Structures and Biological Activities of Diketopiperazines from Marine Organisms: A Review

Diketopiperazines are potential structures with extensive biological functions, which have attracted much attention of natural product researchers for a long time. These compounds possess a stable six-membered ring, which is an important pharmacophore. The marine organisms have especially been proven to be a wide source for discovering diketopiperazine derivatives. In recent years, more and more interesting bioactive diketopiperazines had been found from various marine habitats. This review article is focused on the new 2,5-diketopiperazines derived from marine organisms (sponges and microorganisms) reported from the secondary half-year of 2014 to the first half of the year of 2021. We will comment their chemical structures, biological activities and sources. The objective is to assess the merit of these compounds for further study in the field of drug discovery.


Introduction
The 2,5-diketopiperazines (DKPs), the smallest cyclic dipeptides from the double condensations of two α-amino acids, are abundant in nature and possess a six-membered piperazine rigid backbone [1,2]. The formation of two peptide bonds in DKPs are catalyzed by two major enzymes, the nonribosomal peptide synthetases (NRPSs, >100 kDa) and cyclodipeptide synthases (CDPSs, 30 kDa) [3]. These three-dimensional molecular skeletons carry different substituents, which overcome the planar limitations of most conventional drugs and play an important role in drug discovery [4]. Recently, the interest in DKPs is still high because they have not only antimicrobial, antitumor and antiviral activities [5], but also a relatively rare treatment of ischemic brain injury [6], quorum-sensing signaling [7,8], anti-Alzheimer [9], inhibition of microtubule polymerization [10] and haemosuppressor activity [11].
Bicyclomycin is a classic DKP antibiotic that has been used to treat diarrhea in humans and bacterial diarrhea in calves and pigs and it is also a rho (a member of the RecA-type ATPase) inhibitor [12][13][14]. Chaetocin is a specific DKP dimer containing sulfurs as the first inhibitor of a lysine-specific histone methyltransferase SU(VAR)3-9, which could reduce the H3 isoform trimethylated at the Lys9 (H3K9me3) level and this compound has also been reported to have potent antimyeloma activity [15][16][17]. Recently, chaetocin is proved to be able to increase the efficiency of the efficient epigenetic reprogramming via reducing the aberrant level of H3K9me3 to enhance the developmental competence of porcine somatic cell nuclear transfer embryos. It promotes osteogenic differentiation in mesenchymal stem cells [16,18,19]. Plinabulin (formerly named as NPI-2358), a marine-derived DKP, is currently in a phase 3 trial in combination with docetaxel in non-small cell lung cancer (NCT02504489) [20][21][22]. In addition, some DKPs possess an ability to cross the blood-brain barrier via a passive diffusion process as an ideal candidate for new therapeutic agents for brain diseases [23,24]. As of August 2012, there are approximately 150 global patents related to DKPs and its derivatives, and DKPs are present in nearly 50 bio-complexes in the Research Collaboratory for the Structural Bioinformatics Protein Data Bank [25,26]. DKPs are diamonds in the rough and have huge potential in future therapies.
There have been several reviews reported on DKPs until now. Cao et al. summarized chemical diversity and the biological function of indolediketopiperazines from marinederived fungi [27]. Gomes et al. summed up marine-derived DKP dimers with their structures and biological activity [28]. From 1972 to the first half of the year of 2014, 214 DKPs from marine sources have been reported [5,29]. However, there is no relevant review for summarizing the comprehensive DKPs from a marine source from 2014 to now. On this basis, we now summarize a total of 241 marine-derived DKPs from the second half of 2014 to the first half of 2021 in this paper. In addition, a total of 55 marine-derived variable DKP derivatives from 2011 to the first half of 2021 are also summarized here.

