Lung Cancer)	PANC-1 (Pancreatic Cancer)
109	12.26 ± 0.73	13.43 ± 0.81
Ligand	466.25 ± 17.52	360.61 ± 14.63
Vinblastine sulfate	24.6 ± 0.65	4.68 ± 0.65

).

It is also known an analog of complex 4, containing a copper atom instead of chromium (Figure 3). This complex showed cell viability after treatment of 80.67% for the MCF-7 cell line and 25.88% for the HCEC cell line [20].

Azo derivatives of sulfathiazole form complex 110 with Cu(II) [35]. As shown in

Table 52. Anticancer activity of 110.

Compound	IC50 (µM)
	HepG-2 (Hepatocellular Carcinoma)	MCF-7 (Breast Cancer)
Ligand	>1236.30	>1236.30
110	357.90	179.88
Cisplatin	40.76	-
5-fluorouracil	-	215.26

, this compound is more cytotoxic against HepG-2 and MCF-7 cells than the unbound sulfathiazole ligand, and is more active against the MCF-7 cell line than 5-fluorouracil.

Sulfonamide derivatives of 1,3-diaryltriazene form 111a–e complexes with copper [72]. These compounds were tested for their cytostatic activity against cancer cell lines: colorectal adenocarcinoma (DLD-1), cervix carcinoma (HeLa), breast adenocarcinoma (MDA-MB-231), colon adenocarcinoma (HT-29), endometrial adenocarcinoma (ECC-1), prostate cancer (DU-145 and PC-3), and compared with the normal cells: embryonic kidney (HEK-293), prostate epithelium (PNT-1A) and retinal pigment epithelium (ARPE-19) cells. The reference compound was 5-fluorouracil. The results of these studies are presented in the

Table 53. Anticancer activity of 111a–e (5-FU = 5-fluorouracil).

Cell Line IC50 [µM]	Compound
	111a	111b	111c	111d	111e	5-FU
Cancer cells
DLD-1	47.1  ±  4.7	42.7  ±  3.3	65.2  ±  2.5	58.4  ±  5.8	58.8  ±  3.9	50.2  ±  21.0
HeLa	5.0  ±  0.4	2.1  ±  0.1	63.9  ±  4.3	115.8  ±  9.2	15.2  ±  1.0	19.2  ±  1.2
MDA-MB-231	116.8  ±  14.2	50.0  ±  2.4	48.3  ±  2.5	205.5  ±  25.1	26.0  ±  2.5	22.4  ±  2.5
HT-29	198.9  ±  24.3	94.9  ±  9.4	205.1  ±  20.3	198.7  ±  22.5	84.4  ±  8.4	24.2  ±  2.4
ECC-1	26.2  ±  2.6	39.5  ±  2.5	362.1  ±  38.1	307.5  ±  34.2	97.6  ±  9.7	30.6  ±  3.5
DU-145	104.9  ±  13.5	116.4  ±  14.6	58.3  ±  6.4	160.5   ±  18.0	32.4  ±  3.2	37.3  ±  5.8
PC-3	102.0  ±  10.2	65.3  ±  8.5	196.4  ±  22.6	296.8  ±  32.4	79.2  ±  8.5	45.5  ±  4.5
Normal cells
HEK-239	68.8  ±  8.7	159.2  ±  19.4	134.7  ±  15.6	196.8  ±  23.5	36.3  ±  3.6	65.3  ±  8.6
PNT-1A	76.5  ±  8.5	95.1  ±  11.1	119.5  ±  13.5	125.1  ±  14.8	46.4  ±  4.6	142.3  ±  18.6
ARPE-19	119.0  ±  13.5	131.7  ±  15.6	>300	105.2  ±  13.5	84.3  ±  8.4	75.3  ±  7.5

. In many cases, these compounds exhibited greater cytotoxic activity against cancer cell lines than 5-fluorouracil, while at the same time exhibiting less cytostatic activity against normal cell lines. For example, compound 111b exhibited very strong cytostatic activity against the HeLa cell line (greater than 5-fluorouracil) and was much less active against normal cell lines.

2.12. Silver Complexes

Sulfonamide silver complexes with anticancer properties include complexes with saccharin 112–115 [73] and 116–118 (Figure 16) [74]. Compounds 112–115 are examples of complexes with monophosphane ligands, while compounds 116–118 are complexes with biphosphane ligands.

