Synthesis, Structure, and Cytotoxicity of a New Sulphanyl‐Bridged Thiadiazolyl‐Saccharinate Conjugate: The Relevance of S⋅⋅⋅N Interaction

Abstract

Reports showing that the copper concentration is considerably higher in neoplasms than in normal tissues prompted the need to develop selective copper chelators. We disclosed recently that some N-linked tetrazole-saccharinates bind selectively to copper, forming complexes that are highly cytotoxic towards cancer cells. Because tetrazole-saccharinates are photolabile, due to the photoreactivity of tetrazoles, we proposed thiadiazolyl-saccharinates as an alternative. Herein we describe the synthesis, structure, and monomeric photochemistry of a sulphanyl-bridged thiadiazolyl-saccharinate, 3-[(5-methyl-1,3,4-thiadiazol-2-yl)sulphanyl]-1,2-benzothiazole 1,1-dioxide (MTSB). The monomeric structure, charge density analysis, and characteristic infrared spectrum of MTSB were investigated theoretically, using quantum chemical calculations, and also experimentally, using matrix-isolation infrared spectroscopy. The crystal structure was investigated by combining X-ray crystallography with infrared and Raman spectroscopies. Results show that the structure of isolated MTSB is similar to that found in the crystal, with an S⋅⋅⋅N interaction clearly contributing to the structure of the molecule and of the crystal. Matrix irradiation revealed a high photostability of MTSB, compared to parent tetrazole-saccharinates and to the 5-methyl-1,3,4-thiadiazole building block, emphasizing the photostabilizing effect of the saccharyl system. Finally, in vitro toxicity assays of MTSB showed a copper concentration-dependent toxicity against cancer cells, without affecting normal cells. In particular, MTSB was most effective towards the hepatic (HepG2), neuroblastoma (SH-SY5), and lymphoma cell lines (U937). Thus, MTSB represents a promising lead for cancer chemotherapy based on chelating agents.

In Vitro Assessment of Antimicrobial, Antioxidant, and Cytotoxic Properties of Saccharin–Tetrazolyl and –Thiadiazolyl Derivatives: The Simple Dependence of the pH Value on Antimicrobial Activity

“…Similarly, compound 9 (MTSB) was prepared by coupling 2 and 5-methyl-1,3,4-thiadiazole-2-thiol (8) (Scheme 1 (C)). All of the reactions proceeded smoothly under experimental protocols originally developed by us [56][57][58][59], affording crystalline products in reasonable to very good yields. Scheme 1.…”

“…The synthesis of 3-chloro-1,2-benzisothiazole-1,1-dioxide (2), 2-methyl-(2H)-tetrazole-5-amine (4a), 1-methyl-(1H)-tetrazole-5-amine (4b), N-(1H-tetrazol-5-yl)-N-(1,1-dioxo-1,2-benzisothiazol-3-yl) amine (5) (TS), N-(2-methyl-2H-tetrazol-5-yl)-N-(1,1-dioxo-1,2-benzisothiazol-3-yl) amine (6) (2MTS), N-(1-methyl-2H-tetrazol-5-yl)-N-(1,1-dioxo-1,2-benzisothiazol-3-yl) amine (7) (TSMT), and 3-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]-1,2-benzisothiazole 1,1-dioxide (9) (MTSB) was carried out as previously described [55,56,58,59].…”