Terphenyllin (1), a naturally abundant p-terphenyl metabolite, was isolated from the coral derived fungus Aspergillus candidus together with four natural analogues 2-5. To evaluate their potency and selectivity, a series of new derivatives of 1 were designed and semisynthesized. They were evaluated for their α-glucosidase inhibitory, cytotoxic, and antibacterial activities. Compounds 1, 3, 4, 7, 8, 10, 11, 14, 15, 21, 23, 24, 29, 39, and 40 showed significant α-glucosidase inhibitory activity with IC50 values of 4.79-15 μM, which were stronger than that of the positive controls, 1-deoxynojirimycin (IC50 = 192.0 μM) and acarbose (IC50 = 707.9 μM). Compounds 7 and 10 have relatively higher therapeutic indices (CC50/IC50 = 17 and 10, respectively), representing potential promising leads. The enzyme kinetic studies of compounds 1 and 24 showed a non-competitive inhibition on α-glucosidase with Ki values of 1.50 and 3.45 μM, respectively. Additionally, compounds 14, 21, 26, 29, 32, 35, and 37 were found to exhibit strong cytotoxicity against three tumor cell lines A549 (lung adenocarcinoma epithelial), HeLa (cervical carcinoma), and HepG2 (hepatocellular liver carcinoma) with IC50 values ranging from 0.15 to 5.26 μM. Further study indicated that 32 could induce S-phase arrest in the cell cycle progression.
Keywords: Aspergillus candidus; Cytotoxicity; Semisynthesize; p-Terphenyls; α-Glucosidase inhibitory.
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