Identification and determination of mode of action of compounds for anti-cancer breast activity

Abstract

This PhD thesis is the result of work performed in the laboratory of Dr. Naibedya Chattopadhyay in the Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, during the period 2007-2011. My fellowship, Ph.D.-fee and an annum was funded by the Council of Scientific and Industrial Research, New Delhi. The fundamental aim of this dissertation was discovery of small molecule inhibitors that are orally active against growth factor receptors to stall the growth of breast cancer. To that effect, two novel synthetic series, phenyl naphthalen-1-yl methanone oxime derivatives and benzoxazepine derivatives were studied. The results of this study have been presented in three chapters for better correlation of the data. Chapter 1 We evaluated the anti-proliferative effect of novel phenyl naphthalen-1-yl methanone oxime derivatives in human breast cancer cells. Subsequently, we have determined the effect of most active compound of the series, 6b on the induction of apoptosis of breast cancer cells, regression of xenograft tumor and its molecular target. Chapter 2 We investigated the anti-tumor activity of a new series of benzoxazepine derivatives in breast cancer. We then identified the most potent compound of the series, 4-[4- (Toluene-4-sulfonyl)-2, 3, 4, 5-tetrahydro-benzo[f] [1, 4] oxazepin-3-ylmethyl]- phenol (THBP), studied its effect on the induction of apoptosis of human breast cancer cells, regression of xenograft tumor and determined its molecular target. Chapter 3 We investigated the combinatorial effect of EGFR and IGF-1R inhibition by 6b and THBP on human breast cancer cells.