C-terminal binding proteins (CtBPs) are transcriptional co-repressors involved in developmental processes, and also implicated in a number of breast, ovarian, colon cancers, and resistance against cancer chemotherapy. CtBP is a validated novel potential anti-cancer target. In this project we sought to develop potent and selective small-molecule inhibitors of CtBP. Using a combination of classical medicinal chemistry and modern computational approaches, we designed a potent inhibitor HIPP (hydroxyimino-3-phenylpropanoic acid) that showed an IC50 of 0.24 μM against recombinant CtBP. Further elucidation of the structure-activity relationship (SAR) of HIPP led to the design of more potent inhibitors 3-Cl HIPP (CtBP IC50 = 0.17 μM) and 4-Cl HIPP (CtBP IC50 = 0.18 μM). These compounds also showed inhibition in HCT-116 colon cancer cells with GI50 values ~ 1-4 mM. The compounds showed no off-target toxicity against a closely related protein. This is a starting point for the development of CtBP inhibitors as anti-cancer therapeutics. The second part of this dissertation focuses on C–H activation chemistry. C–H activation is the most atom-economical method of introducing complexity into a molecule, even at late stages of drug/product development. We have used solid-supported palladium nanoparticle catalyst (Pd-MWCNT) to investigate the scope of C–H activation reactions it can catalyse. Pd-MWCNT was found to efficiently catalyse N-chelation directed C-H activation reactions – halogenations, oxygenations and arylations. The turn-over numbers for these reactions were significantly higher than that of the reported homogenous catalyst. The added advantages of reuse/recyclability of catalyst, low contamination of metal in the final product make this catalyst very attractive on an industrial scale. This work serves as a foundation for the further development of Pd-MWCNT catalyst in late-stage synthesis of drugs and/or diversification of products.

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We investigated the gestational expression of androgen receptor (AR) and defined its regulation and that of its co-repressors, PSF and p54nrb, by steroid hormones and myometrial stretch in vivo in pregnant and non-pregnant rats. Our data demonstrate that, 1) myometrial AR expression decreases prior to term; 2) AR expression is up-regulated by MPA treatment and down-regulated by mechanical stretch; (3) myometrial PSF protein expression is down-regulated by estrogen signaling and by mechanical stretch, and up-regulated by androgen signaling; (4) while myometrial PSF mRNA expression is also down-regulated by stretch, the regulation by estrogen and P4 on PSF mRNA appear to be opposite to the effects on PSF protein. We conclude that the decreased androgen signaling in late pregnancy (as a result of decreased AR and PSF expression mediated by hormonal and mechanical signals) may contribute to the mechanisms leading to labor initiation.

We investigated the gestational expression of androgen receptor (AR) and defined its regulation and that of its co-repressors, PSF and p54nrb, by steroid hormones and myometrial stretch in vivo in pregnant and non-pregnant rats. Our data demonstrate that, 1) myometrial AR expression decreases prior to term; 2) AR expression is up-regulated by MPA treatment and down-regulated by mechanical stretch; (3) myometrial PSF protein expression is down-regulated by estrogen signaling and by mechanical stretch, and up-regulated by androgen signaling; (4) while myometrial PSF mRNA expression is also down-regulated by stretch, the regulation by estrogen and P4 on PSF mRNA appear to be opposite to the effects on PSF protein. We conclude that the decreased androgen signaling in late pregnancy (as a result of decreased AR and PSF expression mediated by hormonal and mechanical signals) may contribute to the mechanisms leading to labor initiation.