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Molecules 2015, 20(7), 12029-12044; doi:10.3390/molecules200712029

Article
Synthesis of Novel 1-(4-Substituted pyridine-3-sulfonyl)-3-phenylureas with Potential Anticancer Activity
Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Jean Jacques Vanden Eynde
Received: 2 April 2015 / Accepted: 24 June 2015 / Published: 1 July 2015

Abstract

:
A series of novel 4-substituted-N-(phenylcarbamoyl)-3-pyridinesulfonamides 1127 have been synthesized by the reaction of 4-substituted pyridine-3-sulfonamides 210 with the appropriate aryl isocyanates in presence of potassium carbonate. The in vitro anticancer activity of compounds 11, 12, 1421 and 2426 was evaluated at the U.S. National Cancer Institute and in light of the results, some structure-activity relationships were discussed. The most prominent compound, N-[(4-chlorophenyl)carbamoyl]-4-[4-(3,4-dichlorophenyl)piperazin-1-yl]pyridine-3-sulfonamide (21) has exhibited a good activity profile and selectivity toward the subpanels of leukemia, colon cancer and melanoma, with average GI50 values ranging from 13.6 to 14.9 µM.
Keywords:
sulfonamides; pyridine-3-sulfonamides; sulfonylureas; diarylsulfonylureas; anticancer; antitumor activity

1. Introduction

Sulfonylureas have been used in pharmacotherapy since the 1950s when the first antidiabetic compound carbutamide was released to the market. Since then, several sulfonylureas have been commonly used as antihypoglycemic (e.g., tolbutamide, glipizide, glimepiride), diuretics (torasemide) or herbicides (rimsulfuron). Large numbers of sulfonylurea derivatives have also been tested in preclinical studies among others towards histamine H3 receptor antagonism [1,2], thromboxane A2 receptor antagonism [3,4], antibacterial [5], antimalarial [6] or antifungal activity [7], and in particular, an important part of this research concerns antitumor activity [8,9,10,11,12].
Studies on the antineoplastic activity led to discovery of N1,N3-diarylsulfonylureas (DSUs): LY-181984, LY-186641 (sulofenur) and LY-295501 (Figure 1) which were recognized as a group of compounds with activity against a broad spectrum of syngeneic rodent solid tumors and human tumor xenografts [13].
Figure 1. Anticancer diarylsulfonylureas (DSUs).
Figure 1. Anticancer diarylsulfonylureas (DSUs).
Molecules 20 12029 g001
Due to the high in vivo activity in mouse models, sulofenur and LY-295501 have been evaluated in phase I or II clinical trials on patients with a non-small cell lung carcinoma (NSCLC), renal carcinoma. melanoma, and ovarian cancer [14]. Despite the disappointing results of the tests, mainly due to high hemotoxicity, novel sulfonylurea derivatives with anticancer activity are constantly being developed [15].
Recently, we have reported on the synthesis of a series of 4-substituted pyridine-3-sulfonamides bearing primary sulfonamide moieties [16,17] as an efficient and selective carbonic anhydrase inhibitors (types IIII, Figure 2), whereas 4-piperazin-1-yl-pyridine-3-sulfonamides of type III (Figure 2) exhibited also moderate anticancer activity [17]. It is also well known that selective hCA inhibitors have a proven ability to limit the growth and restrict metastasis in xenograft models of breast cancer [18,19], and therefore they are considered as novel type of anticancer drugs with novel mechanism of action [20,21,22,23,24].
Figure 2. General structure of 4-substituted pyridine-3-sulfonamide derivatives.
Figure 2. General structure of 4-substituted pyridine-3-sulfonamide derivatives.
Molecules 20 12029 g002
These findings prompted us to explore further series of DSUs possessing 1-(4-substituted pyridine-3-sulfonyl)-3-phenylureas core of type IV (Figure 2), and to investigate their anticancer properties.

2. Results and Discussion

2.1. Chemistry

The starting 4-substituted pyridine-3-sulfonamides 2, 410 were prepared according to the known methods [16,17], while the novel compound 4-[(5-methyl-1,3,4-thiadiazol-2-yl)thio]-3-pyridine-sulfonamide (3) was synthesized by the reaction of aromatic nucleophilic substitution of chlorine atom of 1 with 5-methyl-1,3,4-thiadiazole-2-thiol, under forcing conditions of elevated pressure and temperature (Scheme 1).
Scheme 1. Facile synthesis of the starting 4-substituted 3-pyridinesulfonamide derivatives 210.
Scheme 1. Facile synthesis of the starting 4-substituted 3-pyridinesulfonamide derivatives 210.
Molecules 20 12029 g003
Reagents and conditions: (a) thiourea (1.02 eq.), MeCN, reflux, 3 h, [16]; (b) NaOH (2.14 eq.) water/THF 5 °C, 0.5 h, r.t. 5 h [16]; (c) 5-methyl-1,3,4-thiadiazole-2-thiol (1.2 eq.), MeCN r.t. 2 h, 100 °C 24 h, elevated pressure; (d) 4-Ar-piperazine (2 eq.), MeOH, r.t. 28 h, or 4-Ar-piperazine hydrochloride (1.2 eq.), Et3N (2.25 eq.), MeOH r.t. 72 h [17]; (e) H2NNH2 × H2O (6 eq.), MeOH r.t. 16 h, reflux, 4 h [16]; (f) 3-R1-2,4-pentanedione (1.1 eq.), AcOH, reflux, 2 h [17].
The desired, 4-substituted N-(phenylcarbamoyl)pyridine-3-sulfonamides 1127 were obtained by treatment for 24 h of primary sulfonamides 210 with the appropriate aryl isocyanates (i.e., phenyl isocyanate, 4-chlorophenyl isocyanate or 3,4-dichlorophenyl isocyanate) in dry acetone at room temperature in the presence of anhydrous potassium carbonate (Scheme 2). Then, the initially formed intermediate potassium salts of type A were acidified with dilute hydrochloric acid to pH 2, to afford expected diarylsulfonylurea products in moderate to good yields (47%–80%).
Scheme 2. Synthesis of 4-substituted-N-(R2-phenylcarbamoyl)-3-pyridinesulfonamides 1127.
Scheme 2. Synthesis of 4-substituted-N-(R2-phenylcarbamoyl)-3-pyridinesulfonamides 1127.
Molecules 20 12029 g004
Reagents and conditions: (a) arylisocyanate (1.2 eq.), anhydrous K2CO3 (1.0 eq.), dry acetone, r.t. 24 h; (b) H2O 5 mL, 4% HCl pH 2 r.t. 16 h.
The final compounds were characterized by IR and NMR spectroscopy as shown in the Experimental Section. Elemental analyses (C,H,N) were in accordance with the proposed structures. In detail, IR absorption bands corresponding to the stretching vibration of the carbonyl group in -NH(C=O)NH- appeared for compounds 1114 and 2427 in the range of 1716–1732 cm−1, and was shifted to 1630–1648 cm−1 for compounds 1523 possessing a piperazine ring attached at the 4 position. Inspection of the 1H-NMR spectra revealed the characteristic resonance signals of pyridine ring protons appeared as two doublets of H-5 and H-6 at 7.18–7.64 and 8.27–8.96 ppm, respectively, as well as a singlet signal of H-2 at 8.71–9.26 ppm. In turn, the singlet signals attributable to the NH protons of the urea moieties were observed at 8.9–9.4 ppm, whereas a broad singlet of the SO2NH proton was found downfield in the wide region of 9.7–13.4 ppm.

