Format

Send to

Choose Destination
Molecules. 2018 Jan 11;23(1). pii: E145. doi: 10.3390/molecules23010145.

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

Author information

1
School of Chemical Sciences, University of Auckland, 23 Symonds Street, 1142 Auckland, New Zealand. ash_imran@hotmail.com.
2
School of Chemical Sciences, University of Auckland, 23 Symonds Street, 1142 Auckland, New Zealand. lisa.pilkington@auckland.ac.nz.
3
School of Chemical Sciences, University of Auckland, 23 Symonds Street, 1142 Auckland, New Zealand. nhav422@aucklanduni.ac.nz.
4
School of Chemical Sciences, University of Auckland, 23 Symonds Street, 1142 Auckland, New Zealand.
5
Auckland Cancer Society Research Centre and Department of Molecular Medicine and Pathology, University of Auckland, 1142 Auckland, New Zealand. e.leung@auckland.ac.nz.
6
Auckland Cancer Society Research Centre and Department of Molecular Medicine and Pathology, University of Auckland, 1142 Auckland, New Zealand. s.kumara@auckland.ac.nz.
7
Auckland Cancer Society Research Centre and Department of Molecular Medicine and Pathology, University of Auckland, 1142 Auckland, New Zealand. b.denny@auckland.ac.nz.
8
School of Chemical Sciences, University of Auckland, 23 Symonds Street, 1142 Auckland, New Zealand. d.barker@auckland.ac.nz.
9
Institute for Science and Technology in Medicine, Keele University, Stoke-on-Trent ST4 7QB, UK. a.t.y.alsuraifi@keele.ac.uk.
10
Institute for Science and Technology in Medicine, Keele University, Stoke-on-Trent ST4 7QB, UK. c.hoskins@keele.ac.uk.
11
School of Chemical Sciences, University of Auckland, 23 Symonds Street, 1142 Auckland, New Zealand. j.reynisson@auckland.ac.nz.

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.

KEYWORDS:

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

PMID:
29324695
PMCID:
PMC6017400
DOI:
10.3390/molecules23010145
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Multidisciplinary Digital Publishing Institute (MDPI) Icon for PubMed Central
Loading ...
Support Center