Design, Synthesis, and Biological Evaluation of 1 H -Pyrrolo[3,2- c ]quinolines as Potent and Selective Antitubulin Agents Active against Drug-Resistant Cel
Petra Kralova, Jiri Rehulka, Katarzyna Grychowska, Aleksandra Ivanova, Barbora Liskova, Sona Krajcovicova, Sona Gurska, Marian Hajduch, Barbora Lemrova, Katerina Zakova, Veronika Rucilova, Kristyna Hruba, Nina Mjartanova, Tatana Palova, Kristyna Sedlackova, Hana Katrusakova, Olena Mokshyna, Frederic Lamaty, Dominika Leoniec, Esther Uweh, Maria Walczak, Pavel Polishchuk, Paweł Zajdel, Petr Dzubak, Miroslav SouralAbstract
A library of 1H-pyrrolo[3,2-c]quinolines (PQs) was synthesized, and SAR analysis identified compounds with low-nanomolar potency in CCRF-CEM cells (IC50 = 13−18 nM) and selectivity indices > 1000-fold over BJ fibroblasts. The most active derivatives retained activity against daunorubicin-resistant and paclitaxel-resistant sublines, indicating limited cross-resistance, and compounds 4, 14, and 17 showed efflux ratios < 2 in MDR1-MDCK and Caco-2 assays. Colchicine-site engagement was supported by various assays and docking/MD simulations. ADME profiling showed high chemical and plasma stability, plasma protein binding, and moderate-to-high microsomal clearance. After i.p. dosing in CD-1 mice at 12 mg/kg, compound 17 reached a maximum plasma concentration (Cmax) of 879.9 ng/mL (2.73 μM) at tmax = 15 min, with a 103 min half-life and limited brain penetration. In zebrafish embryos, 17 induced concentration-dependent developmental abnormalities (LC50 = 198 nM at 96 hpf), consistent with antimitotic activity but pointing to a narrow therapeutic window.