Diphenylemestrins A−E: diketopiperazine-diphenyl ether hybrids from Aspergillus nidulans

Abstract

A chemical investigation of secondary metabolites (SMs) from Aspergillus nidulans resulted in the identification of five novel dioxopiperazine (DKP)-diphenyl ether hybrids, designated as diphenylemestrins A−E (1−5). These compounds 1−5 represent the first known dimers combining DKP and diphenyl ether structures, with compound 4 featuring an uncommon dibenzofuran as the diphenyl ether component. The structural elucidation and determination of absolute stereochemistry were accomplished through spectroscopic analysis and electronic circular dichroism (ECD) calculations. Notably, diphenylemestrin C (3) exhibited moderate cytostatic activity against NB4 cells, with a half maximal inhibitory concentration (IC₅₀) value of 21.99 μmol·L⁻¹, and induced apoptosis at higher concentrations.

Keywords

Chemical constituents / Biological activity / Aspergillus nidulans / Dioxopiperazines / Structure elucidation

References

[1] Ahuja M, Chiang YM, Chang SL, et al. Illuminating the diversity of aromatic polyketide synthases in Aspergillus nidulans. J Am Chem Soc. 2012; 134(19):8212-8221. https://doi.org/10.1021/ja3016395.

[2] Lin H, Lyu H, Zhou S, et al. Deletion of a global regulator LaeB leads to the discovery of novel polyketides in Aspergillus nidulans. Org Biomol Chem. 2018; 16(27):4973-4976. https://doi.org/10.1039/C8OB01326H.

[3] An CY, Li XM, Luo H, et al. 4-Phenyl-3, 4-dihydroquinolone derivatives from Aspergillus nidulans MA-143, an endophytic fungus isolated from the mangrove plant Rhizophora stylosa. J Nat Prod. 2013; 76(10):1896-1901. https://doi.org/10.1021/np4004646.

[4] Scherlach K, Hertweck C. Discovery of aspoquinolones A-D, prenylated quinoline-2-one alkaloids from Aspergillus nidulans, motivated by genome mining. Org Biomol Chem. 2006; 4(18):3517-3520. https://doi.org/10.1039/B607011F.

[5] An CY, Li XM, Li CS, et al. Aniquinazolines A-D, four new quinazolinone alkaloids from marine-derived endophytic fungus Aspergillus nidulans. Mar Drugs. 2013; 11(7):2682-2694. https://doi.org/10.3390/md11072682.

[6] Lo HC, Entwistle R, Guo CJ, et al. Two separate gene clusters encode the biosynthetic pathway for the meroterpenoids austinol and dehydroaustinol in Aspergillus nidulans. J Am Chem Soc. 2012; 134(10):4709-4720. https://doi.org/10.1021/ja209809t.

[7] Zhang P, Li XM, Li X, et al. New indole-diterpenoids from the algal-associated fungus Aspergillus nidulans. Phytochem Lett. 2015; 12:182-185. https://doi.org/10.1016/j.phytol.2015.03.017.

[8] Bromann K, Toivari M, Viljanen K, et al. Engineering Aspergillus nidulans for heterologous ent-kaurene and gamma-terpinene production. Appl Microbiol Biotechnol. 2016; 100(14):6345-6359. https://doi.org/10.1007/s00253-016-7517-5.

[9] Sanchez JF, Entwistle R, Corcoran D, et al. Identification and molecular genetic analysis of the cichorine gene cluster in Aspergillus nidulans. Med Chem Commun. 2012; 3(8):997-1002. https://doi.org/10.1039/c2md20055d.

[10] Scherlach K, Schuemann J, Dahse HM, et al. Aspernidine A and B, prenylated isoindolinone alkaloids from the model fungus Aspergillus nidulans. J Antibiot. 2010; 63(7):375-377. https://doi.org/10.1038/ja.2010.46.

[11] Yeh HH, Chiang YM, Entwistle R, et al. Molecular genetic analysis reveals that a nonribosomal peptide synthetase-like (NRPS-like) gene in Aspergillus nidulans is responsible for microperfuranone biosynthesis. Appl Microbiol Biotechnol. 2012; 96(3):739-748. https://doi.org/10.1007/s00253-012-4098-9.

[12] Lin TS, Chen B, Chiang YM, et al. Discovery and elucidation of the biosynthesis of aspernidgulenes: novel polyenes from Aspergillus Nidulans by using serial promoter replacement. ChemBioChem. 2019; 20(3):329-334. https://doi.org/10.1002/cbic.201800486.

[13] Oakley CE, Ahuja M, Sun WW, et al. Discovery of McrA, a master regulator of Aspergillus secondary metabolism. Mol Microbiol. 2017; 103(2):347-365. https://doi.org/10.1111/mmi.13562.

[14] Wortman JR, Gilsenan JM, Joardar V, et al. The. 2008 The 2008 update of the Aspergillus nidulans genome annotation: a community effort. Fungal Genet Biol. 2009;46(1,Supplement):S2-S13. https://doi.org/10.1016/j.fgb.2008.12.003.

[15] Cerqueira GC, Arnaud MB, Inglis DO, et al. The Aspergillus genome database: multispecies curation and incorporation of RNA-Seq data to improve structural gene annotations. Nucleic Acids Res. 2014; 42(D1):D705-D710. https://doi.org/10.1093/nar/gkt1029.

[16] Welch TR, Williams RM. Epidithiodioxopiperazines. occurrence, synthesis and biogenesis. Nat Prod Rep. 2014; 31(10):1376-1404. https://doi.org/10.1039/C3NP70097F.