2.2. Anticancer Activity

Compounds 11, 12, 1421 and 2426 were tested in vitro at the U.S. National Cancer Institute (Bethesda, MD, USA) at single high concentration of 10 µM against the NCI panel of 60 cell lines derived from nine different human cancer types: leukemia, non-small-cell lung cancer (NSCLC), colon, central nervous system (CNS), melanoma, ovarian, renal, prostate and breast cancer. Inhibition growth percent (IGP) data compared to no-drug control, obtained for each of the cell lines, are shown in Table 1.
Table 1. Inhibition growth percent (IGP [%]) for tested compounds (11, 12, 1421, 2426) against selected NCI-60 cancer cell lines at single concentration 10−5 M.a
Table 1. Inhibition growth percent (IGP [%]) for tested compounds (11, 12, 1421, 2426) against selected NCI-60 cancer cell lines at single concentration 10−5 M.a
PanelCell LineIGP [%] of Compound
11121415161718192021242526
LeukemiaCCRF-CEM1427307211*852719
K-562667457127020954272*
MOLT-47212765189859208
RPMI-8226**70*17*937210*
SR1516129512919
NSCLCHOP-92**53**2*13128*
NCI-H522725*43*8919511028128
Colon cancerHCC-2998111*1**119273*2*
HCT-15*3937*319*28*41*534
KM12*43*25472414892749*
SW-620*24301021**30*821240*
CNS cancerSF-268*18316**19671*26*
SF-29511136431310*1014748*1
MelanomaLOX IMVI7-5910563474961059
MALME-3M91*58*3665101442*
M14*17162717**90772529*
MDA-MB-435*9161112****931523*
UACC-62*57513338**32*73314210
Ovarian cancerOVCAR-3***42*****7550**
Renal cancerA498151933442517131280760
ACHN*31222521**24*932625*
CAKI-123329*2811*23*655172
UO-311218172719952110110202916
Prostate cancerPC-3116145417*621161015112*
DU-145*165*7**18*67132*
Breast cancerMDA-MB-468*7593***10957**
T-47D2202133176102799226187
a Data obtained from NCI-60 DTP human tumor cell line screening [25,26,27,28,29], * IGP ≤ 0%; – not tested.
The most important conclusion based on this preliminary anticancer assay is the finding that substitution patterns of the urea phenyl ring (R2), has a crucial impact on the cytotoxic activity potency:
(a)
All compounds with 4-chlorophenylcarbamoyl (R2 = 4-Cl) moieties (12, 14, 16, 19, 21 and 25) are characterized by moderate to high activity with IGP range from 17 to 96% against the common cancer cell lines: leukemia (K-562, MOLT-4), colon cancer (HCT-15 and SW-620,) melanoma (LOX IMVI and UACC-62), and renal cancer (ACHN, CAKI-1) (Table 1), as well exhibit high overall activity with the average IGP for the whole panel in the range from 7 to 90%.
(b)
Apparently the introduction of a second chlorine atom in position 3 of the 4-chloro-phenylcarbamoyl moiety (R2 = 3,4-diCl) in compounds 17 and 26 definitely causes a loss of activity. In this case the highest IGP values of 12 and 19% are observed only for the leukemia SR cell line.
(c)
From among of the compounds with unsubstituted phenylcarbamoyl moieties (R2 = H; i.e., 11, 15, 18, 20 and 24) only compounds 15 and 24 exhibit high antiproliferative activity against certain cell lines: leukemia RPMI-8226 (IGP = 70 and 72%), NSCLC HOP-92 (IGP = 53 and 28%), CNS cancer (IGP = SF-295 43 and 48%), melanoma MALME-3M (IGP = 58 and 44%), ovarian cancer OVCAR-3 (IGP = 42 and 50%), prostate cancer PC-3 (IGP = 54 and 51%) or breast cancer MDA-MB-468 (IGP = 59 and 57%), respectively (Table 1). It should be noted that the mentioned cell lines, which are highly susceptible for compounds 15 and 24, do not exhibit significant sensitivity for their 4-chlorophenylurea (R2 = 4-Cl) analogs 16 and 25.
It was stated that among a series of 4-chlorophenylureas (12, 14, 16, 19, 21 and 25) replacement of the benzylthio moiety (R1) at the 4 position of the pyridine ring (compound 12) by a 5-methyl-1,3,4-thiadiazole-2-thiol group in 14 led to a decrease of the susceptibility of NCI-H522 (from 25 to 0%), KM-12 (from 43 to 0%), however the cell lines CCRF-CEM, HCT-116 remain more sensitive to compound 12 (increase from 0 to 25% and from 0 to 43%, respectively). On the other hand removal of the sulfur atom and introduction of a pyrazole moiety in 25 leads to higher activity towards the majority of cell lines, especially for HCT-15, KM 12, SF-268, UO-31 and DU-145 (Table 1).
Additionally, introduction of a chlorine atom in 19 to the phenylpiperazinyl substituent of 16 results in a slight increase of antiproliferative activity towards the NSCLC cell line NCI-H522 (from 0 to 19%), colon cancer HCC-2998 (from 0 to 9%), KM12 (from 4 to 24%), SW-620 (from 21 to 30%), CNS cancer SF-268 (from 6 to 19%), prostate cancer PC-3 (from 17 to 21%), DU-145 (from 7 to 18%) breast cancer T-47D (from 17 to 27%), however it also resulted in loss of activity against renal cancer A498 (from 42 to 13%) melanoma M14 (from 17 to 9%) and MDA-MB-435 (from 12 to 0%) (Table 1). Nevertheless introducing of second chlorine atom at position 3 of the 4-chlorophenylpiperazin-1-yl in 21 causes a huge increase of activity since all mentioned lines demonstrate IGPs over 66%. The average IGP for all cell lines reached 90% and furthermore a cytotoxic effect (IGP > 100%) was observed for sixteen cell lines representing all nine cancer types.
Thus, the most active compound N-[(4-chlorophenyl)carbamoyl]-4-[4-(3,4-dichlorophenyl)-piperazin-1-yl]pyridine-3-sulfonamide (21) was further tested at the NCI five-dose assay (in the range of 0.01–100 µM) (Table 2). A relatively highest sensitivity to this compound was found for the subpanels of leukemia, colon cancer and melanoma, which the average GI50 values range from 13.6 to 14.9 µM (sulofenur (NSC-642684) 25.5–37.5 µM [30]).
Thus, the lowest GI50 was found for the cell lines of melanoma UACC-62 (1.5 µM) and M14 (8.9 µM), leukemia K-562 (3 µM) and CCRF-CEM (8.2 µM), and colon cancer HCT-15 (6.4 µM) as well as for the renal cancer CAKI-1 (6.28 µM) and UO-31 (9.8 µM) cell lines. Furthermore the GI50 values for the most sensitive cell lines (GI50 < 20 µM) for compound 21 are of the same order of magnitude and generally lower than for clinically tested sulofenur (Table 2).
Table 2. Anticancer in vitro data for compound 21 for the most sensitive cell lines (GI50 < 20 µM) a, and comparative data for sulofenur (NSC-642684) b [30].
Table 2. Anticancer in vitro data for compound 21 for the most sensitive cell lines (GI50 < 20 µM) a, and comparative data for sulofenur (NSC-642684) b [30].
PanelCell line21Sulofenur b
GI50 cTGI dLC50 eGI50 cTGI dLC50 e
LeukemiaCCRF-CEM8.243.6>10029.8>100>100
K-5623.0>100>10010.277.1>100
MOLT-419.968.1>10026.498.2>100
RPMI-822614.754.2>10024.485.7>100
SR11.851.6>10057.0>100>100
NSCLCA-549/ATCC14.762.8>10032.797.7>100
HOP-6218.843.5>10032.2>100>100
NCI-H22613.457.9>10037.977.8>100
NCI-H2319.951.9>10028.156.090.8
NCI-H322M18.3>100>10034.295.5>100
NCI-H46017.269.4>10038.3100>100
NCI-H52214.149.4>10027.994.2>100
Colon cancerCOLO 20516.833.065.029.860.890.2
HCC-299815.531.664.331.677.698.4
HCT-11615.134.478.226.267.385.1
HCT-156.468.3>10035.690.2>100
HT2915.945.7>10061.1>100>100
KM1213.0>100>10036.198.9>100
SW-62014.4>100>10035.3>100>100
CNS cancerSF-29512.237.9>10046.7>100>100
SF-53913.129.064.428.369.2>100
SNB-1919.157.6>10040.9>100>100
U25113.036.5>10030.777.4>100
MelanomaM148.953.4>10037.897.5>100
MDA-MB-43518.9>100>10017.648.3>100
SK-MEL-510.936.7>10026.874.098.2
UACC-621.515.5>10023.984.7>100
Ovarian cancerIGROV116.368.1>10012.394.4>100
OVCAR-316.636.781.124.373.8>100
OVCAR-818.6>100>10040.8>100>100
NCI/ADR-RES18.4>100>100
Renal cancer786-016.143.7>10035.3>100>100
A49815.263.1>10045.0>100>100
ACHN11.6>100>10029.4>100>100
CAKI-16.3>100>10042.8>100>100
SN12C18.4>100>10039.2>100>100
UO-319.827.375.025.176.4>100
Prostate cancerPC-314.471.1>10019.047.2>100
DU-14517.355.7>10024.092.0>100
Breast cancerMCF719.797.4>10024.181.8>100
MDA-MB-231/ATCC14.663.3>100
BT-54916.144.7>10032.6>100>100
T-47D13.987.6>10016.474.6>100
MDA-MB-46818.9>100>100
a Data obtained from NCI-60 DTP human tumor cell line screening [25,26,27,28,29]; b Sulofenur (NSC-642684): NCI cancer screen; September 2014 [30]; c GI50: molar concentration [µM] that inhibits 50% net cell growth; d TGI: molar concentration [µM] giving total growth inhibition; e LC50: molar concentration [µM] causing 50% net cell death; – not tested.