Sponge
Cyclo-(R-Pro-6-hydroxyl-S-Ile) (1) was a new DKP isolated from the sponge Callyspongia sp., which was collected from the South China Sea. Compound 1 showed no antibacterial activity against the tested Bacillus subtilis, Staphylococcus aureus and Escherichia coli [30]. Geobarrettins A (2) and B (3), two new DKPs, were obtained from the sub-Arctic sponge Geodia barrette, which was collected at the west of Iceland (-388 m). Before coculturing with allogeneic CD4 + T cells, the maturing human dendritic cells (DCs) were processed by compound 3 with a dose of 10 µg/mL and then reduced the IFN-γ of T cell secretion. Compound 3 had no effect on the DCs secretion of IL-10 but induced the IL-12p40. This above data demonstrated that compound 3 possessed an overall anti-inflammatory activity and may be used to treat the Th1 type inflammation [31]. A novel sulfur-containing DKP, tedanizaine A (4), was collected from the marine sponge Tedania sp. at a depth of 10 m in Zhanjiang, Guangdong province. Compound 4 bearing a thiazolidine unit was separated by integrating molecular networking and became the second example of thiodiketopiperazine. However, the evaluation of cytotoxicity activities did not reveal the inhibitory activity of compound 4 on the growth of the tested A549 (lung carcinoma) and RAW 246.7 (macrophage) cell lines [32]. (−)-Cyclo(L-trans-Hyp-L-Ile) (5) was a new DKP isolated from the marine sponge Axinella sinoxea, collected from a reef habitat around Larak Island, Persian Gulf. Compound 5 had no influence on methicillin-resistant Staphylococcus aureus (MRSA) in the dose of 100 µg/mL [33]. All 5 DKPs from sponge described above are presented in Figure 1.

