The Sulfilimine Analogue of Allicin, S-Allyl-S-(S-allyl)-N-Cyanosulfilimine, Is Antimicrobial and Reacts with Glutathione.

When cells of garlic (Allium sativum) are disrupted by wounding, they produce the defense substance allicin (diallylthiosulfinate). Allicin is an efficient thiol trap and readily passes through cell membranes into the cytosol, where it behaves as a redox toxin by oxidizing the cellular glutathione (GSH) pool and producing S-allylmercaptoglutathione (GSSA). An N-cyanosulfilimine analogue of allicin (CSA), which was predicted to have similar reactivity towards thiol groups but be more stable in storage, was synthesized and its properties investigated. Similarly to allicin, CSA was shown to inhibit the growth of various bacteria, a fungus (baker's yeast), and Arabidopsis roots. A chemogenetic screen showed that yeast mutants with compromised GSH levels and metabolism were hypersensitive to CSA. GSH reacted with CSA to produce allyltrisulfanylglutathione (GS3A), which was a white solid virtually insoluble in water. Yeast Δgsh1 mutants are unable to synthesize GSH because they lack the γ-glutamylcysteine synthetase (GSH1) gene, and they are unable to grow without GSH supplementation in the medium. GS3A in the growth medium supported the auxotrophic requirement for GSH in Δgsh1 mutants. This result suggests that GS3A is being reduced to GSH in vivo, possibly by the enzyme glutathione reductase (GR), which has been shown to accept GSSA as a substrate. The results suggest that CSA has a mode of action similar to allicin and is effective at similar concentrations.

Structure-guided development of purine amide, hydroxamate, and amidoxime for the inhibition of non-small cell lung cancer.

An 8-oxopurine-6-carboxamide compound (1a) was previously identified as an inhibitor of non-small cell lung cancer (NSCLC). In this study, more than 30 purine-6-carboxamide derivatives with variations at the C2, N7, C8, and N9 positions were synthesized to investigate the structure-activity relationship as a basis for the construction of an advanced pharmacophore model. This model suggests that purine-6-hydroxamate and purine-6-amidoxime analogs could form more hydrogen bonds with a target protein to enhance the inhibitory activities against H1975 cells. Among the series of analogs, hydroxamate 17 and amidoxime 19a exhibited excellent potency against H1975 cells (IC50 < 1.5 µM) and other lung cancer cells with either wild-type or mutated epidermal growth factor receptor (EGFR). Mouse experiments indicated that compounds 17 and 19a were efficient anticancer agents with no appreciable toxicity. The mechanisms of action for the induction of cell apoptosis were determined to involve microtubule fragmentation and p53-mediated signaling pathways.