Synthesis and evaluation of antileukemic activity of 2-carbomethoxy-3- substituted indoles

Indole nucleus is a privileged heteroaromatic framework which forms an important class of natural and synthetic active compounds.1 Indoles show a diversity of pharmacological activities including antimicrobials, antifungal, antivirals, anti-inflammatory, antidepressants, anticholinergics, anti-migraine, anti-hypertensive,
including anticancer activity, mostly linked to tubulin metabolism.1-3 The methodology used for the synthesis of 2-carbomethoxy-3-substituted indoles consisted of a reductive cyclization reaction of β,β-substituted acrylate containing an o-nitro group, which were used in the synthesis of the target molecules through sequential Heck-Matsuda arylations4 of acrylate with different arenediazonium salts and Pd(OAc)2 in methanol. To introduce structural variability and evaluate their biological influences, a considerable number of substituted C3 functionalized indoles were synthesized in good yields. Evaluation of antileukemic activity was investigated for all indoles. Three of them have shown remarkable potencies at the nanomolar range against cell lines CEM and RS4;11. The mechanism of action was investigated in detail for the most active 3-arylindole.