Abstract
A series of 12 polysubstituted pyrrolo[3,4-b]pyridin-5-ones were synthesized via a one-pot cascade process (Ugi–3CR/aza Diels-Alder/N-acylation/decarboxylation/dehydration) and studied in vitro using human epithelial cervical carcinoma SiHa, HeLa, and CaSki cell line cultures. Three compounds of the series exhibited significative cytotoxicity against the three cell lines, with HeLa being the most sensitive one. Then, based on these results, in silico studies by docking techniques were performed using Paclitaxel as a reference and αβ-tubulin as the selected biological target. Worth highlighting is that strong hydrophobic interactions were observed between the three active molecules and the reference drug Paclitaxel, to the αβ-tubulin. In consequence, it was determined that hydrophobic–aromatic moieties of bioactive compounds and Paclitaxel play a key role in making stronger interactions to the ligand–target complex. A quantitative structure activity relationship (QSAR) study revealed that the six membered rings are the most significant molecular frameworks, being present in all proposed models for the in vitro-studied cell lines. Finally, also from the docking interpretation, a ligand-based pharmacophore model is proposed in order to find further potential polyheterocyclic candidates to bind stronger to the αβ-tubulin.
Highlights
Cancer is a disease currently killing 13% of the population worldwide mainly because patients do not receive efficient treatments
One polyheterocyclic system that we can synthesize à la carte is the pyrrolo[3,4-b]pyridin-5-one [23], which is considered as a privileged aza-analogue of the isoindolin-1-one [24], the latter being the structural core of various natural and synthetic anticancer agents [25]
Stepwise methodologies have been reported in synthesizing novel pyrrolo[3,4-b]pyridin-5-ones, for example, Devasthale and co-workers synthesized a panel of pyrrolo[3,4-b]pyridin-5-ones, evaluating in vitro their properties as inhibitors of the dipeptidyldipentidase-4 (DPP-4) [26]
Summary
Cancer is a disease currently killing 13% of the population worldwide mainly because patients do not receive efficient treatments. (iii) kinases; (iv) multidomain extra-terminal (MET) proteins; (v) p53 activity; (vi) transcription initiation factor (TIF) proteins; or vii) topoisomerases (TOP), just to highlight a few [15] In this context, one of the most important biological targets in the fight against cancer are the tubulins, which belong to microtubules ( the α and the β) involved in mitosis processes [16,17,18]. The present work describes the use of pyrrolo[3,4-b]pyridin-5-ones (reported or new) against SiHa, HeLa, and CaSki human cervical carcinoma cell cultures, as well as in silico studies through molecular docking techniques to propose a ligand-based pharmacophore model, in addition to a QSAR study For the latter, αβ-tubulin was used as the biological target. The increase in cell division, being the main feature in cancer malignancies, is a highly attractive target for medicinal/synthetic chemists and the design and synthesis of compounds interfering in microtubule dynamics, by means of tubulin-binding, is still being of great importance, as well as in vitro and in silico activity evaluation [19,20]
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