Talaketides A−G, linear polyketides with prostate cancer cytotoxic activity from the mangrove sediment-derived fungus Talaromyces sp. SCSIO 41027

Abstract

Seven novel linear polyketides, talaketides A−G (1−7), were isolated from the rice media cultures of the mangrove sediment-derived fungus Talaromyces sp. SCSIO 41027. Among these, talaketides A−E (1−5) represented unprecedented unsaturated linear polyketides with an epoxy ring structure. The structures, including absolute configurations of these compounds, were elucidated through detailed analyses of nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HR-MS) data, as well as electronic custom distributors (ECD) calculations. In the cytotoxicity screening against prostate cancer cell lines, talaketide E (5) demonstrated a dose-dependent inhibitory effect on prostate cancer PC-3 cell lines, with an IC₅₀ value of 14.44 μmol·L⁻¹. Moreover, compound 5 significantly inhibited the cloning formation of PC-3 cell lines and arrested the cell cycle in S-phase, ultimately inducing apoptosis. These findings indicate that compound 5 may serve as a promising lead compound for the development of a potential treatment for prostate cancer.

Keywords

Mangrove sediment-derived fungus / Talaromyces sp. / Linear polyketides / Cytotoxicity / Prostate cancer.

References

[1] Carroll AR, Copp BR, Davis RA, et al. Marine natural products[J]. Nat Prod Rep, 2023, 40: 275-325.

[2] Newman DJ, Cragg GM. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019[J]. J Nat Prod, 2020, 83: 770-803.

[3] Li K, Chen S, Pang X, et al. Natural products from mangrove sediments-derived microbes: structural diversity, bioactivities, biosynthesis, and total synthesis[J]. Eur J Med Chem, 2022, 230: 114117.

[4] Benjamin CR. Ascocarps of Aspergillus and Penicillium.[J]. Mycologia, 1955, 47: 669-687.

[5] Nicoletti R, Bellavita R, Falanga A. The outstanding chemodiversity of marine-derived Talaromyces[J]. Biomolecules, 2023, 13: 1021.

[6] Zhai MM, Li J, Jiang CX, et al. The bioactive secondary metabolites from Talaromyces species[J]. Nat Prod Bioprospect, 2016, 6: 1-24.

[7] Chen S, He L, Chen D, et al. Talaramide A, an unusual alkaloid from the mangrove endophytic fungus Talaromyces sp. (HZ-YX1) as an inhibitor of mycobacterial PknG[J]. New J Chem, 2017, 41: 4273-4276.

[8] Chen C, Sun W, Liu X, et al. Anti-inflammatory spiroaxane and drimane sesquiterpenoids from Talaromyces minioluteus (Penicillium minioluteum)[J]. Bioorg Chem, 2019, 91: 103166.

[9] Cai J, Zhou XM, Yang X, et al. Three new bioactive natural products from the fungus Talaromyces assiutensis JTY2[J]. Bioorg Chem, 2020, 94: 103362.

[10] Zhang M, Li Q, Li S, et al. An unprecedented ergostane with a 6/6/5 tricyclic 13(14→8)abeo-8, 14-seco skeleton from Talaromyces adpressus[J]. Bioorg Chem, 2022, 127: 105943.

[11] Zang Y, Genta-Jouve G, Escargueil AE, et al. Antimicrobial oligophenalenone dimers from the soil fungus Talaromyces stipitatus[J]. J Nat Prod, 2016, 79: 2991-2996.

[12] Anand BG, Thomas CK, Prakash S. In vitro cytotoxicity and antimicrobial activity of Talaromyces flavus SP5 inhabited in the marine sediment of Southern Coast of India[J]. Chin J Nat Med, 2016, 14: 913-921.

[13] Ren J, Ding SS, Zhu A, et al. Bioactive azaphilone derivatives from the fungus Talaromyces aculeatus[J]. J Nat Prod, 2017, 80: 2199-2203.

[14] Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022[J]. CA Cancer J Clin, 2022, 72: 7-33.

