Design, Synthesis and Anti‐Cancer Activities of Benzyl Analogues of Garlic‐Derived Diallyl Disulfide (DADS) and the Corresponding Diselenides

Abstract

The anti‐cancer activity of garlic mainly arises due to the presence of various organosulfur compounds including diallyl sulfide (DAS), diallyl disulfide (DADS) and diallyl trisulfide (DATS). Herewith, we report a number of 4‐substituted benzyl analogs of DADS and their selenium counterparts for a detailed structure‐activity relationship towards their anti‐proliferative activities in human breast cancer cell lines. Disulfide having 4‐cyano group exhibited highest activity among all disulfides. In contrast, all diselenides exhibited very good anti‐proliferative activities than DADS. Furthermore, unlike disulfides, diselenides were more selective towards cancer cells over normal cells. Some active compounds were further tested for their activities in some organ specific cell lines such as HepG2, PC‐3 and HCT‐116 to understand their efficacy. Elevated level of intracellular reactive oxygen species (ROS) by most of the benzyl diselenides reveals a possible mode of their action. Therefore, this study indicates that the anti‐proliferative activity of DADS can be significantly enhanced upon suitable structural modifications.

SG1002 and Catenated Divalent Organic Sulfur Compounds as Promising Hydrogen Sulfide Prodrugs

“…Moreover, Bhattacherjee et al ( 28 ) recently stated that bis(4-cyanobenzyl)disulfide exhibited the highest antiproliferative activity, among all the 4-substituted benzyl analogues of diallyl disulfide (DADS) studied, in assays using MCF-7 human breast cancer cell lines. These authors found that the half maximal inhibitory concentration (IC 50 ) values (μ M ) for bis(4-cyanobenzyl)disulfide, DADS, and DBDS were 3.66, 16.76, and 43.60, respectively; whereas toward the normal kidney epithelial cell line (NKE) the respective values were 65.71, 45.43, and 70.11.…”

“…In some instances, it is possible to quantitatively correlate biological outcomes with only one parameter: If the RDS is a chemical reaction, this parameter is often pKa, a Hammett electronic substituent constant, or a Taft steric substituent constant ( 92 ). In the following paragraphs, we will describe a particularly interesting and pertinent linear correlation between the cytotoxicities (Log IC 50 ) of a series of symmetric para-substituted DBDSs and Hammett's sigma substituent constants; the existence of this correlation was overlooked by the authors of the paper from which the data were taken ( 28 ).…”

“…Bhattacherjee et al ( 28 ) studied the cytotoxicities (toward human MCF-7 breast cancer cells) of DBDS and of four symmetric para-substituted derivatives bearing fluoro, methoxy, cyano, and nitro substituent groups in both para positions; they found that the difluoro derivative and DBDS exhibited very similar cytotoxicities, that a decrease in potency accompanied the incorporation of nitro and methoxy groups, and that replacement of the para-H atoms by cyano groups led to a dramatic enhancement of cytotoxic activity.…”

“…Participants Country: Mexico (State University of Nuevo León, UANL, Monterrey) Infertile men recruited from UANL's Reproductive Biology Clinic at the University Hospital. Mean age: 34.23 (range[24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. n = 44 men completed the study.…”

An Appraisal of Developments in Allium Sulfur Chemistry: Expanding the Pharmacopeia of Garlic

“…Similarly, other synthetic sulfide derivatives appear to be anti-proliferative in cancer cells, suggesting some commonality in their anti-proliferative effects. This property appears to correspond with the induction of ROS production in cancer cells [108,109] and the S -thiolation of intracellular proteins [110]. Other pronounced biological effects of synthetic sulfide derivatives include neuroprotection by bis [2-(3,4-dimethoxy phenyl) ethenyl] dithioperoxy anhydride and bis [2-(3-methoxy,4-hydroxy phenyl) ethenyl] dithioperoxy anhydride derivatives (Figure 7C,D) [111,112], and cardioprotective properties [113].…”