Improving the solubility of anti-proliferative thieno[2,3-b]quinoline-2-carboxamides

• Published in: Bioorganic & medicinal chemistry Vol. 37; p. 116092
• Main Authors: Haverkate, Natalie A., van Rensburg, Michelle, Kumara, Sisira, Reynisson, Jóhannes, Leung, Euphemia, Pilkington, Lisa I., Barker, David
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.05.2021; Elsevier
• Subjects: 3-b]pyridines; Antiproliferative; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Solubility; Thieno; Thieno; Antiproliferative; 3-b]pyridines; Solubility; Thieno[2 3-b]pyridines
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2021.116092

[Display omitted] •Anti-proliferative thieno[2,3-b]quinolines often have poor solubility.•80 different thieno[2,3-b]quinoline derivatives prepared and analysed.•Tetrahydrothieno[2,3-b][1,6]naphthyridines found to be more soluble. Thieno[2,3-b]pyridines are a class of compounds known for their potent anti-proliferative activities against a range of human cancer cell lines. In this research, a number of strategies to generate analogues that have improved aqueous solubility whilst retaining the potent anti-proliferative actions, compared to previously-explored compounds in this class, were made. Herein we report the synthesis of 80 novel compounds, comprising two series, all based on the thieno[2,3-b]pyridine core structure. Overall, it was found that introducing alternative heterocycles did not notably improve the solubility or retain anti-proliferative activity seen in previously-reported analogues. However, pleasingly it was discovered, that the best strategy for improving the solubility was the alteration of the appended alkyl ring to introduce polar groups such as alcohols, ketones and substituted amine groups. In addition to this finding, we have discovered a thieno[2,3-b]pyridine, 15e, with greater aqueous solubility that has ever been seen for this class of compounds that is also a potent inhibitor of cancer cell growth, with IC50′s in the nanomolar range. This new lead structure will form the basis of future explorations into this class of compounds.