Studies Towards the Synthesis of Anti-cancer agent IIIM-290

Abstract

The chromone alkaloid rohitukine, isolated from the Indian medicinal plant Dysoxylum binectariferum have inspired many synthetic analogues that have reached or in the process of reaching the market as anti-cancer drugs. Recently, in 2019, researchers from CSIR-Indian Institute of Integrative Medicine (Jammu) and Indian Pharmacopeia Commission (Ghaziabad) have identified IIIM-290, a synthetic derivative of rohitukine as a strong inhibitor of CDK-9 protein (IC50 = 1.9 nM, the strongest till now) and cell growth (GI50 < 1μM). This makes IIIM-290 a molecule with strong anti-cancer properties. A complete pre-clinical trial of IIIM-290 shows 71% oral bioavailability whereas all previous rohitukine-derived drugs are intravenously bioavailable. This makes IIIM-290 the strongest and the only orally bioavailable Cdk-9 inhibitor among rohitukine derived leads. Although several syntheses of rohitukine-derived drugs and compounds are present in literature, total synthesis of IIIM-290 has not yet been reported. In this work, we have attempted to synthesize IIIM-290 using simple commercially available starting materials. The chromone moiety present in the molecule has been synthesized successfully and several strategic and tactical approaches are presented and discussed.