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

Abstract

3-Amino-2-arylcarboxamido-thieno[2,3-b]pyridines have been shown to have anti-proliferative activity, but are also known to have poor solubility. This has been previously proposed to be due to their extensive planarity, which allows for intermolecular stacking and crystal packing. We herein report the synthesis of fifteen novel thieno[2,3-b]pyridines that have incorporated bulky, but easily cleavable, ester and carbonate functional groups in an effort to decrease crystal packing. The addition of these ‘prodrug-like’ moieties into the thieno[2,3-b]pyridine resulted in compounds with increased activity against HCT-116 colon cancer cells and the triple-negative breast cancer cell line MDA-MB-231.

Synthesis and Anti-Proliferative Activity of 5-Benzoyl and 5-Benzylhydroxy Derivatives of 3-Amino-2-Arylcarboxamido-Thieno[2-3-b]Pyridines

“…Regarding the substitution of the phenyl ring on the eastern fragment (R 2 ) of the molecule, compounds bearing 2,3 di-substitution such as 2,3-Cl (h), 2,3-Br (i) and 2,3naphthyl (j) largely demonstrated the greatest anti-proliferative activity. This result is consistent with previous iterations of the thieno[2,3-b]pyridine compounds [1,11], further demonstrating that this eastern fragment of the molecular scaffold is highly optimised at this point.…”

“…The synthetic strategy to access the benzoylthieno[2-3-b]pyridines and their alcohol derivatives focused on a convergent synthesis of two distinct regions; carbonitrile fragments 12a-c (A) and an array of 2-chloroacetamide fragments 14a-j (B, Scheme 1). These fragments could then be coupled using previously described methods [1,11], affording the desired library of benzoylthieno[2-3-b]pyridines 4a-j, 5a-j and 6a-b, which could then be reduced to give alcohol derivatives 6a-j and 7a-j (C).…”

“…This, however, will be a challenging task due to the electron-rich heteroatoms of the planar thienopyridine core coordinating with and disrupting the chiral reducing agents employed. Another potential change could be exploring how O-acylation of 7h, 7i and 8h with various esters impacts the activity of these compounds, as recent investigations into O-acylation of similar thienopyridines has shown a positive impact on activity through a potential pro-drug pathway [11].…”

“…The combined organic extracts were then washed with H 2 O (10 mL) and brine (15 mL) and dried with MgSO 4 to give the desired alcohols 7a-j and 8a-j, with no further purification required. This procedure has been previously shown to remove borohydride by-products and provide high-purity samples of structurally similar thieno[2-3-b]pyridines [11].…”