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Mini-Reviews in Organic Chemistry

Author(s): Bing Liu, Ruiyang Lu, Ning Chen*, Hongliang Yuan, Jintong Zhao and Yuechen Zhao

DOI: 10.2174/1570193X20666230512162559

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Research Progress on Activity and Biosynthesis of Diketopiperazines

Page: [891 - 906] Pages: 16

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Abstract

Diketopiperazines (DKPs) are mainly produced by microorganisms. In recent years, active natural products with DKPs structure have been isolated from marine bacteria, actinomycetes and fungi. The stable six-membered ring framework makes DKPs a vital pharmacophore in medicinal chemistry. Several recent studies have demonstrated that it has antibacterial, antifungal, antiviral, antitumor, immunosuppressive, neuroprotective, anti-malaria, anti-prion, and anti-hyperglycemia properties. Some DKPs are signaling molecules for intercellular communication, which can activate or inhibit bacterial Lux R-mediated quorum sensing. They are considered potential new anti-infective drugs that could control biofilm formation by interfering with information communication between microbes. DKPs possess excellent biological activities and have received extensive attention from medicinal chemistry workers. Bioactivity studies of DKPs have revealed that many highly active lead compounds exist in antibacterial, antitumor, and antiviral fields and in treating neurological disorders. This paper reviews the research progress of diketopiperazines in the past ten years.

Keywords: Diketopiperazines, antibiosis, antiviral, bioactivities, pharmacological activities, biosynthesis.

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[1]
Shaala, L.A.; Youssef, D.T.A.; Badr, J.M.; Harakeh, S.M.; Genta-Jouve, G. Bioactive diketopiperazines and nucleoside derivatives from a sponge-derived Streptomyces species. Mar. Drugs, 2019, 17(10), 584.
[http://dx.doi.org/10.3390/md17100584] [PMID: 31623138]
[2]
Jing, Liu; Lauritz, H.; Yiling, Y. Widely distributed bifunctional bacterial cytochrome P450 enzymes catalyze both intramolecular C-C bond formation in cyclo-l-Tyr-l-Tyr and its coupling with nucleobases. Angewandte Chemie, 2022, 61(21), e202200377.
[3]
Song, Z.; Hou, Y.; Yang, Q.; Li, X.; Wu, S. structures and biological activities of diketopiperazines from marine organisms: A Review. Mar. Drugs, 2021, 19(8), 403.
[http://dx.doi.org/10.3390/md19080403] [PMID: 34436242]
[4]
Blunt, J.W.; Carroll, A.R.; Copp, B.R.; Davis, R.A.; Keyzers, R.A.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep., 2018, 35(1), 8-53.
[http://dx.doi.org/10.1039/C7NP00052A] [PMID: 29335692]
[5]
Manivasagan, P.; Venkatesan, J.; Sivakumar, K.; Kim, S.K. Pharmaceutically active secondary metabolites of marine actinobacteria. Microbiol. Res., 2014, 169(4), 262-278.
[http://dx.doi.org/10.1016/j.micres.2013.07.014] [PMID: 23958059]
[6]
Ding, Z.; Li, F.; Zhong, C.; Li, F.; Liu, Y.; Wang, S.; Zhao, J.; Li, W. Structure-based design and synthesis of novel furandiketopiperazine-type derivatives as potent microtubule inhibitors for treating cancer. Bioorg. Med. Chem., 2020, 28(10), 115435.
[http://dx.doi.org/10.1016/j.bmc.2020.115435] [PMID: 32278711]
[7]
Buedenbender, L.; Grkovic, T.; Duffy, S.; Kurtböke, D.I.; Avery, V.M.; Carroll, A.R. Naseseazine C, a new anti-plasmodial dimeric diketopiperazine from a marine sediment derived Streptomyces sp. Tetrahedron Lett., 2016, 57(52), 5893-5895.
[http://dx.doi.org/10.1016/j.tetlet.2016.11.071]
[8]
Guo, X.C.; Zhang, Y.H.; Gao, W.B.; Pan, L.; Zhu, H.J.; Cao, F. Absolute configurations and chitinase inhibitions of quinazoline-containing diketopiperazines from the marine-derived fungus Penicillium polonicum. Mar. Drugs, 2020, 18(9), 479.
[http://dx.doi.org/10.3390/md18090479] [PMID: 32967228]
[9]
Wang, F.; Sarotti, A.M.; Jiang, G.; Huguet-Tapia, J.C.; Zheng, S.L.; Wu, X.; Li, C.; Ding, Y.; Cao, S. Waikikiamides A–C: Complex diketopiperazine dimer and diketopiperazine–polyketide hybrids from a Hawaiian marine fungal strain Aspergillus sp. FM242. Org. Lett., 2020, 22(11), 4408-4412.