3. Experimental Section

3.1. General Procedures

The following instruments and parameters were used: melting points Boetius HMK apparatus; IR spectra: KBr pellets, 400–4000 cm−1 Thermo Mattson Satellite FTIR spectrophotometer; 1H- and 13C-NMR: Varian Gemini 200 apparatus at 200 MHz (1H-NMR) and 50 MHz (13C-NMR), Varian Unity 500 Plus apparatus at 500 MHz (1H-NMR) and 125 MHz (13C-NMR); chemical shifts are expressed in parts per million (ppm) relative to TMS as an internal standard. Elemental analyses were performed on PerkinElmer 2400 Series II CHN Elemental Analyzer, and they were in agreement with the theoretical values within ±0.4% range. The starting 4-chloro-3-pyridinesulfonamide (1) was commercially available (Alfa Aesar, Karlsruhe, Germany), while 4-substituted 3-pyridinesulfonamide 2, 410 were obtained according to methods described previously: 4-benzylthio-3-pyridinesulfonamie (2) [16], 4-(4-substituted-piperazin-1-yl)-3-pyridinesulfonamides 48 [17], and 4-(1H-pyrazol-1-yl)-3-pyridine-sulfonamides 9, 10 [17].

3.2. Synthesis

3.2.1. Procedure for the Preparation of 4-[(5-Methyl-1,3,4-thiadiazol-2-yl)thio]-3-pyridinesulfonamide (3)

In a closed glass pressure tube, a mixture of 4-chloro-3-pyridinesulfonamide (1.92 g, 10 mmol) and 5-methyl-1,3,4-thiadiazole-2-thiol (1.57 g, 12 mmol) in dry acetonitrile (16.5 mL) was stirred at room temperature for 2 h and then at 100 °C for 24 h. The precipitate of the hydrochloride was collected by filtration, washed with acetonitrile (3 × 2 mL) and dried, then suspended in water (8 mL) and slowly adjusted to pH 8 with 1% solution of NaOH. After stirring at room temperature for 3 h, the precipitate was filtered off, washed with water (2 × 1 mL), and dried. Yield 2.49 g (86%); mp 132–135 °C; IR (KBr) νmax 3546, 3344 (NH), 1572 (C=C), 1330, 1163 (SO2) cm1; 1H-NMR (DMSO-d6, 200 MHz) δ: 2.83 (s, 3H, CH3); 7.09 (d, 1H, H-5 pyrid.); 8.00 (s, 2H, NH2); 8.56 (d, 1H, H-6 pyrid.); 8.95 (s, 1H, H-2 pyrid.) ppm; anal. C 33.32, H 2.80, N 19.43% calcd. for C8H8N4O2S3 C 33.02, H 2.84, N 19.33%.

