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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.
Original languageEnglish
Article number145
Number of pages14
JournalMolecules
Volume23
Issue number1
DOIs
Publication statusPublished - 11 Jan 2018

Fingerprint

Solubility
pyridines
solubility
Water
Polymers
Allylamine
Pyridines
Polymer matrix
Sulfur
Scaffolds
Inhibitory Concentration 50
water
Adenocarcinoma
Nitrogen
Cells
Derivatives
polymers
Atoms
viability
drugs

Keywords

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

Cite this

Zafar, A., Pilkington , L. I., Haverkate, N. A., Van Rensburg , M., Leung, E., Kumara , S., ... Reynisson, J. (2018). Investigation into improving the aqueous solubility of the thieno[2,3-b]pyridine anti-proliferative agents. Molecules, 23(1), [145]. https://doi.org/10.3390/molecules23010145
Zafar, Ayesha ; Pilkington , Lisa I. ; Haverkate, Natalie A. ; Van Rensburg , Michelle ; Leung, Euphemia ; Kumara , Sisira ; Denny , William A. ; Barker, David ; Alsuraifi, Ali ; Hoskins, Clare ; Reynisson, Jóhannes . / Investigation into improving the aqueous solubility of the thieno[2,3-b]pyridine anti-proliferative agents. In: Molecules. 2018 ; Vol. 23, No. 1.
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Zafar, A, Pilkington , LI, Haverkate, NA, Van Rensburg , M, Leung, E, Kumara , S, Denny , WA, Barker, D, Alsuraifi, A, Hoskins, C & Reynisson, J 2018, 'Investigation into improving the aqueous solubility of the thieno[2,3-b]pyridine anti-proliferative agents', Molecules, vol. 23, no. 1, 145. https://doi.org/10.3390/molecules23010145

Investigation into improving the aqueous solubility of the thieno[2,3-b]pyridine anti-proliferative agents. / Zafar, Ayesha ; Pilkington , Lisa I. ; Haverkate, Natalie A. ; Van Rensburg , Michelle ; Leung, Euphemia ; Kumara , Sisira ; Denny , William A. ; Barker, David ; Alsuraifi, Ali; Hoskins, Clare; Reynisson, Jóhannes .

In: Molecules, Vol. 23, No. 1, 145, 11.01.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Investigation into improving the aqueous solubility of the thieno[2,3-b]pyridine anti-proliferative agents

AU - Zafar, Ayesha

AU - Pilkington , Lisa I.

AU - Haverkate, Natalie A.

AU - Van Rensburg , Michelle

AU - Leung, Euphemia

AU - Kumara , Sisira

AU - Denny , William A.

AU - Barker, David

AU - Alsuraifi, Ali

AU - Hoskins, Clare

AU - Reynisson, Jóhannes

PY - 2018/1/11

Y1 - 2018/1/11

N2 - 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.

AB - 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.

KW - 1H-pyrrolo[2,3-b]pyridine

KW - polymer formulation

KW - nano aggregates

KW - morpholine substitution

KW - molecular modelling

U2 - 10.3390/molecules23010145

DO - 10.3390/molecules23010145

M3 - Article

VL - 23

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 1

M1 - 145

ER -

Zafar A, Pilkington LI, Haverkate NA, Van Rensburg M, Leung E, Kumara S et al. Investigation into improving the aqueous solubility of the thieno[2,3-b]pyridine anti-proliferative agents. Molecules. 2018 Jan 11;23(1). 145. https://doi.org/10.3390/molecules23010145