All six complexes (except for 118) showed higher cytotoxic activity against A549 and MCF-7 cells than cisplatin and AgNO₃. However, they were also more cytotoxic against normal WI-38 cells. Compound 113 was the most cytotoxic against these two tumor cell lines (

Table 54. Antitumor activity of silver(I) complexes with saccharin 112–118.

Compound	IC50 [µM]
	A549 (Lung Carcinoma)	MCF-7 (Breast Adenocarcinoma)	WI-38 (Fibroblast)
112	1.18 ± 0.44	1.14 ± 0.19	1.41 ± 0.37
113	0.84 ± 0.25	0.82 ± 0.14	0.77 ± 0.25
114	1.01 ± 0.12	0.88 ± 0.16	0.74 ± 0.28
115	1.79 ± 0.33	3.13 ± 1.55	1.31 ± 0.39
116	2.58 ± 0.83	2.32 ± 1.00	9.54 ± 2.40
117	9.11 ± 2.32	3.18 ± 1.01	2.61 ± 1.16
118	86.4 ± 4.75	5.30 ± 1.61	10.78 ± 2.22
AgNO3	21.51 ± 3.63	2.62 ± 1.44	8.14 ± 1.88
Cisplatin	10.92 ± 1.81	4.58 ± 1.25	2.62 ± 1.04

).

Sulfonamide derivatives of 1,3-diaryltriazene form 119a–e complexes with silver [72]. Cytotoxic activity against seven cancerous and three normal cell lines is presented in

Table 55. Antitumor activity of silver(I) complexes 119a–e.

Cell Line IC50 [µM]	Compound
	119a	119b	119c	119d	119e	5-FU
Cancer cells
DLD-1	279.3  ±  12.9	31.6  ±  3.2	3.3  ±  0.3	173.3  ±  10.3	110.7  ±  9.0	50.2  ±  21.0
HeLa	>300	2.8  ±  0.1	3.4  ±  0.2	139.3  ±  28	9.6  ±  0.6	19.2  ±  1.2
MDA-MB-231	96.8  ±  9.6	30.3  ±  3.0	9.8  ±  0.9	>300	148.4  ±  19.5	22.4  ±  2.5
HT-29	185.7  ±  16.5	24.9  ±  2.5	10.1  ±  3.1	240.7  ±  28.5	161.6  ±  16.1	24.2  ±  2.4
ECC-1	207.0  ±  25.6	29.1  ±  3.0	16.2  ±  1.6	103.6  ±  10.3	135.9  ±  13.5	30.6  ±  3.5
DU-145	136.7 ±  16.5	18.6  ±  1.8	4.8  ±  0.4	236.7  ±  28.5	100.3 ±  10.1	37.3  ±  5.8
PC-3	612.0  ±  61.2	28.2  ±  3.5	5.1  ±  0.5	136.6  ±  15.8	111.7  ±  13.4	45.5  ±  4.5
Normal cells
HEK-239	>300	17.8  ±  1.7	9.9  ±  0.9	5.5  ±  0.6	30.5  ±  4.5	65.3  ±  8.6
PNT-1A	209.7  ±  20.9	17.5  ±  17.5	9.2  ±  0.9	139.1  ±  16.5	110.8  ±  11.0	142.3  ±  18.6
ARPE-19	>300	22.0  ±  10.2	9.5  ±  0.9	284.8  ±  30.5	109.4  ±  11.0	75.3  ±  7.5

. Noteworthy is compound 119b, which showed the highest cytotoxic activity against the HeLa cancer cell line among all silver complexes and higher than 5-fluorouracil (5-FU). This compound was less active against normal cell lines compared to cancer cell lines.

2.13. Gold Complexes

Sulfonamide-gold complexes with anticancer activity are shown in the Figure 17. Among the sulfonamide gold complexes, gold complexes with saccharin are known, having a coordination number of 2 or 4 (120–125) [75]. Compounds 120–121 and 123–124 are in the form of salts in which the complex ion is an anion, while compound 122 is a non-ionic complex.

As shown in

Table 56. Antitumor activity of 120–124.

Compound	IC50 [µM]
	A2780/S	A2780/R
120	48.2 ± 0.1	54.0 ± 2.4
121a	52.7 ± 2.4	44.2 ± 3.2
121b	52.4 ± 2.2	40.3 ± 3.7
122	8.5 ± 2.4	15.8 ± 0.2
123	23.6 ± 1.5	40.8 ± 1.8
124	14.9 ± 1.4	14.3 ± 0.9
Cisplatin	2.1 ± 0.3	16.1 ± 0.5

, complexes 120–124 showed less cytotoxic activity than cisplatin against cisplatin-sensitive ovarian cancer A2780/S cells; however, complexes 122 and 124 showed slightly greater activity than cisplatin against the cisplatin-resistant A2780/R cell line.

