Structure guided development of anti-cancer flexible-heteroarotinoid compounds

Flexible-heteroarotinoid compounds have been developed for their anticancer activities. The lead compound SHetA2 is able to inhibit growth of a variety of cancer cell lines and tumors in animal tests, without toxicity to normal tissues. The growth inhibition is about 84% for A2780 ovarian cancer cell cultures; the inhibition efficacy often decreases in real tissues. Therefore, it is desirable to improve efficacy and potency by designing better analogues. We identified the SHetA2 binding site on the receptor protein mortalin using NMR methods. SHetA2 disrupts the interaction of mortalin with other proteins that are upregulated in cancer cells but not in normal cells. Molecular modeling indicated that the binding strength of an analogue could be enhanced by increasing hydrophobicity of the chroman unit and substitution of a certain polar group. Five series of compounds were synthesized to validate the hypotheses. Several redesigned compounds did outperform the parent compound SHetA2, achieving inhibition efficacy of about 94% along with slightly better potency.