[Show abstract][Hide abstract] ABSTRACT: From a high-throughput screening (HTS) hit with inhibitory activity against virus-induced cytophathic in the low micromolar range, we have developed a potent anti-influenza lead through careful optimization without compromising the drug-like properties of the compound. An orally bioavailable compound was identified as a lead agent with nanomolar activity against influenza, representing a 140-fold improvement over the initial hit.
[Show abstract][Hide abstract] ABSTRACT: By using a cell-based high throughput screening campaign, a novel angelicin derivative 6a was identified to inhibit influenza A (H1N1) virus induced cytopathic effect in Madin-Darby canine kidney cell culture in low micromolar range. Detailed structure-activity relationship studies of 6a revealed that the angelicin scaffold is essential for activity in pharmacophore B, while meta-substituted phenyl/2-thiophene rings are optimal in pharmacophore A and C. The optimized lead 4-methyl-9-phenyl-8-(thiophene-2-carbonyl)-furo[2,3-h]chromen-2-one (8g, IC(50) = 70 nM) showed 64-fold enhanced activity compared to the high throughput screening (HTS) hit 6a. Also, 8g was found effective in case of influenza A (H3N2) and influenza B virus strains similar to approved anti-influenza drug zanamivir (4). Preliminary mechanistic studies suggest that these compounds act as anti-influenza agents by inhibiting ribonucleoprotein (RNP) complex associated activity and have the potential to be developed further, which could form the basis for developing additional defense against influenza pandemics.
[Show abstract][Hide abstract] ABSTRACT: BPR0L075 (2) is a potential anticancer drug candidate designed from Combretastatin A-4 (1) based on the bioisosterism principle. Metabolites of 2, proposed from in vitro human microsome studies, were synthesized, leading to the identification of metabolite-derived analogue 10 with 40-350 pM potency against various cancer cell lines. Insights gained from the major inactive metabolite of 2 led to the development of 29, with better pharmacokinetics and improved potency in the tumor xenograft model than 2.
[Show abstract][Hide abstract] ABSTRACT: The synthesis and study of the structure-activity relationships of two new classes of synthetic antitubulin compounds based on 1-aroylindole and 3-aroylindole skeletons are described. Lead compounds 3, 10, and 14 displayed potent cytotoxicities with IC50 = 0.9-26 nM against human NUGC3 stomach, MKN45 stomach, MESSA uterine, A549 lung, and MCF-7 breast carcinoma cell lines. The inhibition of proliferation correlated with in vitro polymerization inhibitory activities. Structure-activity relationships revealed that 6-methoxy substitution of 3-aroylindoles and 5-methoxy substitution of 1-aroylindoles contribute to a significant extent for maximal activity by mimicking the para substitution of the methoxy group to the carbonyl group in the case of aminobenzophenones. Addition of a methyl group at the C-2 position on the indole ring exerts an increased potency. The 3,4,5-trimethoxybenzoyl moiety was necessary for better activity but not essential and can be replaced by 3,5-dimethoxybenzoyl and 3,4,5-trimethoxybenzyl moieties. We conclude that 1- and 3-aroylindoles constitute an interesting new class of antitubulin agents with the potential to be clinically developed for cancer treatment.
[Show abstract][Hide abstract] ABSTRACT: A new series of 3-aminobenzophenone compounds as potent inhibitors of tubulin polymerization was discovered based on the mimic of the aminocombretastatin molecular skeleton. Lead compounds 5 and 11, with alkoxy groups at the C-4 position of B-ring, were potent cytotoxic agents and inhibitors of tubulin polymerization through the binding to the colchicine-binding site of tubulin. The corresponding antitubulin activities of 5 and 11 were similar to or greater than combretastatin A-4 and AVE-8063. Replacement of the methoxy group with a chloro group in the B ring of aminobenzopheneones (3, 8, and 9) caused drastic decrease in cytotoxic and antitubulin activity except in compounds 4 and 10, which could result from a unique alignment between chloro and amino groups located at the para position to each other. SAR information revealed that introduction of an amino group at the C-3 position in B ring of benzophenones, in addition to a methoxy group at the C-4 position, plays an important role for maximal cytotoxicity.