3.2.2. General Procedure for the Preparation of 4-Substituted-N-(R2-phenylcarbamoyl)-3-pyridine-sulfonamides

A mixture of 4-substituted-3-pyridinesulfonamide 210 (1 mmol), the appropriate phenyl isocyanate (1.2 mmol) and anhydrous potassium carbonate (0.14 g, 1 mmol) in dry acetone (15 mL) was stirred at room temperature for 24 h. The precipitate containing potassium salt of type A (Scheme 2) and inorganic salts was collected by filtration and washed with acetone (2 × 5 mL). The solid thus obtained was suspended in water (5 mL), slowly acidified with 4% hydrochloric acid to pH 2, and stirred overnight. The precipitate was filtered off washed with water (2 × 2 mL), and dried. In this manner the following compounds were obtained:
4-(Benzylthio)-N-(phenylcarbamoyl)-3-pyridinesulfonamide (11). Starting from 4-benzylthio-3-pyridinesulfonamide (2, 0.28 g), and phenyl isocyanate (0.14 g), the title compound 11 was obtained (0.32 g, 80%): mp 198–201 °C; IR (KBr) νmax 3369 (NH), 3081 (CAr-H) 2928, 2853 (C-H), 1727 (C=O), 1600, 1579, 1547 (C=C, C=N), 1350, 1160 (SO2) cm−1; 1H-NMR (DMSO-d6, 200 MHz) δ 4.51 (s, 2H, CH2), 7.03 (t, 1H, H-4ʹ Ph), 7.18–7.34 (m, 7H, HAr), 7.47 (m, 2H, HAr), 7.64 (d, J = 5.5 Hz, 1H, H-5 pyrid.), 8.58 (d, J = 5.5 Hz, 1H, H-6 pyrid.), 8.71 (s, 1H, H-2 pyrid.), 8.91 (s, 1H, NH), 11.0 (br.s, 1H, NH) ppm; 13C-NMR (DMSO-d6, 125 MHz) δ 35.52, 119.47, 121.45, 124.06, 128.31, 129.29, 129.61, 129.87, 131.89, 135.62, 138.43, 149.58, 149.67, 150.95, 152.89 ppm; anal. C 57.12, H 4.29, N 10.52% calcd for C19H17N3O3S2 C 56.77, H 4.26, N 10.48%.
4-(Benzylthio)-N-[(4-chlorophenyl)carbamoyl]-3-pyridinesulfonamide (12). Starting from 4-benzyl-thio-3-pyridinesulfonamide (2, 0.28 g), and 4-chlorophenyl isocyanate (0.18 g), the title compound 12 was obtained (0.25 g, 58%): mp 204–207 °C; IR (KBr) νmax 3391 (NH), 3107 (CAr-H) 2851 (C-H), 1725 (C=O), 1599, 1581, 1539, 1494 (C=C, C=N), 1347, 1153 (SO2) cm−1; 1H-NMR (DMSO-d6, 200 MHz) δ 4.50 (s, 2H, CH2), 7.24 (m, 3H, HAr), 7.33 (s, 4H, HAr), 7.46 (m, 2H, HAr), 7.64 (d, J = 5.0 Hz, 1H, H-5 pyrid.), 8.58 (d, J = 5.0 Hz, 1H, H-6 pyrid.), 8.85 (s, 1H, H-2 pyrid.), 8.90 (s, 1H, NH), ppm; 13C-NMR (DMSO-d6, 125 MHz) δ 35.52, 121.13, 121.47, 127.57, 128.32, 129.28, 129.43, 129.89, 131.98, 135.61, 137.53, 149.85, 150.74, 152.68 ppm; anal. C 52.59, H 3.72, N 9.68% calcd for C19H16ClN3O3S2 C 52.21, H 3.60, N 9.78%.
4-(Benzylthio)-N-[(3,4-dichlorophenyl)carbamoyl]-3-pyridinesulfonamide (13). Starting from 4-benzylthio-3-pyridinesulfonamide (2, 0.28 g), and 3,4-dichlorophenylisocyanate (0.23 g), the title compound 13 was obtained (0.27 g, 57%): mp 205–208 °C; IR (KBr) νmax 3377 (NH), 3093 (CAr-H), 2924, 2852 (C-H), 1732 (C=O), 1599, 1578, 1532, 1477 (C=C, C=N), 1352, 1155 (SO2) cm−1; 1H-NMR (DMSO-d6, 200 MHz) δ 4.50 (s, 2H, CH2), 7.24–7.30 (m, 4H, HAr), 7.44–7.52 (m. 3H, HAr), 7.66–7.68 (m, 2H, HAr, H-5 pyrid.), 8.58 (d, 1H, H-6 pyrid.), 8.89 (s, 1H, H-2 pyrid.), 9.03 (s, 1H, NH), ppm; 13C-NMR (DMSO-d6, 50 MHz) δ 35.20, 119.32, 120.27, 121.15, 124.83, 127.90, 128.87, 129.49, 130.91, 131.34, 132.13, 135.20, 138.62, 149.71, 150.11, 150.32, 151.49 ppm; anal. C 48.73, H 3.23, N 8.97% calcd for C19H15Cl2N3O3S2 C 48.17, H 3.00, N 8.85%.
N-[(4-Chlorophenyl)carbamoyl]-4-[(5-methyl-1,3,4-thiadiazol-2-yl)thio]-3-pyridinesulfonamide (14). Starting from 4-[(5-methyl-1,3,4-thiadiazol-2-yl)thio]-3-pyridinesulfonamide (3, 0.29 g), and 4-chloro- phenyl isocyanate (0.18 g), the title compound 14 was obtained (0.28 g, 63%): mp 167–171 °C; IR (KBr) νmax 3297, 3201 (NH), 3076 (CAr-H), 2924, 2855 (C-H), 1716 (C=O), 1610, 1547, 1492 (C=C, C=N), 1350, 1159 (SO2) cm−1; 1H-NMR (DMSO-d6, 200 MHz) δ 2.80 (s, 3H, CH3), 7.18 (d, 1H, H-5 pyrid.), 7.30–7.39 (m, 4H, Ph), 8.63 (d, 1H, H-6 pyrid.), 9.07 (s, 2H, H-2 pyrid. NH), 8.90 (s, 1H, NH), ppm; 13C-NMR (DMSO-d6, 125 MHz) δ 16.47, 121.36, 123.44, 127.60, 129.39, 133.28, 137.61, 145.94, 151.21, 153.96, 157.83, 172.56 ppm; anal. C 40.77, H 2.74, N 15.85% calcd for C15H12ClN5O3S3 C 40.65, H 2.60, N 16.08%.
