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Synthesis and cancer cell cytotoxicity of 6-, 7-, or 8-substituted 2-(hetero)aryl-4-(4-(hetero)aryl-2-oxobut-3-en-1-ylidene)benzothiazepanes

Katarina Magdalenic (UGent) , Donatien Morillon, Steven De Jonghe, Leentje Persoons, Dominique Schols, Kristof Van Hecke (UGent) , Charlotte Grootaert (UGent) , John Van Camp (UGent) and Matthias D'hooghe (UGent)
(2025) JOURNAL OF HETEROCYCLIC CHEMISTRY. 62(2). p.249-256
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Abstract
Cancer chemotherapy is continuously challenged by serious complications like pronounced side effects and multidrug resistance (MDR). Natural products, such as curcumin, offer promising alternatives due to their diverse biological applications and low toxicity. However, curcumin's clinical utility is limited by poor bioavailability, rapid metabolism, and non-specific (PAINS) activity. Building on previous findings, this study explored the structural modification of curcumin-inspired benzothiazepane derivatives in an attempt to enhance their therapeutic potential through modifications of the two peripheral (hetero)aromatic rings and the benzothiazepane scaffold. In this way, eight new 2-(hetero)aryl-4-(4-(hetero)aryl-2-oxobut-3-en-1-ylidene)benzothiazepanes and two 4-thiobutan-2-one "double Michael addition" derivatives were synthesized and tested for cytotoxicity against a panel of eight cancer cell lines. The screening results indicated that bis-(4-hydroxyphenyl) analogs bearing a chlorinated benzothiazepane ring exhibited the highest potency and broad-spectrum activity at the low micromolar range. Bis-substitutions with 3-pyridinyl and 2-furyl groups showed less potent but more specific activity profiles, potentially reducing PAINS effects. 2-Aminothiophenol-derived double Michael addition products demonstrated increased broad-spectrum activity, highlighting the importance of the free aniline amino group for targeted effects. This study underscores the potential of benzothiazepane derivatives as viable cancer cell cytotoxic agents and provides useful insights for future optimization and evaluation.
Keywords
CHEMISTRY, CURCUMINOIDS, benzothiazepanes, cancer, curcumin, cytotoxicity, Michael addition

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Citation

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MLA
Magdalenic, Katarina, et al. “Synthesis and Cancer Cell Cytotoxicity of 6-, 7-, or 8-Substituted 2-(Hetero)Aryl-4-(4-(Hetero)Aryl-2-Oxobut-3-En-1-Ylidene)Benzothiazepanes.” JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 62, no. 2, 2025, pp. 249–56, doi:10.1002/jhet.4936.
APA
Magdalenic, K., Morillon, D., De Jonghe, S., Persoons, L., Schols, D., Van Hecke, K., … D’hooghe, M. (2025). Synthesis and cancer cell cytotoxicity of 6-, 7-, or 8-substituted 2-(hetero)aryl-4-(4-(hetero)aryl-2-oxobut-3-en-1-ylidene)benzothiazepanes. JOURNAL OF HETEROCYCLIC CHEMISTRY, 62(2), 249–256. https://doi.org/10.1002/jhet.4936
Chicago author-date
Magdalenic, Katarina, Donatien Morillon, Steven De Jonghe, Leentje Persoons, Dominique Schols, Kristof Van Hecke, Charlotte Grootaert, John Van Camp, and Matthias D’hooghe. 2025. “Synthesis and Cancer Cell Cytotoxicity of 6-, 7-, or 8-Substituted 2-(Hetero)Aryl-4-(4-(Hetero)Aryl-2-Oxobut-3-En-1-Ylidene)Benzothiazepanes.” JOURNAL OF HETEROCYCLIC CHEMISTRY 62 (2): 249–56. https://doi.org/10.1002/jhet.4936.
Chicago author-date (all authors)
Magdalenic, Katarina, Donatien Morillon, Steven De Jonghe, Leentje Persoons, Dominique Schols, Kristof Van Hecke, Charlotte Grootaert, John Van Camp, and Matthias D’hooghe. 2025. “Synthesis and Cancer Cell Cytotoxicity of 6-, 7-, or 8-Substituted 2-(Hetero)Aryl-4-(4-(Hetero)Aryl-2-Oxobut-3-En-1-Ylidene)Benzothiazepanes.” JOURNAL OF HETEROCYCLIC CHEMISTRY 62 (2): 249–256. doi:10.1002/jhet.4936.
Vancouver
1.
Magdalenic K, Morillon D, De Jonghe S, Persoons L, Schols D, Van Hecke K, et al. Synthesis and cancer cell cytotoxicity of 6-, 7-, or 8-substituted 2-(hetero)aryl-4-(4-(hetero)aryl-2-oxobut-3-en-1-ylidene)benzothiazepanes. JOURNAL OF HETEROCYCLIC CHEMISTRY. 2025;62(2):249–56.
IEEE
[1]
K. Magdalenic et al., “Synthesis and cancer cell cytotoxicity of 6-, 7-, or 8-substituted 2-(hetero)aryl-4-(4-(hetero)aryl-2-oxobut-3-en-1-ylidene)benzothiazepanes,” JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 62, no. 2, pp. 249–256, 2025.
@article{01JW6JGG72WZD0S4RCB4195BBS,
  abstract     = {{Cancer chemotherapy is continuously challenged by serious complications like pronounced side effects and multidrug resistance (MDR). Natural products, such as curcumin, offer promising alternatives due to their diverse biological applications and low toxicity. However, curcumin's clinical utility is limited by poor bioavailability, rapid metabolism, and non-specific (PAINS) activity. Building on previous findings, this study explored the structural modification of curcumin-inspired benzothiazepane derivatives in an attempt to enhance their therapeutic potential through modifications of the two peripheral (hetero)aromatic rings and the benzothiazepane scaffold. In this way, eight new 2-(hetero)aryl-4-(4-(hetero)aryl-2-oxobut-3-en-1-ylidene)benzothiazepanes and two 4-thiobutan-2-one "double Michael addition" derivatives were synthesized and tested for cytotoxicity against a panel of eight cancer cell lines. The screening results indicated that bis-(4-hydroxyphenyl) analogs bearing a chlorinated benzothiazepane ring exhibited the highest potency and broad-spectrum activity at the low micromolar range. Bis-substitutions with 3-pyridinyl and 2-furyl groups showed less potent but more specific activity profiles, potentially reducing PAINS effects. 2-Aminothiophenol-derived double Michael addition products demonstrated increased broad-spectrum activity, highlighting the importance of the free aniline amino group for targeted effects. This study underscores the potential of benzothiazepane derivatives as viable cancer cell cytotoxic agents and provides useful insights for future optimization and evaluation.}},
  author       = {{Magdalenic, Katarina and Morillon, Donatien and De Jonghe, Steven and Persoons, Leentje and Schols, Dominique and Van Hecke, Kristof and Grootaert, Charlotte and Van Camp, John and D'hooghe, Matthias}},
  issn         = {{0022-152X}},
  journal      = {{JOURNAL OF HETEROCYCLIC CHEMISTRY}},
  keywords     = {{CHEMISTRY,CURCUMINOIDS,benzothiazepanes,cancer,curcumin,cytotoxicity,Michael addition}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{249--256}},
  title        = {{Synthesis and cancer cell cytotoxicity of 6-, 7-, or 8-substituted 2-(hetero)aryl-4-(4-(hetero)aryl-2-oxobut-3-en-1-ylidene)benzothiazepanes}},
  url          = {{http://doi.org/10.1002/jhet.4936}},
  volume       = {{62}},
  year         = {{2025}},
}
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