Sulfamethoxazole, an antimicrobial drug, complexes gold, forming complex 126 [76]. However, this compound showed less anti-tumor activity than doxorubicin (used as a reference compound) against the HepG-2 and HCT-116 cell lines (

Table 57. Anticancer activity of 126 against HepG-2 and HCT-116 cell lines.

Compound	IC50 [μg]
	HepG-2 (Hepatocellular Carcinoma)	HCT-116 (Colon Cancer)
126	2.77	3.41
Doxorubicin	0.467	0.471

).

Saccharin 125a and 125b complexes with gold(III) were tested for cytostatic activity against the P388 cell line [77]. Compound 125a showed an IC₅₀ > 34.3 µM, while compound 125b showed an IC₅₀ > 36.0 µM.

The 8-substituted quinoline sulfonamides form 4-coordination complexes with gold(III) (127a–b) [78]. The anticancer activity of these complexes has been tested against cell lines: HBL-100, T-47D (breast cancer), HeLa (cervical cancer), SW1573 (non-small cell lung cancer), A549 (lung cancer) and WiDr (colon carcinoma). The study showed that compound 127b exhibited greater cytotoxic activity than cisplatin against the T-47D cell line and WiDr cell lines (

Table 58. Antitumor activity of 127a–b and cisplatin, used as a reference compound.

Compound	GI50 [µM]
	HBL-100	T-47D	HeLa	SW1573	A549	WiDr
127a	6.6 ± 1.8	24.0 ± 5.7	3.8 ± 0.8	17.0 ± 2.0	32 ± 2.1	26.0 ± 1.1
127b	3.8 ± 0.3	6.5 ± 0.7	3.1 ± 0.5	5.2 ± 0.15	4.7 ± 1.1	9.8 ± 1.2
Cisplatin	1.9 ± 0.16	15 ± 2.3	2.0 ± 0.32	3.0 ± 0.37	1.9 ± 0.64	26 ± 5.3

).

Complexes 128–134 are an example of complexes containing chelating bis(amidate) ligands [79]. Their anticancer activity against the P388 cell line (murine leukemia cells) is shown in

Table 59. Antitumor activity of 128–134 against P388 cell line.

Compound	IC50 [µM]
	P388 Cell Line
128a	0.30
128b	>80.13
129	52.89
130	6.68
131	0.22
132a	0.33
132b	1.58
133	4.35
134	1.09
Cisplatin	8.15

, which shows that complex 131 was the most active (and also more active than cisplatin).

2.14. Group 10 Metal Complexes (Zinc, Cadmium and Mercury)

The structures of sulfonamide complexes with group 10 metals (zinc, cadmium and mercury), are shown in Figure 18. Zn, Cd and Hg form complexes with saccharin (135 and 136a–b), showing cytotoxic activity. In the case of zinc complex 135, saccharin forms an anion, while in the case of complexes 136a–b saccharin is a ligand [80].

135 and 136a–b showed cytotoxic activity against cell lines A549 (lung cancer), MCF-7 (breast cancer) and HT29 (colon cancer), as shown in

Table 60. Antitumor activity of saccharin complexes with zinc, cadmium and mercury (135 and 136a–b) after 48h.

Compound	IC50 [µM]
	A549	MCF-7	HT29	MCF10A
135	1.74 ± 0.06	3.15 ± 0.10	15.40 ± 0.73	7.94 ± 0.18
136a	36.91 ± 0.47	23.01 ± 1.28	36.96 ± 0.75	26.29 ± 1.25
136b	80.06 ± 1.35	8.61 ± 0.98	24.27 ± 1.36	42.76 ± 1.43
Cisplatin	5.21 ± 0.18	10.57 ± 0.39	11.25 ± 1.35	13.80 ± 2.36

. The toxicity of these complexes was compared towards normal human breast epithelial MCF10A cells.

Complex 135 (zinc complex) showed much greater cytotoxic activity than cisplatin against tumor cells: A549 and MCF-7, however it also showed higher cytotoxic activity against normal cells MCF10A than cisplatin. In the case of the HT29 cell line, compound 135 was also the most active of the complexes tested; however, it was less cytotoxic against these cells than cisplatin.