[http://dx.doi.org/10.1021/acs.orglett.0c01411] [PMID: 32433885]
[10]
Bhattacharya, D.; Lai, T.K.; Saha, A.; Selvin, J.; Mukherjee, J. Structural elucidation and antimicrobial activity of a diketopiperazine isolated from a Bacillus sp. associated with the marine sponge Spongia officinalis. Nat. Prod. Res., 2021, 35(14), 2315-2323.
[http://dx.doi.org/10.1080/14786419.2019.1672684] [PMID: 31583909]
[11]
Jin, C. Isolation and characterization of three pairs of indolediketopiperazine enantiomers containing infrequent N-methoxy substitution from the marine algal-derived endophytic fungus Acrostalagmus luteoalbus TK-43 - ScienceDirect. Bioorg. Chem., 2019, 90, 103030.
[12]
Harwoko, H.; Daletos, G.; Stuhldreier, F. Dithiodiketopiperazine derivatives from endophytic fungi Trichoderma harzianum and Epicoccum nigrum. Nat. Prod. Res., 2019, 35(2), 257-265.
[13]
Sangluo, Chen A rare diketopiperazine glycoside from marine-sourced Streptomyces sp. ZZ446. Nat. Prod. Res., 2018.
[PMID: 30580590]
[14]
Meng, L.H.; Wang, C.Y.; Mándi, A.; Li, X.M.; Hu, X.Y.; Kassack, M.U.; Kurtán, T.; Wang, B.G. Three diketopiperazine alkaloids with spirocyclic skeletons and one bisthiodiketopiperazine derivative from the mangrove-derived endophytic fungus Penicillium brocae MA-231. Org. Lett., 2016, 18(20), 5304-5307.
[http://dx.doi.org/10.1021/acs.orglett.6b02620] [PMID: 27723361]
[15]
Canu, N.; Moutiez, M.; Belin, P.; Gondry, M. Cyclodipeptide synthases: A promising biotechnological tool for the synthesis of diverse 2,5-diketopiperazines. Nat. Prod. Rep., 2020, 37(3), 312-321.
[http://dx.doi.org/10.1039/C9NP00036D] [PMID: 31435633]
[16]
Gondry, M.; Jacques, I.B.; Thai, R.; Babin, M.; Canu, N.; Seguin, J.; Belin, P.; Pernodet, J.L.; Moutiez, M. A comprehensive overview of the cyclodipeptide synthase family enriched with the characterization of 32 new enzymes. Front. Microbiol., 2018, 9, 46.
[http://dx.doi.org/10.3389/fmicb.2018.00046] [PMID: 29483897]
[17]
Payne, J.A.E.; Schoppet, M.; Hansen, M.H.; Cryle, M.J. Diversity of nature’s assembly lines – recent discoveries in non-ribosomal peptide synthesis. Mol. Biosyst., 2017, 13(1), 9-22.
[http://dx.doi.org/10.1039/C6MB00675B]
[18]
Yan, L.H.; Li, P.H.; Li, X.M.; Yang, S.Q.; Liu, K.C.; Wang, B.G.; Li, X. Chevalinulins A and B, proangiogenic alkaloids with a spiro[bicyclo[2.2.2]octane-diketopiperazine] skeleton from deep-sea cold-seep-derived fungus Aspergillus chevalieri CS-122. Org. Lett., 2022, 24(14), 2684-2688.
[http://dx.doi.org/10.1021/acs.orglett.2c00781] [PMID: 35389665]
[19]
Liu, Y.; Mándi, A.; Li, X.M.; Meng, L.H.; Kurtán, T.; Wang, B.G. Peniciadametizine A, a Dithiodiketopiperazine with a Unique Spiro[furan-2,7′-pyrazino[1,2-b][1,2]oxazine] Skeleton, and a Related Analogue, Peniciadametizine B, from the Marine Sponge-Derived Fungus Penicillium adametzioides. Mar. Drugs, 2015, 13(6), 3640-3652.
[http://dx.doi.org/10.3390/md13063640] [PMID: 26058014]
[20]
Zhang, P.; Li, X.M.; Wang, J.N.; Wang, B-G. Oxepine-containing diketopiperazine alkaloids from the algal-derived endophytic fungus Paecilomyces variotii EN-291. Helv. Chim. Acta, 2015, 98(6), 800-804.
