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

Abstract

It is now established that the thieno[2,3-<i>b</i>]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 1<i>H</i>-pyrrolo[2,3-<i>b</i>]pyridine core structure. The water solubility was increased by three orders of magnitude, from 1.2 µg/mL (<b>1</b>-thieno[2,3-<i>b</i>]pyridine) to 1.3 mg/mL (<b>3</b>-pyrrolo[2,3-<i>b</i>]pyridine), however, it was only marginally active against cancer cells. The second strategy involved loading a very potent thieno[2,3-<i>b</i>]pyridine derivative (<b>2</b>) 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.