SYNTHESIS AND BIOLOGICAL EVALUATION OF CYCLOPROPANE DERIVATIVE OF COMBRETASTATIN CA-4-PHOSPHATEAbstract
Combretastatin A-4 (CA-4) is an anti-mitotic agent that is gaining rapid recognition amon cancer biologists and clinicians as one of the newer vascular disrupting agents, (VDAs) for cancer therapy. CA-4 belongs to a group of tubulin binding natural products called combretastatin, derived from the African Bush Willow, Combretum caffrum. Due to CA-4’s in vivo efficacy, a number of analogs of CA-4 have been synthesized to maximize its solubility and bioavailability. Combretastatin A-4 phosphate is a more soluble form of CA-4 that has successfully completed for treatment of acute myelogenous leukemia and relapsed ovarian cancer. This review attempts to highlight the various CA-4 analogs that have been synthesized and their effectiveness in clinical. Combretastatin A-4 phosphate (CA-4-P) is a biologically very active compound by binding to the colchicine binding site which lead to the inhibition of microtubule polymerization as well as showing antiagiogenic and anticancer effects by selectively shutting down the tumor blood flow. To avoid the disadvantage of rather low in vivo efficiacy resulting from the isomerization of the cis stilbene derivative to the thermodynamically more stable trans-isomer, our research group started the project for CA-4 analogs synthesis. The incorporation of carbocycles with different ring sizes on the connecting carbon-bridge of the natural compound prevents the system to undergo cis-trans-isomerization. The synthesis of the cyclopropane derivative of CA-4 via the cyclopropanation reaction with diazomethane, and further analogs with incorporated moieties for better water solubility. This is a colorimetric assay that measures the reduction of yellow 3-(4, 5-dimethythiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) by mitochondrial succinate dehydrogenase. The MTT enters the cells and passes into the mitochondria where it is reduced to an insoluble, coloured (dark purple) formazan product. The cells are then solubilised with an organic solvent (e.g. isopropanol) and the released, solubilised formazan reagent is measured spectrophotometrically. Since reduction of MTT can only occur in metabolically active cells the level of activity is a measure of the viability of the cells.
S. Kumar*, C. Kaushal and S. K. Jain
Institute of Pharmacy, Shri Venkateshwara University, Gajroula, Amroha, Uttar Pradesh, India.
03 April, 2017
23 June, 2017
28 June, 2017
01 August, 2017