Actinomycetes
A novel DKP, iso-naseseazine B (18), was isolated from the medium of Streptomyces sp. SMA-1 from the marine sediment of the Yellow Sea, China. Compound 18 could oppose the fluconazole-resistant C. albicans and the diameter of the inhibition zone was 9 mm [39]. The other Streptomyces sp. USC-636 strain was collected from marine sediment in Sunshine Coast, QLD, Australia. Naseseazine C (21) was extracted from the culture of this strain, which exhibited a novel C-6'/C-3 linkage between the two DKP subunits and possessed the activity of antiplasmodial with an IC 50 value of 3.52 µM. However, the analog naseseazines A (19) and B (20) inhibited the malaria parasite at a dose of 20 µM. The special linkage between C-6 and C-3 may be critical to increase bioactivity [40]. (6R,3Z)-3benzylidene-6-isobutyl-1-methyl piperazine-2,5-dione (22), a new DKP, was produced by the Streptomyces sp. strain SCSIO 04496, which was collected from a deep-sea sediment sample of the South China Sea [41]. ∆marF, the methyltransferase gene of maremycins, knockout in strain Streptomyces sp. B9173 (collected from the pacific coast of Chile) obtained the mutant LS26. Six new demethylmaremycins (23)(24)(25)(26)(27)(28) were isolated from the mutant LS26, however, the specific name of these compounds could not be found [42]. Streptomyces sp. MNU FJ-36 was collected from the Katsuwonus sp. intestinal fabric. Three novel  [43]. A novel DKP glycosidem, maculosin-O-α-L-rhamnopyranoside (32), was discovered from the Streptomyces sp. ZZ446, which was collected in coastal soil from Zhoushan Islands, Zhejiang Province. Compound 32 possessed antimicrobial activity against MRSA, E. coli and C. albicans with MIC values of 37, 28 and 26 µg/mL, respectively [44,45]. Actinozine A (33) was a new DKP, which was isolated from the Streptomyces species Call-36 from the Red Sea sponge Callyspongia species. Compound 33 exhibited a moderate antimicrobial activity against S. aureus and C. albicans with inhibition zones of 23 and 19 mm at 100 µg/disc, respectively, and showed a weak activity for the HCT-116 (IC 50 = 146 µM) and MCF-7 (breast cancer, IC 50 = 88.8 µM) cell lines [46]. Streptomyces sp. SY1965 was collected from the Mariana Trench sedimentassociated at a depth of 11,000 m and two new DKPs, streptodiketopiperazines A (34) and B (35) were isolated from the strain. The crude extraction of this strain from the Gauze's liquid medium with sea salt could suppress the human glioma U87MG and U251 cells with an inhibition rate of over 100%. Both compounds 34 and 35 exhibited antifungal activity against C. albicans with a MIC value of 42 µg/mL [47].
A novel DKP, cyclo-(4-trans-6-dihydroxy-proline-D-leucine) (36), was discovered from the Microbulbifer variabilis C-03, which isolated from the Palythoa tuberculosa in the intertidal zone of Wanlitong [48]. One novel DKP namely nocarazepine A (37) was isolated from the Nocardiopsis alba collected from the gorgonian Anthogorgia caerulea, which was sampled from the coast of Xieyang Island, Guangxi Province [49]. Strain AJS-327 was a rare actinomycete (maybe a new linkage within Streptomycetaceae) and collected from the sponge fragment on the beach from La Jolla, CA. It was proved to be a likely novel species because it exhibited an extremely poor 16S rRNA sequence similarity to other members of the actinomycete family Streptomycetaceae. Four new DKPs, photopiperazines A-D (38-41), were isolated from this strain. The olefin geometrical isomers of these four compounds could be interconverted under light conditions, on account of the photopiperazines being sensitive to light. In terms of activity, the mixture of four compounds included compounds 38 (33.5%), 39 (39.7%), 40 (8.4%) and 41 (18.4%). This mixture exhibited a remarkable activity to the cancer cell of U87 (glioblastoma brain cancer), SHOV3 (ovarian cancer), MDA-MB-231(breast cancer) and HCT116 (human colon carcinoma) with IC 50 values of 1.2 × 10 −4 , 2.2 × 10 −4 , 1.6 and 1.6 µg/mL, respectively [50]. Cyclo-(D-8-acetoxyl-Pro-L-Leu) (42) was a novel DKP isolated from Treptomyces sp. SCSIO 41400, which was obtained from a mangrove derived-soil from the Fuli Mangrove Bay Wetland Park, Haikou, Hainan Province of China. Compound 42 could anchor in the binding site of the pancreatic lipase (PL) enzyme and then prevent the substrate from entering and inhibit the PL enzyme activity with an IC 50 value of 27.3 µg/mL [51]. All 25 DKPs from the actinomycetes described above are presented in Figure 2.   (58) and fumitremorgin C (59) were isolated from A. alternate HK-25 and first discovered from fungi. Purities of these compounds were all above 94% [54,55].
Haenamindole (60)  the fungus Aspergillus versicolor MF180151, which was collected from a sediment in Bohai Sea, China. However, these compounds showed no antimicrobial activities [66].
Raistrickindole A (92), a novel DKP containing indole tetraheterocyclic ring system, was discovered from the fungus Penicillium raistrickii IMB17-034 obtained from a mangrove swamp sediment in Sanya, Hainan Province, China. Compound 92 exhibited the inhibitory activity against hepatitis C virus (HCV) with the EC 50
One novel DKP dimer (155) possessing the same planar structure and different stereochemistry with an unnamed and ambiguous compound was isolated from the fungus Aspergillus violaceofuscus, which was collected from sponge Reniochalina sp. from Xisha Islands in the South China Sea. In a dose of 10 µM, compound 155 exhibited anti-inflammatory activity via decreasing LPS-induced expression of IL-10 in THP-1 cells with inhibitory rates of 78.1% [80]. Waspergillamide B (156), a new DKP containing an unusual p-nitrobenzoic acid structure, was obtained from the fungus Aspergillus ochraceus collected from the sponge Agelas oroides from the Mediterranean. Compound 156 had no cytotoxic activity against A2780 (human ovarian carcinoma) cell lines [81]. One new DKP alkaloid namely penicillivinacine (157) was obtained from the fungus Penicillium vinaceum that was isolated from the marine sponge Hyrtios erectus from Yanbu. Compound 157 exhibited significant cytotoxicity activity against MDA-MB-231 cell lines with an IC 50 value of 18.4 µM [82]. Adametizines A (158) and B (159), two novel sulfur-containing DKPs, were separated from the fungus Penicillium adametzioides AS-53, which was isolated from an unidentified marine sponge collected from Hainan Island of China. Compound 158 could inhibit the growth of brine shrimp (A. salina) with the LD 50 (lethal dose 50%) value of 4.8 µM. In addition, compound 158 showed antimicrobial activities against Staphylococcus aureus, Aeromonas hydrophilia and V. parahaemolyticus with an MIC value of 8 µg/mL and compound 159 showed antimicrobial activities against S. aureus with an MIC value of 64 µg/mL. These results revealed that the Cl substitution at C-7 remarkably increased the brine shrimp lethality and antimicrobial activity [83]. SF5280-415 (160) was a novel DKP dimer and isolated from the fungus Aspergillus sp. SF-5280, which was obtained from an unidentified sponge at Cheju Island, Korea. Compound 160 showed enzyme inhibitory activity against the PTP1B enzyme with an IC 50 value of 14.2 µM [84]. All 14 DKPs from sponge-derived fungi described above are presented in Figure 5.
Waikikiamides The reason for the difference in activity was that compounds 163 and 165 possessed an N-O bond but compound 164 did not [87]. All 5 DKPs from fungi of beach origin described above are presented in Figure 5.

