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

Molecules. 2018 Jan 11;23(1):145. doi: 10.3390/molecules23010145.


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.

Keywords: 1H-pyrrolo[2,3-b]pyridine; molecular modelling; morpholine substitution; nano aggregates; polymer formulation.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Polymers
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Pyridines / pharmacology
  • Solubility
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Polymers
  • Pyridines
  • thieno(2,3-b)pyridine