Optimization of N-aryl-6-methoxy-1,2,3,4-tetrahydroquinolines as tubulin polymerization inhibitors.

Abstract Thirteen new N -aryl 1,2,3,4-tetrahydroquinoline compounds ( 4a – f , 6a – c , and 8a – d ) were synthesized and evaluated for antitumor activity and drug-like properties. Compound 4a exhibited high inhibitory potency with low nanomolar GI 50 values of 16–20 nM in cellular assays, including excellent activity against the P-glycoprotein overexpressing cell line KBvin. Compound 4a inhibited colchicine binding to tubulin and tubulin assembly with an IC 50 value of 0.85 μM, superior to the reference compound CA4 (1.2 μM) in the same assay. In addition, 4a also exhibited highly improved water solubility (75 μg/mL) and a suitable log  P value (3.43) at pH 7.4. With a good balance between antitumor potency and drug-like properties, compound 4a could be a new potential drug candidate for further development. Current results on SAR studies and molecular modeling provided more insight about this class of compounds as tubulin polymerization inhibitors targeting the colchicine site.