Fungi from Mangrove Origin
A new DKP namely 5S-hydroxynorvaline-S-Ile (166), together with two firstly discovered in nature namely 3S-hydroxylcyclo(S-Pro-S-Phe) (167) and cyclo(S-Phe-S-Gln) (168), were obtained from mangrove endophytic fungus Penicillium sp. GD6, which was isolated from the stem bark of Bruguiera gymnorrhiza collected from Zhanjiang, China. These compounds showed no activity against the tested MRSA [88]. (−)-asperginulin A (169) and (+)-asperginulin A (170), two dimers DKPs that contained enantiomeric indole, were isolated from the mangrove endophytic fungus Aspergillus sp. SK-28, which was obtained from Kandelia candel from the Shankou Mangrove Nature Reserve in Guangxi Province, China. Compound 170 could inhibit the growth of the barnacle Balanus reticulatus with antifouling activity and low toxicity [89]. Three novel DKPs, saroclazines A-C (171-173), were isolated from the fungus Sarocladium kiliense HDN11-84, which was obtained from a root soil sample of mangrove Thespesia populnea from Guangxi Province, China.  [91,93]. These results showed that compounds possessing two double bonds at C-6 and C-6 or one double bond at C-6/6 conjugating with a keto group at C-5/5 might exhibit higher cytotoxic or antimicrobial activity. All 23 DKPs from mangrove-derived fungi described above are presented in Figure 6.

Fungi from Other Origin
One novel DKP namely isoechinulin D (230) was isolated from the marine fungus Eurotium rubrum MPUC136, which was collected from the seaweed in Chosei-mura, Choseigun, Chiba Prefecture, Japan, and showed weak inhibitory activity against melanin synthesis with an IC 50 value of 60 µM. [108]. Spirotryprostatin G (231), cyclotryprostatins F (232) and G (233), three new DKPs alkaloids, were isolated from the fungus Penicillium brasilianum HBU-136 separated from the Bohai Sea. Compound 231 showed excellent cytotoxic activity against HL-60 cell lines with an IC 50 value of 6.0 µM and compounds 232 and 233 exhibited remarkable cytotoxic activity against MCF-7 cell lines with IC 50 values of 7.6 and 10.8 µM, respectively [109]. A new DKP alkaloid namely penilline C (234) was obtained from the fungus Penicillium chrysogenum SCSIO 07007, which was isolated from a deep-sea hydrothermal vent environment sample of Western Atlantic [110]. Emestrins L (235) and M (236), two novel DKPs, were separated from the fungus Aspergillus terreus RA2905, which was obtained from the sea hare Aplysia pulmonica from the Weizhou coral reefs in the South China Sea. Compound 236 showed antifungal activity against P. aeruginosa ATCC 27853 with the MIC value of 64 µg/mL [111].
Aspamides A-D (237-240), four novel DKPs alkaloids, were separated from the endophyte fungus Aspergillus versicolor DY180635, which was isolated from the sea crab Chiromantes haematocheir from the intertidal zone of Zhoushan, Zhejiang, China. For the virtual screening on the 3CL hydrolase (Mpro) of SARS-CoV-2 (potential drug target to fight COVID-19), the docking scores of compounds 237 and 238 were −5.389 and −4.772, respectively, and the score of positive control ritonavir was −7.039. In the future, these two compounds may be helpful in fighting COVID-19 [112]. One novel DKP namely penicillatide B (241) was isolated from the fungus Penicillium sp., which was collected from the Red Sea tunicate Didemnum sp. Compound 241 showed moderate cytotoxic activity against the HCT-116 cell lines with an IC 50 value of 23.0 µM and exhibited modest antimicrobial activities against S. aureus and V. anguillarum with inhibition zones of 19 and 20 mm, respectively [113]. All 12 DKPs from fungi sourced from other origins described above are presented in Figure 7.

Chemical Structures of Diketopiperazine Derivatives from Marine Organisms
Diketopiperazine derivatives are further modified on the basis of the six-membered piperazine rigid backbone. The following 54 DKP derivatives were described in this paper, of which 53 lacked a carbonyl group and 1 lacked two carbonyl groups in the skeleton ( Table 2).

