Novel indole-based synthetic molecules in cancer treatment: Synthetic strategies and structure-activity relationship

Indole is one of the naturally occurring nitrogen-containing bicyclic heterocyclic ring systems where benzene and pyrrole rings are fused. It has been demonstrated to exhibit versatile biological activities. The indole scaffold regulates many proteins and genes which play a significant role in cancer development. US Food and Drug Administration (FDA) approved anti-cancer drugs having indole rings in their structure including alectinib, sunitinib, osimertinib, anlotinib, and panobinostat. Several research studies have focused on developing new indole derivatives for the treatment of cancer. Various studies have shown that indole C-3 atom; π-bond in between C-3 and C-2; and nitrogen atom can be substituted with varieties of other structural fragments to overcome the problem of drug resistance and toxicity. The anti-cancer potential of various indole derivatives, their synthetic strategies, and structure–activity relationships (SAR) for the further development and advancement of anticancer therapy. The article also summarizes how different proteins like TRK, VEGFR, EGFR, CDKs, ERK, BRD4, genes like Bcl2, intracellular pathways such as PI3K/AKT/mTOR, enzymes like tubulin and topoisomerase II are inhibited by indole derivatives. Synthetic strategies and SAR will help medicinal chemists to design and develop effective indole derivatives as anticancer agents.