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Synlett
DOI: 10.1055/a-2637-7357
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Benzo[d][1,2]thiazepin-5-One 3-Oxides ‒ an Unexplored Scaffold With Anticancer Activity

Demyd S. Milokhov 
1   Chemistry Department, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine (Ringgold ID: RIN111229)
2   Ecology, Hygiene and Ecology Institute Bogomolets National Medical University, Kyiv, Ukraine
,
Mykhailo S. Pomalin
1   Chemistry Department, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine (Ringgold ID: RIN111229)
3   Department of organic synthesis, Enamine Ltd, Kyiv, Ukraine (Ringgold ID: RIN376198)
,
Tetiana M. Lutsiuk
1   Chemistry Department, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine (Ringgold ID: RIN111229)
3   Department of organic synthesis, Enamine Ltd, Kyiv, Ukraine (Ringgold ID: RIN376198)
,
Vasyl Y. Hys
1   Chemistry Department, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine (Ringgold ID: RIN111229)
4   of organic synthesis, Enamine Ltd, Kyiv, Ukraine (Ringgold ID: RIN376198)
,
Pavlo A. Virych
1   Chemistry Department, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine (Ringgold ID: RIN111229)
,
Anton O. Poliudov
3   Department of organic synthesis, Enamine Ltd, Kyiv, Ukraine (Ringgold ID: RIN376198)
5   Chemistry department, National Technical University of Ukraine Igor Sikorsky Kyiv Polytechnic Institute, Kyiv, Ukraine (Ringgold ID: RIN187495)
,
Maria Popova
6   Department for the Synthesis of Macromolecules, Max Planck Institute for Polymer Research, Mainz, Germany (Ringgold ID: RIN28308)
7   Chemistry Department, Kiev National Taras Shevchenko University, Kiev, Ukraine
,
Svetlana Shishkina
8   Department of X-ray Diffraction Studies and Quantum Chemistry, State Scientific Institution “Institute for Single Crystals” National Academy of Science of Ukraine, Kharkiv, Ukraine
9   Department of X-ray Diffraction Studies, Institute of Organic Chemistry National Academy of Sciences of Ukraine, Kyiv, Ukraine (Ringgold ID: RIN202071)
,
Yulian M. Volovenko
7   Chemistry Department, Kiev National Taras Shevchenko University, Kiev, Ukraine
,
Alexey Dobrydnev 
7   Chemistry Department, Kiev National Taras Shevchenko University, Kiev, Ukraine
10   Scientific Support, Enamine Ltd, Kyiv, Ukraine (Ringgold ID: RIN376198)
› Author Affiliations
Supported by: Enamine Ltd
Supported by: Ministry of Education and Science
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Herein, we report a simple and versatile method for the synthesis of previously unknown benzo[d][1,2]thiazepin-5-one 3-oxides through the CSIC (carbanion-mediated sulfonamide intramolecular cyclization) reaction strategy. The starting compounds are readily available methyl 2-(bromomethyl)benzoates and imino((di)methyl)(het/aryl)-λ6-sulfanones. The method works well with a wide range of substrates, proving its applicability for the synthesis of benzo- and heterofused derivatives. It allows for the effortless preparation of target endocyclic keto sulfoximines and easy scale-up without diminishing the yield. The synthetic utility of the target compounds was demonstrated by the preparation of several derivatives, some of them represented two novel heterocyclic systems. In vitro cytotoxicity assay showed selective cytotoxicity of S-phenyl substituted benzo[d][1,2]thiazepin-5-one 3-oxide against triple-negative breast cancer cell line MDA-MB-231. The molecular docking study confirmed good binding affinity of both enantiomeric forms of endocyclic keto sulfoximines to the cancer-associated receptors which are the therapeutic targets in cancer treatment.



Publication History

Received: 28 March 2025

Accepted after revision: 16 June 2025

Accepted Manuscript online:
17 June 2025

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