[http://dx.doi.org/10.1002/hlca.201400328]
[21]
Asiri, I.A.M.; Badr, J.M.; Youssef, D.T.A. Penicillivinacine, antimigratory diketopiperazine alkaloid from the marine-derived fungus Penicillium vinaceum. Phytochem. Lett., 2015, 13, 53-58.
[http://dx.doi.org/10.1016/j.phytol.2015.05.014]
[22]
Meng, L.H.; Zhang, P.; Li, X.M.; Wang, B.G. Penicibrocazines AE, five new sulfide diketopiperazines from the marine-derived endophytic fungus Penicillium brocae. Mar. Drugs, 2015, 13(1), 276-287.
[http://dx.doi.org/10.3390/md13010276] [PMID: 25574740]
[23]
Ye, L.; Sun, K.L.; Yi, W. A cytotoxic pyrrolidinoindoline diketopiperazine dimer from the algal fungus Eurotium herbariorum HT-2. ChemInform, 2013, 24(12), 1049-1052.
[24]
Yamada, K.; Amgad, I.M.K.; Kouno, I. New Diketopiperazine derivatives from culture broth of Staphylococcus sp. Isolated from Corallina officinalis Lineaus. Heterocycles, 2013, 87(5), 1029.
[http://dx.doi.org/10.3987/COM-13-12691]
[25]
Devi, P.; Rodrigues, C.; Naik, C.G.; D’Souza, L. Isolation and characterization of antibacterial compound from a mangrove-endophytic fungus, Penicillium chrysogenum MTCC 5108. Indian J. Microbiol., 2012, 52(4), 617-623.
[http://dx.doi.org/10.1007/s12088-012-0277-8] [PMID: 24293720]
[26]
Zhang, Y-H.; Geng, C.; Zhang, X-W.; Zhu, H.J.; Shao, C.L.; Cao, F.; Wang, C.Y. Discovery of bioactive indole-diketopiperazines from the marine-derived fungus Penicillium brasilianum aided by genomic information. Mar. Drugs, 2019, 17(9), 514.
[http://dx.doi.org/10.3390/md17090514] [PMID: 31480589]
[27]
Li, J.; Hu, Y.; Hao, X.; Tan, J.; Li, F.; Qiao, X.; Chen, S.; Xiao, C.; Chen, M.; Peng, Z.; Gan, M. Raistrickindole A, an anti-HCV oxazinoindole alkaloid from Penicillium raistrickii IMB17-034. J. Nat. Prod., 2019, 82(5), 1391-1395.
[http://dx.doi.org/10.1021/acs.jnatprod.9b00259] [PMID: 31013089]
[28]
Wang, P.; Xi, L.; Liu, P.; Wang, Y.; Wang, W.; Huang, Y.; Zhu, W. Diketopiperazine derivatives from the marine-derived actinomycete Streptomyces sp. FXJ7.328. Mar. Drugs, 2013, 11(12), 1035-1049.
[http://dx.doi.org/10.3390/md11041035] [PMID: 23538868]
[29]
Cai, S.; Kong, X.; Wei, W. Aspergilazine A, a diketopiperazine dimer with a rare N-1 to C-6 linkage, from a marine-derived fungus Aspergillus taichungensis. ChemInform, 2012, 53(21), 2615-2617.
[30]
Wang, M. H.; Zhang, X. Y.; Tan, X. M. Chetocochliodins A-I, Epipoly(thiodioxopiperazines) from Chaetomium cochliodes. J. Nat. Prod., 2020, 83(4), 805-813.
[31]
He, W.; Xu, Y.; Fu, P.; Zuo, M.; Liu, W.; Jiang, Y.; Wang, L.; Zhu, W. Cytotoxic indolyl diketopiperazines from the Aspergillus sp. GZWMJZ-258, endophytic with the medicinal and edible plant Garcinia multiflora. J. Agric. Food Chem., 2019, 67(38), 10660-10666.
[http://dx.doi.org/10.1021/acs.jafc.9b04254] [PMID: 31479263]
[32]
Li, H.; Xu, D.; Sun, W.; Yang, B.; Li, F.; Liu, M.; Wang, J.; Xue, Y.; Hu, Z.; Zhang, Y. HPLC-DAD-directed isolation of linearly fused prenylated indole alkaloids from a soil-derived Aspergillus versicolor. J. Nat. Prod., 2019, 82(8), 2181-2188.
[http://dx.doi.org/10.1021/acs.jnatprod.9b00183] [PMID: 31390200]
[33]
Min, C. Photopiperazines A-D, Photosensitive interconverting diketopiperazines with significant and selective activity against U87 glioblastoma cells, from a rare, marine-derived actinomycete of the family streptomycetaceae. J. Nat. Prod., 82(8), 2262-2267.
