Finding the Ajoene Sweet-Spot: Structure-Activity Relations that Govern its Blood Stability and Cancer Cytotoxicity

Area of Science:

• Medicinal Chemistry
• Organic Chemistry
• Biochemistry

Background:

• Ajoene, an organosulfur compound from garlic, exhibits anti-cancer properties by S-thiolating proteins.
• Limited bioavailability hinders ajoene's therapeutic development.

Purpose of the Study:

• Synthesize ajoene analogues to investigate the role of the vinyl disulfide/sulfoxide core in cytotoxicity and blood stability.
• Incorporate polar side groups to enhance aqueous solubility.

Main Methods:

• Synthesis of ajoene derivatives with modifications to the vinyl disulfide core and side groups.
• Evaluation of cytotoxicity and blood stability of synthesized analogues.
• Computational analysis (global electrophilicity index, Fukui function) to assess S-thiolysis reactivity.
• Thermodynamic calculations (entropy, enthalpy) to determine the exergonic nature of S-thiolysis.

Main Results:

• Vinyl disulfide analogues were more cytotoxic than those lacking the double bond, but had lower blood stability.
• Computational analysis indicated higher electrophilicity at the allyl-S sulfur of the disulfide.
• S-thiolysis was found to be exergonic for vinyl disulfides.
• Dihydro and deoxydihydroajoenes exhibited reduced potency but significantly improved blood stability.

Conclusions:

• Deoxydihydroajoenes represent promising candidates for further therapeutic development due to their improved blood stability.
• Modifications to the ajoene structure can balance cytotoxicity and pharmacokinetic properties.