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-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.

Validating TDP1 as an Inhibition Target for the Development of Chemosensitizers for Camptothecin-Based Chemotherapy Drugs

“…As our initial work with thieno[2,3-b]pyridines and TDP1 was conducted with a relatively small library [35,38], we first carried out in vitro studies to validate thieno [2,3-b]pyridines as inhibitors of TDP1. One of our laboratories has synthesized and acquired [ 100 thieno [2,3b]pyridines derivatives [35,38,[69][70][71][72][73][74][75][76][77]. By using this extensive library, we screened for inhibition of TDP1 activity using a fluorescence-based inhibition assay with a synthetic oligonucleotide biosensor as substrate [78].…”

Disruption of Crystal Packing in Thieno[2,3-b]pyridines Improves Anti-Proliferative Activity

“…The purpose of prodrugs is generally to optimize the absorption, distribution, metabolism, and excretion (ADME) of the parent compound, and a variety of different chemical moieties can be attached to the potential drug structure in order to improve these properties. As the thienopyridines have historically had poor solubility [ 2 , 15 ], it was thought that modification via addition of such a chemical moiety could aid absorption and cell penetration, after which the protecting group could be cleaved by intracellular esterases to allow the thienopyridines to exert their potent cytotoxic effect. In order to improve the pharmacokinetic profile of this class of anti-proliferatives, we sought to synthesise a range of related prodrugs and assess if addition of these moieties affected their activity.…”

Molecular modelling insights into a physiologically favourable approach to eicosanoid biosynthesis inhibition through novel thieno[2,3-b]pyridine derivatives

“…This hetero-bicyclic scaffold has been studied for its versatile activities against inflammatory disorders, albeit for other subcellular targets 31–33 . Thienopyridine derivatives have also been reported for their potent anti-proliferative activities 34 , 35 . Moreover, our target thieno[2,3- b ]pyridine is a close congener to benzothiophene, a nucleus recently tested for inhibition of COX1/2 and 5-LOX 36 ( Figure 2 ).…”