الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
The ubiquitin-proteasome system plays a fundamental role in selective protein proteasomal degradation. Protein ubiquitination is an enzymatic process that requires the action of a series of enzymes (E1, E2 and E3), a number of which have being studied as potential anticancer drug targets at the E2 and E3 level. We have focused our studies on Rad6B, an E2 ubiquitin conjugating enzyme that is over-expressed in human breast cancer, and associated with loss of epithelial polarity, aneuploidy, resistance to chemotherapeutics drugs, and β -catenin stabilization. We have used the Rad6B crystal structure to guide the design and synthesis of new diamino-triazines that were found to directly interfere with the Rad6B active site. We have made further design modifications to candidate Rad6B inhibitors based on molecular modeling considerations, to provide further triazine-based compounds either as 4-amino-6- un/substituted phenyl amino 6 c-f,8a-o, 9a-e and 11a-l or 4,6- bis un/substituted phenyl amino 15a-e for synthesis and evaluation towards the discovery of further selectively active E2-inhibitory anticancer compounds, and to study structure activity relationships. The thesis consists of the following parts: 1-Introduction: It includes a brief literature survey about breast cancer, the currently available drug used for its treatment and their different mechanisms of action. In addition to a summary about ubiquitin system (E2 ubiquitin conjugating enzyme Rad6B) as a new strategy for breast cancer therapeutics. Also, it deals with the reported chemical methods for the Abstract ii synthesis of the diamino-s-triazine nucleus. 2- Research objectives: This part involves the basis upon which the synthesized compounds were designed. Based on the role of Rad6B (E2 ubiquitin conjugating enzyme) in postreplication repair of DNA and the overexpression of this enzyme in human breast cancer. This directed our interest to search for Rad6B inhibitors which could be a good strategy for breast cancer therapies. Also, the synthetic schemes (I,II,III,IV and V) adopted for the synthesis of the targeted compounds were outlined.