[34]
Qin, G.F.; Tang, X.L.; de Voogd, N.J.; Li, P.L.; Li, G.Q. Cytotoxic components from the Xisha sponge Fascaplysinopsis reticulata. Nat. Prod. Res., 2020, 34(6), 790-796.
[http://dx.doi.org/10.1080/14786419.2018.1502765] [PMID: 30445862]
[35]
Zhong, W.; Wang, J.; Wei, X. Variecolortins A–C. Three pairs of spirocyclic diketopiperazine enantiomers from the marine-derived fungus Eurotium sp. SCSIO F452. Organic Letters, 2018.
[36]
Liu, C.C.; Zhang, Z.Z.; Feng, Y.Y.; Gu, Q.Q.; Li, D.H.; Zhu, T.J. Secondary metabolites from Antarctic marine-derived fungus Penicillium crustosum HDN153086. Nat. Prod. Res., 2019, 33(3), 414-419.
[http://dx.doi.org/10.1080/14786419.2018.1455045] [PMID: 29600717]
[37]
Li, F.; Guo, W.; Wu, L.; Zhu, T.; Gu, Q.; Li, D.; Che, Q. Saroclazines A–C, thio-diketopiperazines from mangrove-derived fungi Sarocladium kiliense HDN11-84. Arch. Pharm. Res., 2018, 41(1), 30-34.
[http://dx.doi.org/10.1007/s12272-017-0961-7] [PMID: 29103141]
[38]
Gao, N.; Shang, Z.C.; Yu, P.; Luo, J.; Jian, K-L.; Kong, L-Y.; Yang, M-H. Alkaloids from the endophytic fungus Penicillium brefeldianum and their cytotoxic activities. Chin. Chem. Lett., 2017, 28(6), 1194-1199.
[http://dx.doi.org/10.1016/j.cclet.2017.02.022]
[39]
Ye, X.; Chai, W.; Xiao, Y.L. Novel propanamide analogue and antiproliferative diketopiperazines from mangrove Streptomyces sp. Q24. Nat. Prod. Res., 2017, (12), 1390-1396.
[PMID: 27806640]
[40]
Gu, B.; Zhang, Y.; Ding, L. Preparative separation of sulfur-containing diketopiperazines from marine fungus Cladosporium sp using high-speed counter-current chromatography in stepwise elution mode. Mar Drugs., 2015, 13(1), 354-365.
[41]
Peng, Jixing Okaramines S-U, three new indole diketopiperazine alkaloids from Aspergillus taichungensis ZHN-7-07. Tetrahedron, 2015.
[42]
Gao, H.; Zhu, T.; Li, D. Prenylated indole diketopiperazine alkaloids from a mangrove rhizosphere soil derived fungus Aspergillus effuses H1-1. Arch. Pharm. Res., 2013, 36(8), 952-956.
[43]
Gao, H.; Liu, W.; Zhu, T.; Mo, X.; Mándi, A.; Kurtán, T.; Li, J.; Ai, J.; Gu, Q.; Li, D. Diketopiperazine alkaloids from a mangrove rhizosphere soil derived fungus Aspergillus effuses H1-1. Org. Biomol. Chem., 2012, 10(47), 9501-9506.
[http://dx.doi.org/10.1039/c2ob26757h] [PMID: 23111956]
[44]
Wang, F.Z.; Huang, Z.; Shi, X.F.; Chen, Y.C.; Zhang, W.M.; Tian, X.P.; Li, J.; Zhang, S. Cytotoxic indole diketopiperazines from the deep sea-derived fungus Acrostalagmus luteoalbus SCSIO F457. Bioorg. Med. Chem. Lett., 2012, 22(23), 7265-7267.
[http://dx.doi.org/10.1016/j.bmcl.2012.08.115] [PMID: 23079524]
[45]
Huiling wen a-b-Xiaorui-Liu-a-Qing-Zhang-a-Yanfang-Deng-a-Yi-Zang-a-Jianping-Wang-a-Junjun-Liu-a-Qun-Zhou-a-Linzhen-Hu-c-Hucheng-Zhu-a-Chunmei-Chen-*a-and-Yonghui-Zhang*a. Three New Indole Diketopiperazine Alkaloids from Aspergillus ochraceus. Chem. Biodivers., 2018.
[46]
Yang, L.; Mahal, A.; Liu, Y.; Li, H.; Wu, P.; Xue, J.; Xu, L.; Wei, X. Two new 2,5-diketopiperazines produced by Streptomyces sp. SC0581. Phytochem. Lett., 2017, 20, 89-92.