Zinc forms also 137a–d complexes with sulfonamides, containing a carboxyl group [81]. The cytotoxic activity of the 137a–d complexes is summarized in

Table 61. IC₅₀ values of complexes 137a–d.

Compound	IC50 [µM]
	H-157 (Lung Cancer)	BHK-21 (Hamster Kidney Fibroblasts)
137a	1.82 ± 0.11	2.19 ± 0.15
137b	2.48 ± 0.13	3.01 ± 1.43
137c	3.17 ± 0.28	2.93 ± 0.17
137d	1.97 ± 0.17	2.74 ± 0.12
Vincristine	1.08 ± 0.09	1.08 ± 0.09

. The most active zinc complex against the H-157 cell line was compound 137a (however, less cytotoxic than vincristine). This compound was also less cytotoxic to non-cancerous BHK-21 cells than vincristine.

Another example of a sulfonamide zinc complex is complex 138, which is a complex of sulfaclozine (SCZ) with zinc [30]. This complex was more cytotoxic to the MCF-7 cell line than sulfaclozine, but was less cytotoxic to the CaCo-2 cell line (

Table 62. Anticancer activity of 79 against MCF-7 and CaCo-2 cell lines.

Compound	IC50 (µg/mL)
	MCF-7	CaCo-2
Sulfaclozine	215.24 ± 0.67	97.6 ± 0.45
138	111.91 ± 0.36	198.44 ± 0.25

).

Compound 139, which is a cadmium-containing analogue of complex 4 (Figure 3), showed no cytotoxic activity against the MCF-7 cell line (cell viability after treatment was 100%) [20].

Compound 140 is an analog of compound 108, containing a zinc atom in place of a copper atom [71]. The compound shows inhibition of carbonic anhydrase hCA IX at K_i = 28 nM and hCA XII at K_i = 6.8 nM. Comparing the data in Table 50, it appears that compound 140 is less active against hCA IX and hCA XII than compound 108.

Zinc forms a complex 141 with the azo derivative of sulfafurazole [34]. This compound shows cytostatic activity IC₅₀ = 137.81 ± 10.23 µg/mL against the A-549 cell line and IC₅₀ = 98.94 ± 5.78 µg/mL against the PANC-1 cell line. Thus, it is more active than the unbound sulfafurazole ligand, but less active than vinblastine sulfate and an analog containing a copper atom (compare Table 16 and Table 38).

The azo derivative of sulfathiazole forms a complex 142 with zinc [35]. The compound shows cytotoxic activity against the HepG-2 cell line at IC₅₀ > 658.45 µM and against the MCF-7 cell line at IC₅₀ = 30.28 µM. The complex is therefore more cytotoxic against both of these cell lines than the unbound ligand (IC₅₀ > 1236.30 µM against both cell lines) and more cytotoxic against the MCF-7 cell line than 5-fluorouracil, with IC₅₀ = 215.26 µM.

Sulfanilamide Schiff base derivatives form a complex with cadmium 143 and 144 [82]. The results of cytotoxicity tests on the HeLa cell line showed that complex 143 is more active than the free sulfanilamide ligand (complete inhibition of cell growth using this complex was observed at a concentration of 48.1 μg/mL, while using the ligand, this concentration was 57.1 μg/mL). Comparing the analogue of complex 143, containing bromine atoms instead of chlorine (144), with its ligand, a similar correlation can be observed—complex 144 (showing complete inhibition of HeLa cell growth at a concentration of 22.5 μg/mL) is more cytostatically active than its free ligand (showing complete inhibition of HeLa cell growth at a concentration of 39.8 μg/mL).

2.15. Complexes of Metals Outside the d Block of the Periodic Table

Sulfonamides are also known to complex with metals outside the d block of the periodic table. Their structures are shown in Figure 19.

2.15.1. Metal Complexes of the s-Block

Examples of s-block sulfonamide metal complexes are magnesium and calcium complexes, 145 and 146, respectively [83]. The calcium complex (146) showed slightly greater anti-cancer activity against colon cancer cells than doxorubicin, used as a reference compound (

Table 63. Anticancer activity of 145–146.

Compound	IC50 [μg]
	Liver Cancer Cells	Colon Cancer Cells
145	0.54	1.54
146	0.94	0.67
Doxorubicin	0.4	0.69

).

It is also known strontium complex 147, which is an analogue of chromium complex 4 [20], but it wasn’t active against MCF-7 cell line (Cell viability after treatment was 100%).