N-(Phenylcarbamoyl)-4-(4-phenylpiperazin-1-yl)-3-pyridinesulfonamide (15). Starting from 4-(4-phenylpiperazin-1-yl)-3-pyridinesulfonamide (4, 0.32 g), and phenyl isocyanate (0.14 g), the title compound 15 was obtained (0.32 g, 73%): mp 154–156 °C; IR (KBr) νmax 3466 (NH), 3059 (CAr-H), 2826 (C-H), 1640 (C=O), 1599, 1524, 1504 (C=C, C=N), 1314 1138 (SO2) cm−1; 1H-NMR (DMSO-d6, 200 MHz) δ 3.33 (s, 4H, 2 × CH2), 3.82 (s, 4H, 2 × CH2), 6.77–7.06 (m, 4H, HAr), 7.12–7.40 (m, 7H, HAr, H-5 pyrid.), 8.39 (d, 1H, H-6 pyrid.), 8.77 (s, 1H, H-2 pyrid.), 8.92 (s, 1H, NH), 12.10 (br.s, 1H, NH), ppm; 13C-NMR (DMSO-d6, 50 MHz) δ 48.14, 51.06, 114.35, 115.68, 118.31, 119.34, 121.61, 128.72, 129.15, 129.29, 140.59, 150.82, 156,69 ppm; anal. C 60.39, H 5.30, N 16.01%. calcd for C22H23N5O3S, C 60.26, H 5.36, N 15.68%.
N-[(4-Chlorophenyl)carbamoyl]-4-(4-phenylpiperazin-1-yl)-3-pyridinesulfonamide (16). Starting from 4-(4-phenylpiperazin-1-yl)-3-pyridinesulfonamide (4, 0.32 g), and 4-chlorophenylisocyanate (0.18 g), the title compound 16 was obtained (0.27 g, 56%): mp 145–149 °C; IR (KBr) νmax 3478, 3290 (NH), 3070 (CAr-H), 2836 (C-H), 1641 (C=O), 1603, 1519, (C=C, C=N), 1320, 1133 (SO2) cm−1; 1H-NMR (DMSO-d6, 200 MHz) δ 3.30 (s, 4H, 2 × CH2), 3.96 (s, 4H, 2 × CH2), 6.78 (t, 1H, H-4 Ph), 6.94 (d, 2H, H-2,6 Ph), 7.14–7.31 (m, 5H, HAr and H-5 pyrid.), 7.44 (d, 2H, H-2ʹ,6ʹ Ph), 8.32 (d, 1H, H-6 pyrid.), 8.89 (s, 1H, H-2 pyrid.), 8.95 (s, 1H, NH), 13.0 (br.s, 1H, NH), ppm; 13C-NMR (DMSO-d6, 125 MHz) δ 48.57, 51.11, 116.09, 119.81, 128.83, 129.53, 129.71, 151.12, 156.82 ppm; anal. C 55.99, H 4.70, N 14.84%. calcd for C22H22ClN5O3S, C 55.78, H 4,96, N 14.71%.
N-[(3,4-Dichlorophenyl)carbamoyl]-4-(4-phenylpiperazin-1-yl)-3-pyridinesulfonamide (17). Starting from 4-(4-phenylpiperazin-1-yl)-3-pyridinesulfonamide (4, 0.32 g), and 3,4-dichlorophenyl isocyanate (0.23 g), the title compound 17 was obtained (0.24 g, 47%): mp 172–175 °C; IR (KBr) νmax 3425 (NH), 3062 (CAr-H), 2919, 2855 (C-H), 1630 (C=O), 1599, 1577, 1540, 1506 (C=C, C=N), 1371, 1140 (SO2) cm−1; 1H-NMR (DMSO-d6, 200 MHz) δ 3.29 (s, 4H, 2 × CH2), 4.02 (s, 4H, 2 × CH2), 6.79 (t, 1H, H-4 Ph), 6.93 (d, 2H, H-2,6 Ph), 7.18–7.32 (m, 5H, HAr and H-5 pyrid.), 7.85 (s, 1H, H-2ʹ Ph), 8.27 (d, 1H, H-6 pyrid.), 8.88 (s, 1H, H-2 pyrid.), 9.12 (s, 1H, NH), 13.4 (br.s, 1H, NH), ppm; 13C-NMR (DMSO-d6, 125 MHz) δ 48.58, 50.89, 113.65, 116.10, 118.16, 118.95, 119.83, 121.83, 129.47, 129.71, 130.74, 131.24, 142.68, 146.01, 151.08, 156.64 ppm; anal. C 52.18, H 4.18, N 13.83%. calcd for C22H21Cl2N5O3S, C 51.78, H 4.05, N 13.86%.
4-[4-(4-Chlorophenyl)piperazin-1-yl]-N-(phenylcarbamoyl)-3-pyridinesulfonamide (18). Starting from 4-[4-(4-chlorophenyl)piperazin-1-yl]-3-pyridinesulfonamide (4, 0.35 g), and phenyl isocyanate (0.14 g), the title compound 18 was obtained (0.36 g, 76%): mp 177–181 °C; IR (KBr) νmax 3404, 3278 (NH), 3083 (CAr-H), 2923, 2855 (C-H), 1648 (C=O), 1650 1598, 1496 (C=C, C=N), 1311 1128 (SO2) cm−1; 1H-NMR (DMSO-d6, 200 MHz) δ 3.34 (s, 4H, 2 × CH2), 3.81 (s, 4H, 2 × CH2), 6.86 (t, 1H, H-4ʹ Ph), 6.98 (d, J = 8.9 Hz, 2H, H-2,6 Ph), 7.16 (t, 2H, H-3ʹ5ʹ Ph), 7.26 (d, J = 8.9 Hz, 2H, H-3,5 Ph), 7.31 (d, 1H H-5 pyrid.), 7.38 (d, 2H, H-2ʹ,6ʹ Ph), 8.40 (d, 1H, H-6 pyrid.), 8.77 (s, 1H, H-2 pyrid.), 8.92 (s, 1H, NH), ppm; 13C-NMR (DMSO-d6, 125 MHz) δ 48.32, 51.21, 117.52, 118.64, 123.22, 129.11, 129.37, 129.61, 150.02, 157.06 ppm; anal. C 55.99, H 4.70, N 14.84%. calcd for C22H22ClN5O3S, C 55.59, H 4.65, N 14.87%.
