Affiliation: | 1. Chemistry Department, University of Minho, Campus de Gualtar, Braga, Portugal
These authors contributed equally to this work.;2. Life and Health Sciences Research Institute (ICVS), University of Minho, Campus de Gualtar, Braga, Portugal
ICVS/3B's – PT Government Associate Laboratory, Braga/Guimarães, Portugal
These authors contributed equally to this work.;3. Life and Health Sciences Research Institute (ICVS), University of Minho, Campus de Gualtar, Braga, Portugal
ICVS/3B's – PT Government Associate Laboratory, Braga/Guimarães, Portugal
Contribution: Conceptualization (lead), Methodology (lead), Supervision (equal), Writing - review & editing (equal);4. Life and Health Sciences Research Institute (ICVS), University of Minho, Campus de Gualtar, Braga, Portugal;5. Chemistry Department, University of Minho, Campus de Gualtar, Braga, Portugal |
Abstract: | An in silico study focused on known cancer-related target proteins, identified a selection of imidazo4,5-b]pyrrolo3,4-d]pyridines as potentially active. These compounds were prepared by a novel synthetic approach, designed and developed in-house, based on the reaction of 5-amino-4-cyanoformimidoyl imidazoles with N-substituted cyanoacetamides. The substituted imidazolylpyrrolones obtained, were cyclized intramolecularly to generate the intended imidazo4,5-b]pyrrolo3,4-d]pyridines in a process catalyzed by DBU. Treating the imidazolylpyrrolones with an excess of triethyl orthoformate and heating at 80 °C in the presence of acid catalysis led to imidazopyrrolodiazepines. These compounds were screened for their anticancer potential, using the renal cell carcinoma cell line model (A498 and 786-O cell lines). Two compounds exhibited IC50 values in the low micromolar range with a good selectivity index, when compared to non-neoplastic kidney cell line HK2 and the reference compounds rapamycin, cediranib and sunitinib. |