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

doi:10.3390/molecules23010145

Paper

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

Published Jan 1, 2018 · A. Zafar, L. Pilkington, Natalie A. Haverkate

Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry

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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.

Study Snapshot

Thieno[2,3-b]pyridine anti-proliferative agents can be improved by increasing their water solubility and increasing their cancer cell killing potency by loading them into a polymer matrix.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

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

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References

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Modifications at C-5 can lead to compounds with greater antiproliferative activity than modifications at 3-amino and 2-aryl carboxamide functionalities.

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This study demonstrates an efficient synthesis of 3-amino-2-carboxamide pyrrolo[2,3-b]quinolines and fused-ring pyrrolopyridines using a Thorpe-Ziegler transformation, enabling the production of nitrogen analogues of thienopyr

Hydration Free Energy as a Molecular Descriptor in Drug Design: A Feasibility Study

Calculated hydration energy (Ghyd) can effectively serve as a molecular descriptor in drug design, with a preference for values of 5 kcal/mol or less for successful candidate development.

Evidence that phospholipase C is involved in the antitumour action of NSC768313, a new thieno[2,3-b]pyridine derivative

Thieno[2,3-b]pyridine derivatives inhibit cancer cell growth by targeting phospholipase C, potentially enhancing the effectiveness of mitotic poisons in cancer treatment.

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