Synthesis, Z/E Isomerism, and Cytotoxic Activity of β-Hydroxy Oximes Derived from Indenoquinoxalinone, Tryptanthrin, and a Tricyclic Isatin Analogue: A Combined Experimental and DFT Study

Abstract

Indolo[2,3-b]quinoxalines and their N-substituted derivatives exhibit anticancer activity. In this work, a convenient two-step protocol comprising base-promoted aldol condensation followed by oximation was used for the synthesis of novel β-hydroxy oximes from heterocyclic ketones. The oximes were obtained as Z/E mixtures with one isomer predominating, and DFT calculations confirmed the E-configuration as thermodynamically preferred by 1.0–1.4 kcal/mol. High isomerization barriers (49–56 kcal/mol) via nitrogen inversion indicate kinetic stability of the β-hydroxy oximes at room temperature. The tryptanthrin-based β-hydroxyketone 5 (6-hydroxy-6-(2-oxopropyl)indolo[2,1-b]quinazolin-12(6H)-one) proved most potent, with IC50 values of 58 µM (MCF-7), 59 µM (PC-3) and 135 µM (SKOV-3); its derivative 6-hydroxy-6-(2-(hydroxyimino)propyl)indolo[2,1-b]quinazolin-12(6H)-one oxime (compound 8) was less effective, while other derivatives were inactive or showed only weak effects. MCF-7 and PC-3 cells were more sensitive than SKOV-3 cells. Hence, compounds 5 and 8 are promising leads for further SAR optimization and anti-cancer evaluation.