Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents

Reynisson, Johannes

Abstract

It is now established that the thieno[2,3-b]pyridines are a potent class of antiproliferatives. One of the main issues encountered for their clinical application is their low water solubility. In order to improve this, two strategies were pursued. First, a morpholine moiety was tethered to the molecular scaffold by substituting the sulphur atom with nitrogen, resulting in a 1H-pyrrolo[2,3-b]pyridine core structure. The water solubility was increased by three orders of magnitude, from 1.2 µg/mL (1-thieno[2,3-b]pyridine) to 1.3 mg/mL (3-pyrrolo[2,3-b]pyridine), however, it was only marginally active against cancer cells. The second strategy involved loading a very potent thieno[2,3-b]pyridine derivative (2) into a cholesteryl-poly(allylamine) polymer matrix for water solubilisation. Suppression of human pancreatic adenocarcinoma (BxPC-3) viability was observed to an IC50 value of 0.5 µg/mL (1.30 µM) in conjunction with the polymer, which is a five-fold (×5) increase in potency as compared to the free drug alone, demonstrating the utility of this formulation approach.

Citation

Reynisson, J. (2018). Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents. Molecules, https://doi.org/10.3390/molecules23010145

• Acceptance Date: Jan 10, 2018
• Publication Date: Jan 11, 2018
• Journal: Molecules
• Publisher: MDPI
• DOI: https://doi.org/10.3390/molecules23010145
• Keywords: morpholine substitution; 1H-pyrrolo[2,3-b]pyridine; molecular modelling; nano aggregates; polymer formulation
• Publisher URL: http://www.mdpi.com/1420-3049/23/1/145