Investigation into improving the aqueous solubility of the thieno[2,3-b]pyridine anti-proliferative agents

Ayesha Zafar, Lisa I. Pilkington , Natalie A. Haverkate, Michelle Van Rensburg , Euphemia Leung, Sisira Kumara , William A. Denny , David Barker, Ali Alsuraifi, Clare Hoskins, Jóhannes Reynisson

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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.
Original languageEnglish
Article number145
Number of pages14
Issue number1
Publication statusPublished - 11 Jan 2018


  • 1H-pyrrolo[2,3-b]pyridine
  • polymer formulation
  • nano aggregates
  • morpholine substitution
  • molecular modelling


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