Self-assembling benzothiazole-based gelators: a mechanistic understanding of in vitro bioactivation and gelation

Citossi, Francesca, Smith, Thomas, Lee, Jong Bong, Segal, Joel, Gershkovich, Pavel, Stocks, Michael John, Bradshaw, Tracey D., Kellam, Barrie and Marlow, Maria (2018) Self-assembling benzothiazole-based gelators: a mechanistic understanding of in vitro bioactivation and gelation. Molecular Pharmaceutics, 15 (4). pp. 1578-1586. ISSN 1543-8392

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Low molecular weight gelators (LMWGs) of chemotherapeutic drugs represent a valid alternative to the existing poly-mer-based formulations used for targeted delivery of anticancer drugs. Herein we report the design and development of novel self-assembling gelators of the antitumour benzothiazole 5F 203 (1). Two different types of derivatives of 1 were synthesized, formed by an amide (2) and a carbamate (3a-3d) linker, respectively, which showed potent in vitro anti-tumour activity against MCF-7 mammary and IGROV-1 ovarian carcinoma cells. In contrast, MRC-5 fibroblasts were inherently resistant to the above derivatives (GI50>10 μM), thus revealing stark selectivity against the malignant cell lines over the non-transformed fibroblasts. Western blots assays demonstrated induction of CYP1A1 by 1 and its deriva-tives only in sensitive malignant cells (MCF-7), corroborating conservation of CYP1A1-mediated mechanism of action. The ability to form stable gels under relatively high strains was supported by rheological tests; in addition, their inner morphology was characterized as possessing a crossed-linked nanostructure, with formation of thick aggregates with variable widths between 1100 nm and 400 nm and lengths from 8 μm to 32 μm. Finally, in vitro dissolution studies proved the ability of hydrogel 2 to release 48% of 2 within 80 hours, therefore demonstrating its ability to act as a plat-form for localized delivery.

Item Type: Article
Additional Information: Copyright © 2018 American Chemical Society
Keywords: benzothiazole derivatives, low molecular weight gelators, CYP1A1 induction, in vitro antitumour activity
Schools/Departments: University of Nottingham, UK > Faculty of Science > School of Pharmacy
Identification Number:
Depositing User: Eprints, Support
Date Deposited: 07 Mar 2018 15:36
Last Modified: 05 Mar 2019 04:30

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