New meroterpenoids featuring a rare 3/5/6/6/11/6/6 fused-ring skeleton from Penicillium brefeldianum SMU03 and their antifibrotic activities

Abstract

Penicine A (1), a meroterpenoid featuring a novel 3/5/6/6/11/6/6 polycyclic backbone, together with two new metabolites, penicines B (2) and C (4), and six known compounds, were isolated from the mangrove rhizosphere soil-derived fungus Penicillium brefeldianum SMU03. The structures of these metabolites were elucidated through extensive spectroscopic analysis combined with quantum chemical calculations. Notably, 1 exhibits a highly unusual molecular architecture, incorporating a dioxaspiro[4.5]decane motif and a rare bridgehead double bond (anti-Bredt system). A plausible biosynthetic pathway, involving sequential intermolecular [4 + 2] cycloaddition reactions, is proposed. Additionally, meroterpenoids 1 and 3 demonstrate significant antifibrotic activity in transforming growth factor β1 (TGF-β1)-induced human renal proximal tubular epithelial cells.

Keywords

Penicillium brefeldianum SMU03 / Meroterpenoid / Antifibrotic activity / Plausible biosynthetic pathway

References

[1] Cheng X, Liang X, Zheng ZH, et al. Penicimeroterpenoids A-C, meroterpenoids with rearrangement skeletons from the marine-derived fungus Penicillium sp. SCSIO 41512. Org Lett. 2020; 22(16):6330-6333. https://doi.org/10.1021/acs.orglett.0c02160.

[2] Xia GY, Wang LY, Zhang JF, et al. Three new polyoxygenated bergamotanes from the endophytic fungus Penicillium purpurogenum IMM 003 and their inhibitory activity against pancreatic lipase. Chin J Nat Med. 2020; 18(1):75-80. https://doi.org/10.1016/S1875-5364(20)30007-8.

[3] Chen XH, Zhou GL, Sun CX, et al. Penicacids E-G, three new mycophenolic acid derivatives from the marine-derived fungus Penicillium parvum HDN17-478. Chin J Nat Med. 2020; 18(11):850-854. https://doi.org/10.1016/S1875-5364(20)60027-9.

[4] Yan YM, Ai J, Zhou LL, et al. Lingzhiols, unprecedented rotary door-shaped meroterpenoids as potent and selective inhibitors of p-Smad 3 from Ganoderma lucidum. Org Lett. 2013; 15(21):5488-5491. https://doi.org/10.1021/ol4026364.

[5] Luo Q, Di L, Dai WF, et al. Applanatumin A, a new dimeric meroterpenoid from Ganoderma applanatum that displays potent antifibrotic activity. Org Lett. 2015; 17(5):1110-1113. https://doi.org/10.1021/ol503610b.

[6] Pittayakhajonwut P, Theerasilp M, Kongsaeree P, et al. Pughiinin A, a sesquiterpene from the fungus Kionochaeta pughii BCC 3878. Planta Med. 2002; 68(11):1017-1019. https://doi.org/10.1055/s-2002-35653.

[7] Cheng X, Ma FP, Yan YM, et al. Aspertaichunol A, an immunomodulatory polyketide with an uncommon scaffold from the insect-derived endophytic Aspergillus taichungensis SMU01. Org Lett. 2022; 24(40):7405-7409. https://doi.org/10.1021/acs.orglett.2c02978.

[8] Schotte C, Li L, Wibberg D, et al. Synthetic biology driven biosynthesis of unnatural tropolone sesquiterpenoids. Angew Chem Int Ed. 2020; 59(52):23870-23878. https://doi.org/10.1002/anie.202009914.

[9] Zhang JY, Liu L, Wang B, et al. Phomanolides A and B from the fungus Phoma sp.: meroterpenoids derived from a putative tropolonic sesquiterpene via hetero-Diels-Alder reactions. J Nat Prod. 2015; 78(12):3058-3066. https://doi.org/10.1021/acs.jnatprod.5b00969.

[10] Liu JW, Lu JY, Zhang C, et al. Tandem intermolecular [4 + 2] cyclo additions are catalysed by glycosylated enzymes for natural product biosynthesis. Nat Chem. 2023; 15(8):1083-1090. https://doi.org/10.1038/s41557-023-01260-8.

[11] Chen QB, Gao J, Jamieson C, et al. Enzymatic itermolecular hetero-Diels-Alder reaction in the biosynthesis of tropolonic sesquiterpenes. J Am Chem Soc. 2019; 141(36):4052-14056. https://doi.org/10.1021/jacs.9b06592.

[12] Kumar K, Wang P, Sanchez R, et al. Development of kinase-selective, harmine-based DYRK1A inhibitors that induce pancreatic human β-cell proliferation. J Med Chem. 2018; 61(17):7687-7699. https://doi.org/10.1021/acs.jmedchem.8b00658.

[13] Yang ML, Kuo PC, Hwang TL, et al. Anti-inflammatory principles from Cordyceps sinensis. J Nat Prod. 2011; 74(9):1996-2000. https://doi.org/10.1021/np100902f.

[14] Chinworrungsee M, Wiyakrutta S, Sriubolmas N, et al. Cytotoxic activities of trichothecenes isolated from an endophytic fungus belonging to order hypocreales. Arch Pharm Res. 2008; 31(5):611-616. https://doi.org/10.1007/s12272-001-1201-x.

[15] Zheng YG, Wang YJ, Wu ZX, et al. Preparation and application of glycosylated derivative of brefeldin A. China: CN103739644A, 2014. 2014.

[16] Peng XP, Wang Y, Liu PP, et al. Aromatic compounds from the halotolerant fungal strain of Wallemia sebi PXP-89 in a hypersaline medium. Arch Pharm Res. 2011; 34(6):907-912. https://doi.org/10.1007/s12272-011-0607-0.

[17] Caliskan H, Ozer M, Sabudak T, et al. A new pyran derivative analog from the whole plant of Cirsium italicum. J Asian Nat Prod Res. 2021; 23(10):1009-1014. https://doi.org/10.1080/10286020.2020.1816977.

[18] Ye WX, Zhao MR, Wang L, et al. Isolation, identification, and bioactive metabolites of coral-derived fungus Aspergillus sp. SCSIO 40435 from the South China Sea. Acta Microbiol Sin. 2022; 62:1819-1831. https://doi.org/10.13343/j.cnki.wsxb.20210568.

[19] Luo Q, Tian L, Di L, et al. (±)-Sinensilactam A, a pair of rare hybrid metabolites with potent Smad 3 phosphorylation inhibition from Ganoderma sinensis. Org Lett. 2015; 17:1565-1568. https://doi.org/10.1021/acs.orglett.5b00448.

[20] Frisch MJ, Trucks GW, Schlegel HB, et al. Gaussian 16 revision C. 01. Gaussian, Inc.: Wallingford CT. 2010.

[21] Luo Q, Wei XY, Yang J, et al. Spiro meroterpenoids from Ganoderma applanatum. J Nat Prod. 2017; 80(1):61-70. https://doi.org/10.1021/acs.jnatprod.6b00431.