[15] Attard G, Parker C, Eeles RA, et al. Prostate cancer[J]. Lancet, 2016, 387: 70-82.

[16] Nelson WG, De Marzo AM, Isaacs WB. Mechanisms of disease: Prostate cancer[J]. N Engl J Med, 2003, 349: 366-381.

[17] Wang X, Luo X, Gan X, et al. Analysis of regulating activities of 5'-epiequisetin on proliferation, apoptosis, and migration of prostate cancer cells in vitro and in vivo[J]. Front Pharmacol, 2022, 13: 920554.

[18] Cai J, Wang X, Gan X, et al. New chlorinated metabolites and antiproliferative polyketone from the mangrove sediments-derived fungus Mollisia sp. SCSIO41409[J]. Mar Drugs, 2022, 21: 32.

[19] Xie Y, Guo L, Huang J, et al. Cyclopentenone-containing tetrahydroquinoline and geldanamycin alkaloids from Streptomyces malaysiensis as potential anti-androgens against prostate cancer cells[J]. J Nat Prod, 2021, 84: 2004-2011.

[20] Cai J, Wang X, Yang Z, et al. Thiodiketopiperazines and alkane derivatives produced by the mangrove sediment-derived fungus Penicillium ludwigii SCSIO 41408[J]. Front Microbiol, 2022, 13: 857041.

[21] Seco JM, Quiñoá E, Riguera R. The assignment of absolute configuration by NMR[J]. Chem Rev, 2004, 104 : 17-117.

[22] Cai J, Gao L, Wang Y, et al. Discovery of a novel anti-osteoporotic agent from marine fungus-derived structurally diverse sirenins[J]. Eur J Med Chem, 2024, 265: 116068.

[23] Bai J, Liu D, Yu S, et al. Amicoumacins from the marine-derived bacterium Bacillus sp. with the inhibition of NO production[J]. Tetrahedron Lett, 2014, 55: 6286-6291.

[24] Peng B, Cai J, Xiao Z, et al. Bioactive polyketides and benzene derivatives from two mangrove sediment-derived fungi in the Beibu Gulf[J]. Mar Drugs, 2023, 21: 327.

[25] Suzuki S, Horii F, Kurosu H. Theoretical investigations of the γ-gauche effect on the ¹³C chemical shifts produced by oxygen atoms at the γ position by quantum chemistry calculations[J]. J Mol Struct, 2009, 919 : 290-294.

[26] Boyd S, Brookfield JL, Critchlow SE, et al. Structure-based design of potent and selective inhibitors of the metabolic kinase PFKFB3[J]. J Med Chem, 2015, 58: 3611-3625.

[27] Chang F, Lee JT, Navolanic PM, et al. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy[J]. Leukemia, 2003, 17: 590-603.

[28] Hamidi A, Song J, Thakur N, et al. TGF-b promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85a[J]. Sci Signal, 2017, 10: eaal4186. aal4186

[29] Chen C, Xiao L, Luo X, et al. Identifying marine-derived tanzawaic acid derivatives as novel inhibitors against osteoclastogenesis and osteoporosis via downregulation of NF-κB and NFATc1 activation[J]. J Med Chem, 2024, 67 : 2602-2618.

[30] Ye Y, Liang J, She J, et al. Two new alkaloids and a new butenolide derivative from the Beibu Gulf sponge-derived fungus Penicillium sp. SCSIO 41413[J]. Mar Drugs, 2022, 21: 27.

[31] Tian C, Yang C, Wu T, et al. Discovery of cinnoline derivatives as potent PI3K inhibitors with antiproliferative activity[J]. Bioorg Med Chem Lett, 2021, 48: 128271.

Funding

Key-Area Research and Development Program of Guangdong Province(2023B1111050008)

National Natural Science Foundation of China(U23A20528)

National Natural Science Foundation of China(U20A20101)

Guangdong Local Innovation Team Program(2019BT02Y262)

Postdoctoral Fellowship Program of CPSF(GZC20232777)