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


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Cabral L. I. L., Bras E. M., Henriques M. S. C., Marques C., Frija L. M. T., Barreira L., ...Daha Fazla

CHEMISTRY-A EUROPEAN JOURNAL, sa.13, ss.3251-3262, 2018 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Basım Tarihi: 2018
  • Doi Numarası: 10.1002/chem.201705319
  • Dergi Adı: CHEMISTRY-A EUROPEAN JOURNAL
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Index Chemicus (IC)
  • Sayfa Sayıları: ss.3251-3262
  • İstanbul Kültür Üniversitesi Adresli: Evet

Özet

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 center dot center dot center dot 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.