Synthesis and in vitro biological evaluation of thiosulfinate derivatives for the treatment of human multidrug-resistant breast cancer

Abstract

Organosulfur compounds derived from Allium vegetables have long been recognized for various therapeutic effects, including anticancer activity. Allicin, one of the main biologically active components of garlic, shows promise as an anticancer agent; however, instability makes it unsuitable for clinical application. The aim of this study was to investigate the effect of stabilized allicin derivatives on human breast cancer cells in vitro. In this study, a total of 22 stabilized thiosulfinate derivatives were synthesized and screened for their in vitro antiproliferative activities against drug-sensitive (MCF-7) and multidrug-resistant (MCF-7/Dx) human adenocarcinoma breast cancer cells. Assays for cell death, apoptosis, cell cycle progression and mitochondrial bioenergetic function were performed. Seven compounds (4b, 7b, 8b, 13b, 14b, 15b and 18b) showed greater antiproliferative activity against MCF-7/Dx cells than allicin. These compounds were also selective towards multidrug-resistant (MDR) cells, a consequence attributed to collateral sensitivity. Among them, 13b exhibited the greatest anticancer activity in both MCF-7/Dx and MCF-7 cells, with IC values of 18.54±0.24 and 46.50±1.98 μmol/L, respectively. 13b altered cellular morphology and arrested the cell cycle at the G/M phase. Additionally, 13b dose-dependently induced apoptosis, and inhibited cellular mitochondrial respiration in cells at rest and under stress. MDR presents a significant obstacle to the successful treatment of cancer clinically. These results demonstrate that thiosulfinate derivatives have potential as novel anticancer agents and may offer new therapeutic strategies for the treatment of chemoresistant cancers.

Plant-Derived Natural Products in Cancer Research: Extraction, Mechanism of Action, and Drug Formulation

“…More recently, several stabilized allicin derivatives were synthesized and tested for their activity on drug-sensitive (MCF-7) and multidrug-resistant (MCF-7/Dx) human breast cancer cells. Some of these derivatives were more effective than free allicin on inducing apoptosis [581].…”

Allicin and Digestive System Cancers: From Chemical Structure to Its Therapeutic Opportunities

“…Various stabilized allicin derivatives were synthesized and examined for their activity on multidrug-resistant (MCF-7/Dx) and drug-sensitive (MCF-7) human breast cancer cells. Some of these derivatives were more beneficial than free allicin on starting apoptosis ( 170 ).…”

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

“…In the work of Roseblade et al, the synthesis and biological assessment of a series of 22 aromatic and aliphatic thiosulfinates were determined. These compounds were screened in an in vitro breast-cancer model using human adenocarcinoma breast-cancer cell lines MCF-7 and multidrug resistant (MDR) subline MCF-7/Dx [60]. Respective synthetic analogs S -butyl butane-1-sulfinothioate and S -4-methoxyphenyl-4-methoxybenzenesulfinothioate (Figure 3A,B) were identified as lead anticancer agents, having greater potency than that of allicin.…”

“…Structures of novel synthetic sulfur compounds based on the naturally occurring thiosulfinate allicin. Several thiosulfinate derivatives have anticancer properties, like ( A ) S -butyl butane-1-sulfinothioate, ( B ) S -4-methoxyphenyl 4-methoxybenzenesulfinothioate [60], and ( C ) novel antithrombotic agent difluoroallicin [61]. …”