N-[(4-Chlorophenyl)carbamoyl]-4-[4-(4-chlorophenyl)piperazin-1-yl]pyridine-3-sulfonamide (19). Starting from 4-[4-(4-chlorophenyl)piperazin-1-yl]-3-pyridinesulfonamide (5, 0.35 g), and 4-chloro- phenyl isocyanate (0.18 g), the title compound 19 was obtained (0.28 g, 56%): mp 178–182 °C; IR (KBr) νmax 3427, 3180 (NH), 3050 (CAr-H), 2920, 2854 (C-H), 1642 (C=O), 1626, 1583, 1540, 1497 (C=C, C=N), 1278, 1153 (SO2) cm−1; 1H-NMR (DMSO-d6, 200 MHz) δ 3.32 (s, 4H, 2 × CH2), 3.95 (s, 4H, 2 × CH2), 6.96 (d, 2H, H-2,6 Ph), 7.17 (d, 2H, H-3,5 Phʹ), 7.23–7.31 (m, 3H, H-3,5 Ph and H-5 pyrid.), 7.44 (d, 2H, H-2,6 Phʹ), 8.33 (d, 1H, H-6 pyrid.), 8.90 (s, 1H, H-2 pyrid.), 8.93 (s, 1H, NH), ppm; anal. C 52.18, H 4.18, N 13.83%. calcd for C22H21Cl2N5O3S, C 52.38, H 3.98, N 13.71%.
4-[4-(3,4-Dichlorophenyl)piperazin-1-yl]-N-(phenylcarbamoyl)-3-pyridinesulfonamide (20). Starting from 4-[4-(3,4-dichlorophenyl)piperazin-1-yl]-3-pyridinesulfonamide (6, 0.39 g), and phenyl isocyanate (0.14 g), the title compound 20 was obtained (0.40 g, 80%): mp 177–180 °C; IR (KBr) νmax 3443 (NH), 3058 (CAr-H), 2837 (C-H), 1639 (C=O), 1595, 1526, 1510, 1485 (C=C, C=N), 1314, 1141 (SO2) cm−1; 1H-NMR (DMSO-d6, 200 MHz) δ 3.39 (s, 4H, 2 × CH2), 3.79 (s, 4H, 2 × CH2), 6.86 (t, 1H, H-4ʹ Ph), 6.96 (dd, Jortho = 8.2 Hz, Jmeta = 2.2 Hz, 1H, H-6 3,4-diClPh), 7.16 (m, 3H, H-5 3,4-diClPh and H-3,5 Ph), 7.30 (d,h 1H, H-5 pyrid.), 7.36–7.44 (m, 3H, H-2,6 Ph and H-2,3 4-diClPh), 8.40 (d, 1H, H-6 pyrid.), 8.77 (s, 1H, H-2 pyrid.), 8.91 (s, 1H, NH), ppm; anal. C 52.18, H 4.18, N 13.83%. calcd for C22H21Cl2N5O3S, C 52.51, H 4.11, N 13.81%.
N-[(4-Chlorophenyl)carbamoyl]-4-[4-(3,4-dichlorophenyl)piperazin-1-yl]pyridine-3-sulfonamide (21). Starting from 4-[4-(3,4-dichlorophenyl)piperazin-1-yl]-3-pyridinesulfonamide (6, 0.39 g), and 4-chlorophenyl isocyanate (0.18 g), the title compound 21 was obtained (0.35 g, 65%): mp 164–168 °C; IR (KBr) νmax 3469 (NH), 3095 (CAr-H), 2925, 2837 (C-H), 1641 (C=O), 1591, 1525, 1489 (C=C, C=N), 1306. 1141 (SO2) cm−1; 1H-NMR (DMSO-d6, 200 MHz) δ 3.38 (s, 4H, 2 × CH2), 3.93 (s, 4H, 2 × CH2), 6.94 (dd, 1H, H-6 3,4-diClPh), 7.17 (m, 3H, H-5 3,4-diClPh and H-3,5 Ph), 7.28 (d, 1H, H-5 pyrid.), 7.38–7.46 (m, 3H, H-2,6 Ph and H-2 3,4-diClPh), 8.33 (d, 1H, H-6 pyrid.), 8.89 (s, 1H, H-2 pyrid.), 8.92 (s, 1H, NH), ppm; 13C-NMR (DMSO-d6, 50 MHz) δ 47.32, 50.33, 113.71, 113.75, 115.44, 116.42, 119.47, 119.99, 124.43, 128.42, 129.28, 130.78, 131.82, 140.32, 150.41, 156.49 ppm. anal. C 48.86, H 3.73, N 12.95%. calcd. for C22H20Cl3N5O3S, C 48.82, H 3.70, N 12.81%.
N-[(4-Chlorophenyl)carbamoyl]-4-[4-(2,5-dimethylphenyl)piperazin-1-yl]-3-pyridinesulfonamide (22). Starting from 4-[4-(2,5-dimethylphenyl)piperazin-1-yl]-3-pyridinesulfonamide (7, 0.35 g), and 4-chlorophenyl isocyanate (0.18 g), the title compound 22 was obtained (0.36 g, 72%): mp 171–174 °C; IR (KBr) νmax 3302 (NH), 3023 (CAr-H), 2945, 2918, 2857 (C-H), 1642 (C=O), 1516 (C=C, C=N), 1320, 1129 (SO2) cm−1; 1H-NMR (DMSO-d6, 200 MHz) δ 2.24 (s, 6H, 2 × CH3), 2.96 (br.s, 4H, 2 × CH2), 3.93 (br.s, 4H, 2 × CH2), 6.78 (d, 1H, H-4 Ph), 6.86 (s. 1H, H-6 Ph), 7.06 (d, 1H, H-3 Ph), 7.17 (d, 2H, H-3,5 Ph) 7.30 (d, 1H, H-5 pyrid.), 7.47 (d, 2H, H-2,6 Ph), 8.33 (d, 1H, H-6 pyrid.), 8.89 (s, 1H, H-2 pyrid.), 8.97 (s, 1H, NH), ppm; 13C-NMR (DMSO-d6, 125 MHz) δ 17.84, 21.48, 51.83, 51.93, 114.17, 115.86, 119.66, 120.46, 124.45, 128.77, 129.24, 130.32, 131.33, 136.27, 141.13, 146.81, 151.24, 156.94, 157.63 ppm; anal. C 57.65, H 5.24, N 14.01%. calcd for C24H26ClN5O3S, C 57.21, H 5.44, N 14.07%.
N-[(4-Chlorophenyl)carbamoyl]-4-[4-(pyridin-2-yl)piperazin-1-yl]-3-pyridinesulfonamide (23). Starting from 4-[4-(pyridin-2-yl)piperazin-1-yl]-3-pyridinesulfonamide (8, 0.32 g), and 4-chlorophenyl isocyanate (0.18 g), the title compound 23 was obtained (0.30 g, 64%): mp 187–193 °C; IR (KBr) νmax 3307 (NH), 3073 (CAr-H), 2923, 2854 (C-H), 1638 (C=O), 1609, 1593, 1505, (C=C, C=N), 1315, 1149 (SO2) cm−1; 1H-NMR (DMSO-d6, 200 MHz) δ 3.67 (s, 4H, 2 × CH2), 3.76 (s, 4H, 2 × CH2), 6.66 (t, 1H, H-5′ pyrid.), 6.85 (d, 1H, H-3′ pyrid.), 7.13 (m, 3H, H-3,5 Ph, H-5 pyrid), 7.46 (d, 2H, H-2,6 Ph), 7.56 (t, 1H, H-4′ pyrid.), 8.13 (d, 1H, H-6′ pyrid.), 8.29 (d, 1H, H-6 pyrid.), 8.81 (s, 1H, H-2 pyrid.), 8.91 (s, 1H, NH), ppm; 13C-NMR (DMSO-d6, 125 MHz) δ 45.01, 50.73, 107.79, 113.70, 113.76, 119.61, 124.16, 128.70, 130.79, 138.30, 141.43, 145.69, 148.25, 149.24, 156.08, 158.07, 159.38 ppm; anal. C 53.33, H 4.48, N 17.77%. calcd for C21H21ClN6O3S, C 52.44, H 4.19, N 17.67%.
