New N-Adducts of Thiadiazole and Thiazoline with Levoglucosenone and Evaluation of Their Significant Cytotoxic (Anti-Cancer) Activity

Tomasz Poplawski; Grzegorz Galita; Joanna Sarnik; Anna Macieja; Roman Bielski; Donald E Mencer; Zbigniew J Witczak

doi:10.3390/cancers16010216

New N-Adducts of Thiadiazole and Thiazoline with Levoglucosenone and Evaluation of Their Significant Cytotoxic (Anti-Cancer) Activity

Cancers (Basel). 2024 Jan 2;16(1):216. doi: 10.3390/cancers16010216.

Authors

Tomasz Poplawski¹, Grzegorz Galita², Joanna Sarnik³, Anna Macieja¹, Roman Bielski⁴, Donald E Mencer⁵, Zbigniew J Witczak⁴

Affiliations

¹ Department of Pharmaceutical Microbiology and Biochemistry, Medical University, 92-215 Lodz, Poland.
² Department of Clinical Chemistry and Biochemistry, Medical University, 92-215 Lodz, Poland.
³ Department of Rheumatology, Medical University, 90-050 Lodz, Poland.
⁴ Department of Pharmaceutical Sciences, Nesbitt School of Pharmacy, Wilkes University, 84 W. South Street, Wilkes-Barre, PA 18766, USA.
⁵ Department of Chemistry and Biochemistry, Wilkes University, 84 W. South Street, Wilkes-Barre, PA 18766, USA.

Abstract

The conjugate N-adducts of thio-1,3,4-diazole and 2-thiazoline with levoglucosenone were synthesized via a stereoselective, base-catalyzed conjugate N-Michael addition to levoglucosenone at C-4. Structural assignments were established using 1H and 13C NMR analysis, and X-ray single-crystal analysis for one of the compounds. The biological properties of the novel compounds were tested on a cell model. Cytotoxicity was analyzed via colorimetric assay. Two distinct types of cell death, apoptosis and necrosis, were analyzed by determining the phosphatidylserine levels from the outer leaflet of the plasma membrane, caspase activation, and lactate dehydrogenase release. We also evaluated DNA damage using an alkaline comet assay. The level of oxidative stress was measured with a modified comet assay and an H2DCFDA probe. The thio-1,3,4-diazole adduct (FCP23) and the 2-thiazoline adduct (FCP26) exhibit similar cytotoxicity values for cancer cells (ovarian (A2780), breast (MCF-7), cervix (HeLa), colon (LoVo), and brain (MO59J and MO59K)), but their mechanism of action is drastically different. While FCP23 induces oxidative stress, DNA damage, and necrosis, FCP26 induces apoptosis through caspase activation.

Keywords: DNA damage; apoptosis; levoglucosenone; thiadiazole; thiazoline.

Grants and funding

This research received no external funding. Crystallographic data for the structure FCP26 reported in this paper have been deposited into the Cambridge Crystallographic Data Centre and allocated the deposition number CCDC 2212572. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax þ 44 1223 336033 or e-mail deposit@ccdc.com.ac.uk).