Actinomycetes
A mixture of two new tautomers DKP derivatives named isomethoxyneihumicin (242 and 243) were obtained from the actinomycete Nocardiopsis alba KM6-1, which was collected from marine sediment in Chichijima, Ogasawara, Japan. The mixture showed excellent cytotoxic activity against Jurkat cell lines with the IC 50 value of 6.98 µM and in a dose of 15 µM, compounds 242 and 243 made the cell cycle of Jurkat cell lines staying in the G2/M phase with the inhibition ratio of 66% in 12 h. These consequences indicated that the mixed compounds inhibited the growth of Jurkat cell lines via arresting the cell cycle at the G2/M phase [114]. Two novel DKP derivatives namely nocazines A (244) and B (245) were isolated from Nocardiopsis dassonvillei HR10-5, which was obtained from marine sediment in the estuary of Yellow River, Dongying, China. However, compounds 244 and 245 did not exhibit cytotoxic or antimicrobial activities for the tested cancer cell lines and microorganisms [115].
Nocazines  [44]. One novel tricyclic DKP derivative namely strepyrazinone (252) was obtained from Streptomyces sp. B223, which was isolated from the marine sediment of Laizhou Bay. Compound 252 displayed remarkable cytotoxic activity against the HCT-116 cell lines with the IC 50 value of 0.34 µM [117]. All 11 DKP derivatives from actinomycetes described above are presented in Figure 8.

Fungi
Varioloids A (253) and B (254) were two novel oxepine-containing DKP derivatives and obtained from the endophytic fungus Paecilomyces variotii EN-291, which was collected from red alga Grateloupia turuturu on the coast of Qingdao. Compounds 253 and 254 showed significant antimicrobial activities against F. graminearum with the MIC values of 8 and 4 µg/mL, respectively. In addition, compounds 253 and 254 also inhibited the growth of A. hydrophila, E. coli, M. luteus, S. aureus, V. anguillarum, V. harveyi and V. parahaemolyticus with the MIC values in the range of 16-64 µg/mL [118]. Four novel oxepine-containing DKP derivatives namely oxepinamides H−K (255-258) and four novel 4-quinazolinone DKP derivatives namely puniceloids A−D (259-262) were isolated from the fungus Aspergillus puniceus SCSIO z021, which was collected from deep-sea sediment in Okinawa Trough.  Protuboxepins C (263) and D (264), two novel oxepin-containing DKP derivatives, were obtained from the fungus Aspergillus sp. SCSIO XWS02F40, which was isolated from the sponge Callyspongia sp. from the sea area near Xuwen County, Guangdong Province, China. Compounds 263 and 264 showed moderate cytotoxic activities against Hela cell lines with the IC 50 values of 61 and 114 µM, respectively [120,121]. Pyranamides A−D (265-268), secopyranamide C (269) and protuboxepins F−J (270-274), ten novel DKP derivatives, were isolated from the marine sponge-derived fungus Aspergillus versicolor SCSIO 41016, which was also separated from Callyspongia sp. Compound 270 showed modest cytotoxic activities against the ACHN, OS-RC-2 and 786-O cell lines (three renal carcinoma cell lines) with the IC 50 values of 27, 34.9 and 47.1 µM, respectively [122]. Chrysopiperazines A-C (275-277) were three new DKP derivatives and obtained from the fungus Penicillium chrysogenum, which was collected from gorgonian Dichotella gemmacea in South China Sea. The oxepine-containing DKPs were found from the genus Penicillium for the first time [123]. One novel DKP derivative namely quinadoline D (278) was isolated from the fungus Penicillium sp. L129, which was collected from the rhizosphere-soil of Limonium sinense (Girald) Kuntze from Yangkou Beach, Qingdao, China [124]. Two novel DKP derivatives namely aspamides F (279) and G (280) were isolated from the endophyte fungus A. versicolor DY180635. For the virtual screening on the 3CL hydrolase of SARS-CoV-2, the docking scores of compounds 279 and 280 were −5.146 and −4.962, respectively [112].
Three novel DKP derivatives namely 3-hydroxyprotuboxepin K (286), 3,15-dehydroprotuboxepin K (287) and versiamide A (288) were isolated from the fungus Aspergillus creber EN-602 derived from marine red alga Rhodomela confervoides on the coast of Qingdao, China. Compound 286 showed enzyme inhibitory activity against the angiotensin converting enzyme with the IC 50 value of 22.4 µM. In addition, compound 287 exhibited antimicrobial activities against Edwardsiella tarda, E. coli, M. luteus, P. aeruginosa and V. harveyi with the MIC values in the range of 8-64 µg/mL and compound 288 exhibited antimicrobial activities against A. hydrophila, E. coli, M. luteus and P. aeruginosa with the MIC values between 16 and 64 µg/mL [128]. Protuboxepins A (289) and B (290) were two novel oxepincontaining DKP derivatives and were isolated from the fungus Aspergillus sp. SF-5044, which was collected from the intertidal sediment from Dadaepo Beach, Busan, Korea. Compound 289 exhibited weak cytotoxic activities against HL-60, MDA-MB-231, Hep3B (human liver carcinoma), 3Y1 and K562 cell lines with the IC 50 values of 75, 130, 150, 180 and 250 µM, respectively. Compound 289 possessed a disrupting microtubule dynamics ability and induced apoptosis in cancer because it could bind to α,β-tubulin and stabilize tubulin polymerization and then leading to chromosome misalignment and metaphase arrest in cancer [129,130].

