Molecular simulation of polyketides isolated from the endophyte Phialophora verrucosa

Document Type: Original Article

Authors

1 Department of Pharmacognosy, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, P.O. Box 71524, Assiut, Egypt

2 Department of Biochemical Engineering, Graduate School of Science and Engineering, Yamagata University, Yonezawa, Yamagata 992-8510, Japan

Abstract

Endophytic fungi are a wealth of new bioactive metabolites with vast applications in drug discovery. The methyl alcohol extract obtained from the culture of the Phialophora verrucosa Medlar., the endophytic fungus of Senecio flavus (Asteraceae), was found to be cytotoxic to HepG2 and MCF-7 cell lines (IC50 of 20.01 and 28.44 μg/mL), respectively, compared to 5-flurouracil (IC50, 11.05 and 12.46). A chromatographic study led to the isolation of five polyketides; 3,6,7-trihydroxy-α-tetralone 1, 6-hydroxyisosclerone 2, 2,3-dihydro-8-hydroxy-2-methyl-benzopyran-1-one 3, altechromone A 4 and aloesol 5. Compounds 2, 4 and 5, are isolated for the first time from the genus Phialophora. Molecular docking analysis simulation was applied to evaluate the inhibitory activities of the isolated compounds against vascular endothelial growth factor receptor (VEGFR2), and cyclin-dependent kinases (CDKs), to illuminate the compounds responsible for the extract cytotoxic activity. Compounds 1 and 5 showed promising results and binding affinities to the examined enzymes.

Graphical Abstract

Molecular simulation of polyketides isolated from the endophyte Phialophora verrucosa

Keywords


AbdElhameid, M.K., Labib, M.B., Negmeldin, A.T., Al-Shorbagy, M., Mohammed, M.R., 2018.Design, synthesis, and screening of ortho-amino thiophene carboxamide derivatives on hepatocellular carcinomaas VEGFR-2 inhibitors. J. Enzym. Inhib. Med. Chem. 33, 1472-1493.

Alderidge, D.C., Davies, A.B., Jackson, M.R., Turner, W.B., 1974. Pentaketide metabolites of the fungus Phialophora lagerbergii. J. Chem. Soc. Perkin I, 1540-1541.

Anderson, J.R., Edwards, R.L., Whalley, A.J.S., 1983. Metabolites of the higher fungi. 3-Methyl-3,4-dihydroisocoumarins and related compounds from the ascomycete family xylariaceae. J. Chem. Soc. Perkin Trans 1, 2185-2192.

Arora, D., Sharma, C., Jaglan, S., Lichtfouse, E., 2019. Pharmaceuticals from Microbes: Impact on Drug Discovery. in Sharma N, Sharma V, Abrol V, Panghal A, Jaglan S. (Ed.). An Update on Bioactive Natural Products from Endophytic Fungi of Medicinal Plants. Springer International Publishing, Cham, pp. 122-153.

Ayer, W.A., Racok, J.S., 1990.The metabolites of Talaromyces flavus: Part 1. Metabolites of the organic extracts. Can. J. Chem. 68, 2085-2094.

Barakat, A., El-Senduny, F.F., Almarhoon, Z., Al-Rasheed, H.H., Badria, F.A., Al-Majid, A.M., Ghabbour, H.A., El-Faham, A., 2019. Synthesis, X-ray crystal structures, and preliminary antiproliferative activities of new s-triazine-hydroxybenzylidene hydrazone derivatives. J. Chem. https://doi.org/10.1155/2019/9403908.

Campbell, C.K., Johnson, E., Warnock, D.W., 2011. Identification of Pathogenic Fungi (2nd Ed.). Chichester: Wiley. ISBN 978-1444330700.

Chowdhury, N.S., Sohrab, M.H., Rana, M.S., Hasan, C.M., Jamshidi, S., Rahman, K.M., 2017. Cytotoxic naphthoquinone and azaanthraquinone derivatives from an endophytic Fusarium solani. J. Nat. Prod. 80, 1173-1177.

Elkhayat, E.S., Goda, A.M., 2017.Antifungal and cytotoxic constituents from the endophytic fungus Penicillium sp. Bull. Fac. Pharm. Cairo Univ. 55, 85-89.

El-Khayat, E.S., Ibrahim, S.R., Mohamed, G.A., 2012. Plant endophytes, renewable source of new natural products. Nat. Prod. J. 2, 225-234.

Gray, L.E., Gardner, H.W., Weisleder, D., Leib, M., 1999. Production and toxicity of 2,3-dihydro-5-hydroxy-2-methyl-4H-1-benzopyran-4-one by Phialophora gregata. Phytochemistry 50, 1337-1340.

Guo, H., Liu, Z.M., Chen, Y.C., Tan, H.B., Li, S.N., Li, H.H., Gao, X.X., Liu, H.Z., Zhang, W.M. , 2019. Chromone-derived polyketides from the deep-sea fungus Diaporthe phaseolorum FS431. Mar. Drugs 17, 182-193.