2.15.2. Metal Complexes of the p-Block

The antimicrobial drug, sulfapyridine, forms a six-coordinated complex 148 with bismuth(III) [84]. Complex 148 with IC₅₀ = 44 μM showed greater cytotoxic activity against the K562 leukemia cell line than the free sulfapyridine ligand used as a reference compound, with IC₅₀ > 100 μM.

The cytotoxic activity (as a cell viability after treatment) of the tin (149) and lead (150) complex is shown in

Table 64. Anticancer activity of 149–150.

Compound	Cell Viability After Treatment (%)
	MCF-7 (Breast Cancer)	HCEC (Human Corneal Epithelial Cells)
149	70.89	26.79
150	100	25.72
Ligand	100	22.97

[20]. Tin complex (149) was more cytotoxic than the lead complex, 150 (which wasn’t active) and then uncomplexed sufonamide.

2.15.3. Uranium Complex

Sulfaclozine forms complex 151 with uranium, occurring as a uranyl ion [85]. The cytotoxic activity of 151 against Caco-2 cell line is shown in

Table 65. Antitumor activity of 151, carbimazole, 6-mercaptopurine and sulfaclozine.

Compound	IC50 [µg/mL]
	Caco-2 (Colorectal Adenocarcinoma)
151	42.15
Carbimazole	103.477
6-mercaptopurine	98.79
Sulfaclozine	97.6

. The activity of this complex was compared with three reference compounds: carbimazole, 6-mercaptopurine and the free ligand sulfaclozine. Compound 151 is more cytotoxic against this cell line compared to the three given reference compounds.

3. Conclusions

Sulfonamides form many complexes with anti-cancer properties with metals: Ti, Mn, Re, Fe, Ru, Os, Ir, Pd, Pt, Cu, Ag, Au, Zn, Cd, Hg, U and Bi. The sulfonamide group can complex the metal atom via a nitrogen atom or an oxygen atom, or it may not participate in complexation (in this case, the metal atom is complexed by other structural elements of the molecule, containing donor atoms). The most popular type of sulfonamide complexes with metals such as rhenium, ruthenium, iridium, and osmium are “piano stool” complexes. The examples of these compounds presented here show that sulfonamide-metal complexes exhibit high anticancer activity, often greater than the reference compounds commonly used in medicine to treat cancer. Modification of the structure of sulfonamide ligands alters the cytotoxic activity of the complexes. One of the most popular sulfonamide ligands in anti-cancer complexes is saccharin. Some of the described complexes, such as for example 66c, 82, 122, 124 show cytotoxic activity against cell lines resistant to some commonly used anticancer drugs (cisplatin). Many sulfonamide metal complexes, especially rhenium complexes, are involved in the inhibition of cancer-related carbonic anhydrase hCA IX and hCA XII. Most often, these are complexes of primary benzenesulfonamides. The described heterometallic complexes showed higher activity than complexes containing one metal atom—comparing complexes 15 and 16, which contain only iron, with complexes 17 and 18 (which contain—in addition to iron—another metal), it can be concluded that the addition of another metal to the complex molecule results in increased cytotoxicity against the MDA-MB-231 cell line, but also increased cytotoxicity against the normal BJ cell line. The results of these studies may be helpful in developing new sulfonamide complexes with metals to enhance anti-cancer activity against specific cell lines. Complexes 64 and 65 as an effective drug for photodynamic therapy in oncology. Their ability to make phototoxicity in the visible and near-infrared regions of electromagnetic radiation, as well as under hypoxic conditions, carry a promise for targeted anticancer therapy. Additional axial sulfonamide ligands in cisplatin and carboplatin (compounds 83 and 84) positively affect the activity of known platinum drugs (increasing cytotoxicity against cancerous cells, while decreasing cytotoxicity against healthy cells). Comparing the anti-cancer activity of complexes of the same ligand but with different metals, it can be deduced that swapping its metal atom for another has a major effect on activity. For example, comparing complexes of azo derivatives of sulfathiazole with various metals (copper, cobalt, nickel and zinc), 40, 41, 110, 142 it can be deduced that the most cytostatic active against MCF-7 and HepG-2 cell lines is the cobalt(II) complex (40). However, when comparing the cytotoxic activity of carboxylate sulfonamide complexes (analogues of chromium complex 4) with various metals based on cell viability parameters, it can be concluded that the manganese complex (an analogue of complex 4 containing manganese instead of chromium) is the most active of these compounds. Optically active sulfonamide complexes differ in their anticancer activity depending on the enantiomer, as can be seen in the example of chiral ruthenium complexes 53–54.