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Title: Medicinally active dihalocyclopropanes
Author: Wong, Sio Lan
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2015
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Although mounting evidence suggests that Tamoxifen exerts cardioprotective effects against atherosclerosis, the findings that associate Tamoxifen and atherosclerosis at a molecular level are inconsistent and unclear. Tamoxifen is a potent autophagy inducer and we believe that the cardioprotective effect of Tamoxifen may be arisen from this autophagy inducing ability. This is because recent studies have shown that enhanced autophagy may be beneficial at both early and advanced stages of atherosclerosis. However, the estrogenic activity of Tamoxifen in the endometrium cells increases the risk of endometrial cancer in the patients treated with Tamoxifen. We, therefore, would like to minimize this risk by developing derivatives of Tamoxifen which induce autophagy, but with no apparent estrogenic activities. We started our project based on the syntheses of dichlorocyclopropyl analogues of Tamoxifen as Magarian et al. reported that the introduction of a dichlorocyclopropyl moiety in place of the olefinic link in Tamoxifen can significantly reduce the estrogen agonist activity. We found that, however, those dichlorocyclopropanes were not particularly stable and degraded easily through dichlorocyclopropyl ring openings. Thus, we moved to synthesize the difluorocyclopropyl and other classes of derivatives of Tamoxifen. A wide range of structurally different analogous of Tamoxifen have been synthesized and biologically tested for induction of autophagy, of which some display the desired autophagic activity in a dose-dependent manner but lower than that of Tamoxifen. Tamoxifen was observed to be cytotoxic to cells at high doses (>5 M), but this toxicity is not observed with our drug molecules. We ascertained that the presence of an amioethoxy basic side chain in conjunction with a diaryl backbone were essential pharmacophores for the induction of autophagy. Additionally, neither the antiestrogenic nor estrogenic activity is responsible for the autophagic effect of our drug candidates as they did not bind to estrogen receptor. Based on the results of ours and others in the literature, we propose that our novel aminoethoxy difluorocyclopropanes may be AEBS inhibitors. Selected compounds are in the process of being patented.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry