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 among 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, several 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 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 leads to the inhibition of microtubule polymerization as well as showing antiangiogenic and anticancer effects by selectively shutting down the tumor blood flow. To avoid the disadvantage of rather low in-vivo efficacy 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 from undergoing 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, colored (dark purple) formazan product. The cells are then solubilized with an organic solvent (e.g., isopropanol) and the released, solubilized formazan reagent is measured spectrophotometrically. Since, the 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