Ajoene is an organosulfur compound found in crushed garlic, that exerts its anti-cancer activity by S-thiolating cysteine residues on proteins. Its development is hampered due to limited bioavailability. In this study, we synthesised analogues of ajoene to probe the significance of the ajoene vinyl disulfide/sulfoxide core with respect to cytotoxicity and blood stability. Polar side groups were also incorporated to improve aqueous solubility. It was found that derivatives containing a vinyl disulfide functional group (4-7, as in ajoene), were more cytotoxic compared to analogues in which the double bond was removed, although the latter showed superior blood stability. It was found that the allyl-S sulfur of the disulfide was more electrophilic to Sthiolysis based on calculations of the global electrophilicity index (ω); and the condensed electrophilic Fukui function fk+ . S-Thiolysis was found to be exergonic for the vinyl disulfides based on entropy and enthalpy computations with a deprotonated thiolate. Derivatisation to the dihydro (10, 12) and deoxydihydroajoenes (9, 11) produced analogues that were slightly less potent but with greatly improved blood stability. Taken together, the deoxydihydroajoenes present themselves as good candidates for further therapeutic development.