N-(Phenylcarbamoyl)-4-(3,4,5-trimethyl-1H-pyrazol-1-yl)-3-pyridinesulfonamide (24). Starting from 4-(3,4,5-trimethyl-1H-pyrazol-1-yl)-3-pyridinesulfonamide (9, 0.27 g), and phenyl isocyanate (0.14 g), the title compound 24 was obtained (0.33 g, 87%): mp 161–164 °C; IR (KBr) νmax 3254, 3199 (NH), 3079, 3018 (CAr-H), 2927, 2860 (C-H), 1730 (C=O), 1583, 1499 (C=C, C=N), 1363, 1350, 1170 (SO2) cm−1; 1H-NMR (DMSO-d6, 200 MHz) δ 1.93 (s, 3H, CH3), 2.05 (s, 3H, CH3), 2.17 (s, 3H, CH3), 7.04 (t, 1H, H-4 Ph), 7.28 (m, 4H, Ph), 7.57 (d, J = 5.2 Hz, 1H H-5 pyrid.), 8.96 (d, J = 5.2 Hz, 1H, H-6 pyrid.), 9.08 (s, 1H, H-2 pyrid.), 9.27 (s, 1H, NH), 9.7 (br.s, 1H, NH), ppm; 13C-NMR (DMSO-d6, 125 MHz) δ 8.56, 10.61, 12.64, 114.15, 119.43, 124.07, 124.21, 129.65, 132.08, 138.48, 144.97, 149.67, 150.12, 152.88, 155.93 ppm; anal. C 56.09, H 4.97, N 18.17%. calcd for C18H19N5O3S, C 55.78, H 4.89, N 18.18%.
N-[(4-Chlorophenyl)carbamoyl]-4-(3,4,5-trimethyl-1H-pyrazol-1-yl)-3-pyridinesulfonamide (25). Starting from 4-(3,4,5-trimethyl-1H-pyrazol-1-yl)-3-pyridinesulfonamide (9, 0.27 g), and 4-chloro- phenyl isocyanate (0.18 g), the title compound 25 was obtained (0.31 g, 75%): mp 178–182 °C; IR (KBr) νmax 3247, 3186 (NH), 3010, 3035 (CAr-H), 2992, 2862 (C-H), 1727 (C=O), 1588, 1552, 1496 (C=C, C=N), 1384, 1363, 1170 (SO2) cm−1; 1H-NMR (DMSO-d6, 200 MHz) δ 1.93 (s, 3H, CH3), 2.05 (s, 3H, CH3), 2.16 (s, 3H, CH3), 7.35 (s, 4H, Ph), 7.57 (d, 1H H-5 pyrid.), 8.96 (d, 1H, H-6 pyrid.), 9.21 (s, 1H, H-2 pyrid.), 9.26 (s, 1H, NH), ppm; 13C-NMR (DMSO-d6, 50 MHz) δ 8.13, 10.19, 12.21, 113.75, 120.69, 123.83, 127.29, 129.11, 131.64, 137.07, 138.09, 144.56, 149.28, 149.72, 152.40, 155.57 ppm; anal. C 51.49, H 4.32, N 16.68%. calcd for C18H18ClN5O3S, C 51.22, H 4.20, N 16.57%.
N-[(3,4-Dichlorophenyl)carbamoyl]-4-(3,4,5-trimethyl-1H-pyrazol-1-yl)-3-pyridinesulfonamide (26). Starting from 4-(3,4,5-trimethyl-1H-pyrazol-1-yl)-3-pyridinesulfonamide (9, 0.27 g), and 3,4-dichloro-phenyl isocyanate (0.23 g), the title compound 26 was obtained (0.25 g, 55%): mp 163–166 °C; IR (KBr) νmax 3324 (NH), 3104 (CAr-H), 2924, 2856 (C-H), 1727 (C=O), 1599, 1581, 1477 (C=C, C=N), 1381 1169 (SO2) cm−1; 1H-NMR (DMSO-d6, 200 MHz) δ 1.92 (s, 3H, CH3), 2.04 (s, 3H, CH3), 2.14 (s, 3H, CH3), 7.25 (dd, 1H, H-6 Ph), 7.55 (m, 2H, H-5 Ph, H-5 pyrid.), 7.69 (d, 1H H-2 Ph), 8.96 (d, 1H, H-6 pyrid.), 9.26 (s, 1H, H-2 pyrid.), 9.40 (s, 1H, NH), ppm; 13C-NMR (DMSO-d6, 125 MHz) δ 8.55, 10.60, 12.64, 114.16, 119.69, 120.63, 124.29, 125.50, 131.48, 131.85, 132.12, 138.51, 138.78, 144.96, 149.97, 150.13, 152.75, 156.00 ppm; anal. C 47.58, H 3.77, N 15.41% calcd for C18H17Cl2N5O3S, C 47.45, H 3.81, N 15.38%.
4-(4-Butyl-3,5-dimethyl-1H-pyrazol-1-yl)-N-[(4-chlorophenyl)carbamoyl]-3-pyridinesulfonamide (27). Starting from 4-(4-butyl-3,5-dimethyl-1H-pyrazol-1-yl)-3-pyridinesulfonamide (10, 0.31 g), and 4-chlorophenyl isocyanate (0.18 g), the title compound 27 was obtained (0.35 g, 76%): m.p. (EtOAc/Et2O). 138–142 °C ; IR (KBr) νmax 3344 (NH), 3127, (CAr-H), 2947, 2865 (C-H), 1726 (C=O), 1602, 1579, 1541, 1495 (C=C, C=N), 1385, 1164 (SO2) cm−1; 1H-NMR (DMSO-d6, 200 MHz) δ 0.90 (t, 3H, CH3), 1.36 (m, 4H, 2 × CH2), 2.07 (s, 3H, CH3), 2.19 (s, 3H, CH3), 2.36 (t, 2H, CH2), 7.36 (s, 4H, Ph), 7.60 (d, 1H H-5 pyrid.), 8.96 (d, 1H, H-6 pyrid.), 9.25 (s, 1H, H-2 pyrid.), 9.27 (s, 1H, NH), ppm; 13C-NMR (DMSO-d6, 125 MHz) δ 10.61, 12.68, 14.55, 22.46, 23.22, 32.85, 119.09, 121.04, 124.19, 127.66, 129.51, 132.13, 137.50, 138.48, 144.91, 149.77, 149.79, 152.80, 155.88 ppm; anal. C 54.60, H 5.24, N 15.16% calcd for C21H24ClN5O3S, C 54.21, H 5.16, N 14.99%.