[17] Seya H, Nozawa K, Nakajima S, et al. Studies on fungal products. Part 8. Isolation and structure of emestrin, a novel antifungal macrocyclic epidithiodioxopiperazine from Emericella striata. X-Ray molecular structure of emestrin. J Chem Soc, Perkin trans 1. 1986(0):109-116.

[18] Li Y, Yue Q, Krausert NM, et al. Emestrins: anti-cryptococcus epipolythiodioxopiperazines from Podospora australis. J Nat Prod. 2016; 79(9):2357-2363. https://doi.org/10.1021/acs.jnatprod.6b00498.

[19] Herath KB, Jayasuriya H, Ondeyka JG, et al. Isolation and structures of novel fungal metabolites as chemokine receptor (CCR2) antagonists. J Antibiot. 2005; 58(11):686-694. https://doi.org/10.1038/ja.2005.94.

[20] Onodera H, Hasegawa A, Tsumagari N, et al. MPC1001 and Its analogues: new antitumor agents from the fungus Cladorrhinum species. Org Lett. 2004; 6(22):4101-4104. https://doi.org/10.1021/ol048202d.

[21] Nozawa K, Udagawa SI, Nakajima S, et al. Studies on fungal products. XIV. emestrin B, a new epitrithiodioxopiperazine, from Emericella striata. Chem Pharm Bull. 1987; 35(8):3460-3463. https://doi.org/10.1248/cpb.35.3460.

[22] Li Q, Chen CM, Wei MS, et al. Niduterpenoids A and B: two sesterterpenoids with a highly congested hexacyclic 5/5/5/5/3/ 5 ring system from the fungus Aspergillus nidulans. Org Lett. 2019; 21(7):2290-2293. https://doi.org/10.1021/acs.orglett.9b00581.

[23] Li Q, Chen CM, He Y, et al. Prenylated quinolinone alkaloids and prenylated isoindolinone alkaloids from the fungus Aspergillus nidulans. Phytochemistry. 2020;169:112177. https://doi.org/10.1016/j.phytochem.2019.112177.

[24] Li Q, Zheng YY, Fu AM, et al. 30-norlanostane triterpenoids and steroid derivatives from the endophytic fungus Aspergillus nidulans. Phytochemistry. 2022;201:113257. https://doi.org/10.1016/j.phytochem.2022.113257.

[25] Fu AM, Chen CM, Li Q, et al. Niduenes A-F, six functionalized sesterterpenoids with a pentacyclic 5/5/5/5/ 6 skeleton from endophytic fungus Aspergillus nidulans. Chin Chem Lett. 2024; 35(9): 109100. https://doi.org/10.1016/j.cclet.2023.109100.

[26] Bode HB, Bethe B, Höfs R, et al. Big effects from small changes: possible ways to explore nature’s chemical diversity. ChemBioChem. 2002; 3(7):619-627.3.0.CO;2-9> https://doi.org/10.1002/1439-7633(20020703)3:7<619::AID-CBIC619>3.0.CO;2-9. doi: 10.1002/1439-7633(20020703)3:7<619::AID-CBIC619>3.0.CO;2-.

[27] Hu ZX, Ye Y, Zhang YH. Large-scale culture as a complementary and practical method for discovering natural products with novel skeletons. Nat Prod Rep. 2021; 38(10):1775-1793. https://doi.org/10.1039/D0NP00069H.

[28] Seya H, Nakajima S, Kawai K, et al. 1985; 657-658.

[29] Qi JZ, Wu J, Kang SJ, et al. The chemical structures, biosynthesis, and biological activities of secondary metabolites from the culinary-medicinal mushrooms of the genus Hericium: a review. Chin J Nat Med. 2024; 22(8):676-698. https://doi.org/10.1016/S1875-5364(24)60590-X.

[30] Li XB, Zhou YH, Zhu RX, et al. Identification and biological evaluation of secondary metabolites from the endolichenic fungus Aspergillus versicolor. Chem Biodivers. 2015; 12(4):575-592. https://doi.org/10.1002/cbdv.201400146.

[31] Wang L, Dong JY, Song HC, et al. Screening and isolation of antibacterial activities of the fermentative extracts of freshwater fungi from Yunnan Province, China. Ann Microbiol. 2008; 58(4):579-584. https://doi.org/10.1007/BF03175561.

[32] Wang J, Chen M, Wang M, et al. The novel ER stress inducer Sec C triggers apoptosis by sulfating ER cysteine residues and degrading YAP via ER stress in pancreatic cancer cells. Acta Pharm Sin B. 2022, 12(1): 210-227.

[33] Li Q, Fu A, Wei M, et al. Asperemestrins A-D, emestrin hybrid polymers with bridged skeletons from the endophytic fungus Aspergillus nidulans. Org Lett. 2022; 24(37): 6800-6804. https://doi.org/10.1021/acs.orglett.2c02701.

[34] Zhu H, Chen C, Tong Q, et al. Asperflavipine A: a cytochalasan heterotetramer uniquely defined by a highly complex tetradecacyclic ring system from Aspergillus flavipes QCS12. Angew Chem Int Ed. 2017; 56(19):5242-5246. https://doi.org/10.1002/anie.201701125.

[35] Lin S, He Y, Li F, et al. Structurally diverse and bioactive alkaloids from an insect-derived fungus Neosartorya fischeri. Phytochemistry. 2020;175:112374. https://doi.org/10.1016/j.phytochem.2020.112374.