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 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. 3- Theoretical discussion: It deals with the theoretical discussion of the methods adopted for the synthesis of the designed compounds, as well as the methods reported in literature for the preparation of the intermediates. Additionally, it presents a summarized data about the spectroscopic methods 1H NMR and 13C NMR used for characterization and conformation of the newly synthesized compounds. 4- Experimental: Novel triazine-based compounds were synthesized using the following routes: 1- Heating equivalent amounts of (substituted) anilines (1a-e) and dicyandiamide under acidic condition (3M HCl) at 90°C afforded arylbiguanides hydrochlorides (2a-e), neutralization using sodium methoxide in methanol at room temperature yielded 1-Arylbiguanide (3a-e). 2- Condensation of 1-arylbiguanides (3a-e) with excess dimethyl oxalate in methanol gave methyl ester triazine intermediates (4a-e). 3- Reduction of 4a-c using lithium aluminium hydride in anhydrous THF under inert atmosphere of nitrogen afforded the hydroxymethyl intermediates (5a-c). 4- Esterification of 5a-c using the appropriate nitrobenzoyl chloride in basic conditions yielded the desired triazines (6a-f). 5- Basic hydrolysis of methyl esters (4a-c) by refluxing with aqueous NaOH in methanol for 4h, followed by neutralization using 1N HCl provided the corresponding carboxylic acids (7a-c). 6- Reacting carboxylic acids (7a-c) and the appropriate un/substituted benzyl bromide at room temperature in the presence of TBAF in acetonitrile afforded the inverted esters (8 a-o). 7- Refluxing the methyl esters (4a-e) with phenyl hydrazine in ethanol containing catalytic amount of glacial acetic acid for 5-18h gave the corresponding hydrazides (9a-e). 8- Condensation of 3a-c using excess diethyl oxalate in ethanol produced the ethyl ester triazine intermediates (10a-c). 9- Refluxing the ethyl esters (10a-c) and substituted benzyl amines in dioxane containing catalytic amount of glacial acetic acid for 18h afforded the amides (11a-l). 10- Refluxing two equivalent of an anilinium chloride and sodium dicyanamide for 18h gave 1,5-diarylbiguanide hydrochlorides (12a-e) which upon neutralization with sodium methoxide in methanol at room temperature yielded 1,5-diarylbiguanides (13a-e). 11- Condensation of 1,5-diarylbiguanides (13a-e) with excess dimethyl oxalate in methanol containg catalytic amount of sodium methoxide to form methyl ester triazine intermediates(14a-e). 12- Finally, The methyl esters (14a-e) were converted to the corresponding hydrazides (15a-e) by refluxing with excess hydrazine hydrate in absolute ethanol for 3h. 5- Biological screening: The newly synthesized compounds 6a-c, 8a-o, 9a-e, 11a-l and 15a-e were subjected to invitro anticancer activity against breast cancer cell lines (MDA-MB-231, MCF-7 and MCF10-A) using doxorubicin and MG-132 as references drugs using cell titer blue assay. MDA-MB-231 was used to explore the Rad6B inhibitory activity of the tested compounds. Compounds 9a-e elicited the most active and selective inhibitory activity on MDA-MB-231 at low concentration, while compounds 11a,b,i and 15d showed a moderate activity with lower degree of selectivity. 6- Molecular modeling: This part involves a molecular docking study using Leadit 1.2 software. The calculated binding affinities and orientations between the human Rad6B protein x-ray structure and the synthesized triazines were studied 4-amino-6-un/substituted phenylamino carbohydrazide derivatives 9a-e exhibited the best docking score. 7- References: This part includes 154 references covering the period 1942-2013.