PO-458 The role of functional groups in the antitumor properties of antrafuran

Abstract

IntroductionRecently we have discovered a promising anticancer agent Anthrafuran (LCTA-2034, (S)−3-(3-aminopyrrolidine-1-carbonyl)−4,11-dihydroxy-2-methylanthra [2,3-b]furan-5,10-dione methanesulfonate) which targeted topoisomerases (Top) 1, 2 and protein kinases Aur B, Aur C, Pim-1 and Pim-3 important for tumour cell biology. LCTA-2034 demonstrated an outstanding antitumor efficacy in vivo that makes this class attractive for anticancer drug development [Treshalina E.M. et al. Eur. J. Pharm. Sci., 2017] To evaluate the role of the key functional groups and investigate structure-activity relationships within this class, we next have synthesised a series of new analogues of LCTA-2034 using anthra[2,3-b]furan scaffold.Material and methodsTo prepare new derivatives of anthra[2,3-b]furan several synthetic schemes were developed and used for pointed modifications of LCTA-2034. Comparison of antiproliferative activity (IC50) of LCTA-2034 and its new analogues was performed on a murine leukaemia L1210 cell line. Cells were incubated for 48 hour at 37°C in a humidified CO2-controlled atmosphere, counted in a Coulter counter, and IC50 values were calculated.Results and discussionsReplacement of the methyl group at the position 2 of LCTA-2034 by hydrogen led to a slight decrease of antiproliferative potency of new analogues. The congeners bearing different diamines in the carboxamide moiety potently inhibited tumour cell growth at low micromolar to submicromolar concentrations. Introduction of the trifluoromethyl group at the position 2 decreased the potency of the corresponded analogue. Substitution of hydroxy groups in the core structure for amino, methoxy groups or chlorine atoms also significantly reduced cytotoxicity compared to the parent LCTA-2034. Transformation of the carboxamide group in LCTA-2034 into the aminomethyl spacer linked to 3-aminopyrrolidine residue also dramatically increased IC50 value. These data were in agreement with results of molecular modelling of binding of LCTA-2034 and its analogues with intracellular targets Aur B and DNA duplex.ConclusionOur results strongly suggest that the carboxamide group, as well as 4,11-hydroxy groups, are critical for the cytotoxic efficacy of LCTA-2034 and shown perspective direction for further drug development studies in this class of anticancer compounds. The study was partially supported by RFBR (17-53-45105) and DST (INT/RUS/RFBR/P-291).