10 / 2021-10-08 10:54:15

Structure-based design, SAR Study of Phenylahistin Derivatives for Anti-cancers and Discovery of Novel Furanyl Skeletons

Phenylahistin; Structure-based Design; SAR; Anticancer; Furanyl Skeletons

Phenylahistin is a marine natural product from Aspergillus ustus reported by Kanoh et al. Phenylahistin derivative’s Plinabulin targeted the colchicine site as a microtubule inhibitor, which is applying for NDA to treat the chemotherapy-induced neutropenia (CIN), and the non-small cell lung cancer (NSCLC). To develop more potent anti-microtubule derivatives and novel skeletons, the co-crystal complexes of plinabulin derivatives were further summarized and analyzed. Then, based on the co-crystal structures, a total of 53 novel A/B/C-rings Phenylahistin derivatives were designed and synthesized. The anti-proliferative activities were evaluated by MTT; and the summary of SAR studies were showed in above Figure. Compound 1 (IC₅₀ = 14.0 nM, NCI-H460) with furan group was more potent than plinabulin (IC₅₀ = 26.2 nM) against human lung cancer NCI-H460 cell line, which also exhibited significant high cytotoxicity activities against various human cancer cell lines in nanomolar level. In particular, the methoxymethyl group of the furan could replace the alkyl group of imidazole at 5-position to maintain the cytotoxic activity, which was different from the previous reports that the tert-butyl moiety at the 5-position of imidazole was essential for the activity of such compounds. Immunofluorescence assay indicated that Compound 1 could inhibit microtubule polymerization efficiently. Furthermore, the binding mode of Compound 1 was observed that the methoxymethyl substituent group at the 5-position of furan might have influences with H8 and T7 loops to interfere with the microtubule assembly. The theoretical calculated LogPo/w and PCaco of Compound 1 (PCaco = 1303.22) were better than plinabulin (PCaco = 377.79), which could enhance its cytostatic activity. Thus, Compound 1 could be considered as a potential scaffold in treatment of cancer and CIN.