Characteristics of Bioactive Diketopiperazines and Their Derivatives from Marine Organisms
In this review, 241 DKPs and 54 DKP derivatives isolated from marine organisms were summarized, among which fungi and actinomycetes were the most abundant sources. These marine organisms come from a wide range of sources and the red dots ( Figure 9) and yellow dots ( Figure 10) represent the collection points for marine biological samples, which produced DKPs and DKP derivatives, respectively. DKPs and DKP derivatives of fungi sources were 199 (82.6%) and 43 (79.6%), respectively, and those of actinomycetes sources were 25 (10.4%) and 11 (20.4%), respectively (Figure 11a,b). In addition, DKPs of sponge and bacteria sources were 5 (2.1%) and 12 (5%), respectively (Figure 11a).   These DKPs had antimicrobial (20,18.3%), cytotoxic (39,35.8%), enzyme inhibition (5, 4.6%), antiviral (14, 12.8%), antioxidant (11,10.1%) and other activities (20,18.3%) (Figure 11c). Furthermore, these DKP derivatives also had antimicrobial (9, 30%), cytotoxicity (9, 30%), enzyme inhibition (5, 16.7%) activities and a possessed transcriptional activation (7, 23.3%) effect (Figure 11d). Subtle differences in chemical structures are closely related to the bioactivity. For example, compound 96 possessing a unique disulfide bridge in the six-membered piperazine skeleton showed much more significant cytotoxic activity than compounds 93-95, 97 and 98. Compounds 163 and 165 exhibited remarkable antiproliferative activities but compound 164 was inactive, which indicated that the N-O bond played an important role for their bioactivity. In addition, the absolute configurations might be closely associated with the activity intensity. For instance, the antioxidant activity of compounds 144 (IC 50 = 37 µM) and 145 (IC 50 = 69 µM) were relevant to the absolute configurations of C-2 and C-3. Different substituents in the same chemical skeleton may lead to different activities. For example, compound 158 bearing a Cl atom at C-7 exhibited stronger antimicrobial and brine shrimp inhibition activity than compound 159.

Conclusions
In recent years, the number of papers and patents related to DKPs is on the rise continuously and many novel DKPs had been isolated from marine sources. More and more researchers are turning their attention to the six-membered ring rigid structure with great potential for biological activity. It is a heterocyclic scaffold with restricted conformation, which can control stereochemistry at up to four positions. These features provide its potential to break the planarity of traditional drugs. Natural DKPs have more interesting structural complexity and biological characteristics and possibly can be further chemically synthesized or modified to increase their activity, promoting the natural product and synthetic chemistry to complement each other. In addition, DKPs can be used as the quorum sensing signal molecule of Shewanella baltica (a kind of unique microorganism produced during transporting the large yellow croaker at 4 • C) and inhibiting the production of DKPs can slow down the spoilage of the large yellow croaker [7]. Furthermore, thaxtomin A has good herbicidal activity and achieves an herbicidal purpose by inhibiting cellulose synthesis [133]. With the tremendous advancement of technology, the known compound can be initially eliminated through the Global Natural Products Social (GNPS) molecular networking project [134]. It would be helpful for targeting directly to discover new natural DKPs and further enrich the library of DKPs.
To sum up, DKPs are potential bioactive chemical substances that are valuable for further exploration from natural sources, especially from marine environments. The conversion of promising bioactive DKPs into clinical drugs for the treatment of diseases needs much more time and energy for researchers. DKPs are regarded as unprocessed diamonds, attracting scientists to take efforts to study their pharmacological properties and therapeutic effects.