[http://dx.doi.org/10.1016/j.phytol.2017.04.012]
[47]
Zou, X. A new prenylated indole diketopiperazine alkaloid from Eurotium cristatum. Molecules, 2014, 19(11), 17839-17847.
[48]
Kong, X.; Cai, S.; Zhu, T.; Gu, Q.; Li, D.; Luan, Y. Secondary metabolites of a deep sea derived fungus Aspergillus versicolor CXCTD-06-6a and their bioactivity. J. Ocean Univ. China, 2014, 13(4), 691-695.
[http://dx.doi.org/10.1007/s11802-014-2216-2]
[49]
Hwang, I.H.; Che, Y.; Swenson, D.C.; Gloer, J.B.; Wicklow, D.T.; Peterson, S.W.; Dowd, P.F. Haenamindole and fumiquinazoline analogs from a fungicolous isolate of Penicillium lanosum. J. Antibiot., 2016, 69(8), 631-636.
[http://dx.doi.org/10.1038/ja.2016.74] [PMID: 27328870]
[50]
Guo, X.; Liu, X.; Pan, J.; Yang, H. Synergistic algicidal effect and mechanism of two diketopiperazines produced by Chryseobacterium sp. strain GLY-1106 on the harmful bloom-forming Microcystis aeruginosa. Sci. Rep., 2015, 5(1), 14720.
[http://dx.doi.org/10.1038/srep14720] [PMID: 26423356]
[51]
Gao, C.; Lin, L.; Long, B.; Chen, Y.; He, B.; Sun, H.; Huang, R. A new diketopiperazine from the gorgonian coral Menella kanisa. Nat. Prod. Res., 2014, 28(7), 473-476.
[http://dx.doi.org/10.1080/14786419.2013.879134] [PMID: 24479814]
[52]
Zhang, Q.; Wang, S.Q.; Tang, H.Y.; Li, X.J.; Zhang, L.; Xiao, J.; Gao, Y.Q.; Zhang, A.L.; Gao, J.M. Potential allelopathic indole diketopiperazines produced by the plant endophytic Aspergillus fumigatus using the one strain-many compounds method. J. Agric. Food Chem., 2013, 61(47), 11447-11452.
[http://dx.doi.org/10.1021/jf403200g] [PMID: 24188331]
[53]
Cai, R.; Jiang, H.; Xiao, Z.; Cao, W.; Yan, T.; Liu, Z.; Lin, S.; Long, Y.; She, Z. (−)- and (+)-Asperginulin A, a pair of indole diketopiperazine alkaloid dimers with a 6/5/4/5/6 pentacyclic skeleton from the mangrove endophytic fungus Aspergillus sp. SK-28. Org. Lett., 2019, 21(23), 9633-9636.
[http://dx.doi.org/10.1021/acs.orglett.9b03796] [PMID: 31762277]
[54]
He, F.; Han, Z.; Peng, J.; Qian, P.Y.; Qi, S.H. Antifouling indole alkaloids from two marine derived fungi. Nat. Prod. Commun., 2013, 8(3), 1934578X1300800.
[http://dx.doi.org/10.1177/1934578X1300800313] [PMID: 23678803]
[55]
Wei, X.; Su, J-C.; Hu, J-S.; He, X.X.; Lin, S.J.; Zhang, D.M.; Ye, W.C.; Chen, M.F.; Lin, H.W.; Zhang, C.X. Probing indole diketopiperazine-based hybrids as environmental-induced products from Aspergillus sp. EGF 15-0-3. Org. Lett., 2022, 24(1), 158-163.
[http://dx.doi.org/10.1021/acs.orglett.1c03795] [PMID: 34898224]
[56]
Liu, H.; Fan, J.; Zhang, P.; Hu, Y.; Liu, X.; Li, S.M.; Yin, W.B. New insights into the disulfide bond formation enzymes in epidithiodiketopiperazine alkaloids. Chem. Sci., 2021, 12(11), 4132-4138.
[http://dx.doi.org/10.1039/D0SC06647H] [PMID: 34163685]
[57]
Li, H.; Mirzayans, P.M.; Butler, M.S.; Lacey, A.E.; Vuong, D.; Chen, R.; Kalaitzis, J.A.; Moggach, S.A.; Lacey, E.; Piggott, A.M.; Chooi, Y.H. Discovery of brevijanazines from Aspergillus brevijanus reveals the molecular basis for p -nitrobenzoic acid in fungi. Chem. Commun., 2022, 58(43), 6296-6299.
[http://dx.doi.org/10.1039/D2CC01679F] [PMID: 35537125]