Abstract
This article provides an overview of the small molecule cancer treatment drug Combretastatin A-4 (CA-4) followed by progress towards a divergent synthesis of three CA-4 analogues. CA-4 is the lead drug in a subclass of microtubule inhibitors known as vascular disrupting agents. Issues with drug longevity, water solubility and normal cell toxicity have lead to the search for analogues with CA-4 as a model. Analogues bearing different bridging groups and heterocyclic rings have proven to be more effective than Combretastatin A-4 against many cancer cell lines. With this in mind our group has set out to prepare 2-(1,2,3-trazolyl)indole, 2-aroylindole and 2-styryl indole analogues of CA-4. The Hemetsberger-Knittel method was used to prepare substituted indoles from α-azidocinnamates in good yields. Regioselective annulation was observed during thermolysis of unsymmetrical α-azidocinnamates yielding 2-methoxy-5,6-disubstituted indole esters. Subsequent oxidation state adjustments and coupling provided 2-aroylindoles. One carbon homologation gave substituted ethynyl indoles as functional dipolarophiles in catalyzed 1,3-dipolar cycloadditions to produce a 2-(1,2,3-triazolyl)indole.
How to Cite
Shields, B. J., (2014) “Design and Synthesis of Heterocyclic Combretastatin Analogues”, Capstone, The UNC Asheville Journal of Undergraduate Scholarship 27(1).
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