3.3. In Vitro Anticancer Screening

Antitumor evaluation of compounds 11, 12, 1421 and 2426 was performed at the National Cancer Institute according to NCI-60 DTP Human Tumor Cell Line Screen procedure [25,26,27,28,29].

4. Conclusions

We have obtained a novel series of 4-substituted N-(R2-phenylcarbamoyl)-3-pyridinesulfonamide derivatives 1127 by the reaction of 4-substituted pyridine-3-sulfonamides 210 with aryl isocyanates in the presence of potassium carbonate. The compounds 11, 12, 1421 and 2426 have been screened in vitro for their anticancer activity at the U.S. National Cancer Institute. We found that many of the investigated compounds exhibited structure-dependent moderate or weak anticancer activity. Considering the structure-activity relationships, we conclude that in general the presence of a 4-chlorophenylcarbamoyl moiety attached to the sulfonamide functionality exerts in most cases a favorable influence on anticancer activity and selectivity of the tested diarylsulfonylurea derivatives 12, 14, 16, 19, 21 and 25. Thus, the most active compound, N-[(4-chlorophenyl)carbamoyl]-4-[4-(3,4-dichlorophenyl)piperazin-1-yl]pyridine-3-sulfonamide (21) exhibited a good activity profile and selectivity toward the subpanels of either leukemia and colon cancer, or melanoma, with average GI50 values ranging from 13.6 to 14.9 µM, and could be considered as a lead compound for further optimization.

Supplementary Materials

Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/20/07/12029/s1.

Acknowledgments

The authors are very grateful to Joel Morris, Chief of Drug Synthesis and Chemistry Branch (DSCB), National Cancer Institute (Bethesda, MD, USA) for the in vitro screening. The publishing fee covering the cost to publish in open access was supported by the Ministry of Science and Higher Education of the Republic of Poland, from the quality promoting subsidy under the Leading National Research Centre (KNOW) programme for the years 2012–2017.

Author Contributions

K.S. carried out the synthesis of all compounds, analyzed spectroscopic and biological data and participated in preparing the text of this manuscript. J.S. created the concept of this work, gained founds, coordinated biological tests and wrote the manuscript together with K.S.

Conflicts of Interest

The authors declare no conflict of interest.

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  • Sample Availability: Samples of the compounds 227 are available from the authors.
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