Hanse, E.A., Nelsen, C.J., Goggin, M.M., Anttila, C.K., Mullany, L.K., Berthet, C., Kaldis, P., Crary, G.S., Kuriyama, R., Albrecht, J.H., 2009. Cdk2 plays a critical role in hepatocyte cell cycle progression and survival in the setting of cyclin D1 expression in vivo. Cell Cycle 8, 2802-2809.

He, J-W, Wang, C-X, Yang, L, Chen, G-D, Hu, D, Guo, L-D, Yao, X-S, Gao, H., 2016. A pair of new polyketide enantiomers from three endolichenic fungal strains Nigrospora sphaerica, Alternaria alternata, and Phialophora sp. Nat. Prod. Commun. 11, 829-831.

Meng, X-Y, Zhang, H-X, Mezei, M., Cui, M., 2011. Molecular docking a powerful approach for structure-based drug discovery. Curr. Comput. Aided Drug Des. 7, 146-157.

Meng, F., 2013. Molecular dynamics simulation of VEGFR2 with sorafenib and other urea-substituted aryloxy compounds. J. Theor. Chem. http://dx.doi.org/10.1155/2013/739574

Mrid, B.R., Bouchmaa, N., Bouargalne, Y., Ramdan, B., Karrouchi, K., Kabach, I., El Karbane, M., Idir, A., Zyad, A., Nhiri, M., 2019. Phytochemical characterization, antioxidant and in vitro cytotoxic activity evaluation of Juniperus oxycedrus Subsp. oxycedrus Needles and Berries. Molecules 24, 502-520.

Nalli, Y., Mirza, D.N., Wani, Z.A., Wadhwa, B., Mallik, F.A., Raina, C., Riyaz-Ul-Hassan, S., Ali, A., 2015.Phialomustin A-D, new antimicrobial and cytotoxic metabolites from an endophytic fungus, Phialophora mustea. RSC Adv. 5, 95307-95312.

Orfali, R.S., Ebrahim, W., El-Shafae, A.M., 2017. Secondary metabolites from Alternaria sp., a fungal endophyte isolated from the seeds of Ziziphus jujuba. Chem. Nat. Compd. 53, 1031-1034.

Rocha-Santos, T., Duarte, A.C., 2014. Introduction to the Analysis of Bioactive Compounds in Marine Samples. Comprehensive Analytical Chemistry 65, pp. 1-13.

Shafiq, M.I., Steinbrecher, T., Schmid, R., 2012. Fascaplysin as a specific inhibitor for CDK4: insights from molecular modelling. PLoS One 7, e42612.

Sherr, C.J., Beach, D., Shapiro, G.I., 2016. Targeting CDK4 and CDK6: from discovery to therapy.Cancer Discov. 6, 353-367.

Shi, X-N., Li, H., Yao, H., Liu, X., Li, L., Leung, K-S., Kung, H-f., Lu, D., Wong, M-H., Lin, M.C., 2015.In silico identification and in vitro and in vivo validation of anti-psychotic drug fluspirilene as a potential CDK2 inhibitor and a candidate anti-cancer drug. PloS One 10, e0132072.

Strobel, G., Daisy, B., 2003. Bioprospecting for microbial endophytes and their natural products. Microbiol. Mol. Biol. Rev. 67, 491-502.

Wang, L., Xu, B., Wang, J., Su, Z., Lin, F., Zhang, C., Kubicek, C.P., 2012. Bioactive metabolites from Phoma species, an endophytic fungus from the Chinese medicinal plant Arisaema erubescens. Appl. Microbiol. Biotechnol. 93,1231-1239.

Weissman, K.J., Leadlay, P.F., 2005.Combinatorial biosynthesis of reduced polyketides. Nat. Rev. Microbiol. 3, 925-936.

Xu, J., Kjer, J., Sendker, J., Wray, V., Guan, H., Edrada, R., Lin, W., Wu, J., Proksch, P., 2009.Chromones from the endophytic fungus Pestalotiopsis sp. isolated from the Chinese Mangrove plant Rhizophora mucronata. J. Nat. Prod. 72, 662-665.

Ye, F., Chen, G-D., He, J-W., Li, X-X., Sun, X., Guo, L-D., Li, Y., Gao, H., 2013.Xinshengin, the first altenusin with tetracyclic skeleton core from Phialophora spp. Tetrahedron Lett. 54, 4551-4554.

Zhao, J., Wang, X., Sun, W., Mou, Y., Peng, Y., Zhou, L., 2013. Medium optimization for palmarumycin C13 production in liquid culture of endophytic fungus Berkleasmium sp. Dzf12 using response surface methodology. Electron. J. Biotechnol. 16, 16-26.