Self-Assembling Benzothiazole-Based Gelators: A Mechanistic Understanding of in Vitro Bioactivation and Gelation.

Low molecular weight gelators (LMWGs) of chemotherapeutic drugs represent a valid alternative to the existing polymer-based formulations used for targeted delivery of anticancer drugs. Herein we report the design and development of novel self-assembling gelators of the antitumor 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 antitumor 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 nontransformed fibroblasts. Western blots assays demonstrated induction of CYP1A1 by 1 and its derivatives only in sensitive malignant cells (MCF-7), corroborating conservation of a 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 the formation of thick aggregates with variable widths between 1100 and 400 nm and lengths from 8 to 32 µm. Finally, in vitro dissolution studies proved the ability of hydrogel 2 to release 48% of 2 within 80 h, therefore demonstrating its ability to act as a platform for localized delivery.

Kinetically Controlled Coassembly of Multichromophoric Peptide Hydrogelators and the Impacts on Energy Transport.

We report a peptide-based multichromophoric hydrogelator system, wherein π-electron units with different inherent spectral energies are spatially controlled within peptidic 1-D nanostructures to create localized energy gradients in aqueous environments. This is accomplished by mixing different π-conjugated peptides prior to initiating self-assembly through solution acidification. We can vary the kinetics of the assembly and the degree of self-sorting through the choice of the assembly trigger, which changes the kinetics of acidification. The hydrolysis of glucono-δ-lactone (GdL) provides a slow pH drop that allows for stepwise triggering of peptide components into essentially self-sorted nanostructures based on subtle pKa differences, whereas HCl addition leads to a rapid formation of mixed components within a nanostructure. Using 1H NMR spectroscopy and fiber X-ray diffraction, we determine the conditions and peptide mixtures that favor self-sorting or intimate comixing. Photophysical investigations in the solution phase provide insight into the correlation of energy-transport processes occurring within the assemblies to the structural organization of the π-systems.

Antitumour benzothiazoles. Part 32: DNA adducts and double strand breaks correlate with activity; synthesis of 5F203 hydrogels for local delivery.

Potent, selective antitumour AhR ligands 5F 203 and GW 610 are bioactivated by CYPs 1A1 and 2W1. Herein we reason that DNA adducts' generation resulting in lethal DNA double strand breaks (DSBs) underlies benzothiazoles' activity. Treatment of sensitive carcinoma cell lines with GW 610 generated co-eluting DNA adducts (R(2)>0.7). Time-dependent appearance of γ-H2AX foci revealed subsequent DNA double strand breaks. Propensity for systemic toxicity of benzothiazoles steered development of prodrugs' hydrogels for localised delivery. Clinical applications of targeted therapies include prevention or treatment of recurrent disease after surgical resection of solid tumours. In vitro evaluation of 5F 203 prodrugs' activity demonstrated nanomolar potency against MCF-7 breast and IGROV-1 ovarian carcinoma cell lines.