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THE EVALUATION OF NOVEL CONJUGATED UNSATURATED KETONES AS CANDIDATE ANTINEOPLASTIC AGENTS

Date

2021-09-21

Journal Title

Journal ISSN

Volume Title

Publisher

ORCID

0000-0003-3712-5790

Type

Thesis

Degree Level

Doctoral

Abstract

Cancer is a huge medical problem. One of the ways of treating this complaint is by the use of anticancer drugs. However this therapy suffers from two major drawbacks namely undue toxicity to non-malignant cells and the development of drug resistance. The compounds which comprise the basis of this thesis are conjugated unsaturated ketones which differ structurally from contemporary anticancer medication and some of these compounds have noteworthy antineoplastic properties. These unsaturated ketones have a greater affinity for thiols than hydroxyl and amino groups. Hence the toxicity to nucleic acids may be absent or much lower than that of many contemporary anticancer agents. This thesis describes the development of three series of cytotoxic compounds. Series 15 are a cluster of 3,5-bis(benzylidene)-4-piperidones which in general are far more toxic to various tumor cells than to non-malignant ones. Some physicochemical constants of the aryl substituents correlated with potencies. In addition, attempts to condense various aldehydes with 2,2,6,6-tetramethyl-4-piperidone led to the isolation of some acyclic 1,5-diaryl-1,4-dien-3-ones. Series 33 were created by placing a N-acyl group on some of the enones in series 15. The biodata was very encouraging with very high potencies to tumor cells while significantly lower toxicity to normal cells was noted. Representative compounds caused apoptosis in some malignant cells. Series 71 are quaternary ammonium salts which were prepared to preferentially react with tumor mitochondria rather than this organelle of normal cells. These molecules too demonstrated higher toxicity to neoplasms than non-malignant cells and representative compounds have drug-like properties. This study has revealed the encouraging antineoplastic properties of several different clusters of compounds and provided direction for future studies.

Description

Keywords

Cytotoxins, bioassays, apoptosis, organic syntheses, structure-activity relationships, neoplasms, selective toxicity

Citation

Degree

Doctor of Philosophy (Ph.D.)

Department

Pharmacy and Nutrition

Program

Chemistry

Advisor

Citation

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DOI

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