Synthesis and biological activity evaluation of 3-(hetero) arylideneindolin-2-ones as potential c-Src inhibitors

Abstract

Inhibition of c-Src is considered one of the most studied approaches to cancer treatment, with several heterocyclic compounds approved during the last 15 years as chemotherapeutic agents. Starting from the biological evaluation of an in-house collection of small molecules, indolinone was selected as the most promising scaffold. In this work, several functionalised indolinones were synthesised and their inhibitory potency and cytotoxic activity were assayed. The pharmacological profile of the most active compounds, supported by molecular modelling studies, revealed that the presence of an amino group increased the affinity towards the ATP-binding site of c-Src. At the same time, bulkier derivatizations seemed to improve the interactions within the enzymatic pocket. Overall, these data represent an early stage towards the optimisation of new, easy-to-be functionalised indolinones as potential c-Src inhibitors.

Aromatase inhibition plus/minus Src inhibitor saracatinib (AZD0530) in advanced breast cancer therapy (ARISTACAT): a randomised phase II study

“…[42] Next generation, more selective Src inhibitors are currently being developed and tested in pre-clinical environments. [43,44] These include the novel Src kinase inhibitor NXP900, with a unique and novel mechanism of Src inhibition by interfering with catalytic and scaffolding functions, by targeting the native inactive conformation of Src. This compound demonstrated higher potency and selectivity than any other Src inhibitor, on a panel of breast cancer cell lines and also demonstrated potency in vivo.…”

Medicinal Chemistry Perspectives on Recent Advances in Src Kinase Inhibitors as a Potential Target for the Development of Anticancer Agents: Biological Profile, Selectivity, Structure‐Activity Relationship

“…The nitrogen atom of indolin-2one ring formed hydrogen bond with Leu276 amino acid residue Src kinase. [29] Three unique sets of 4-aryl-4H-chromene candidates were synthesized and tested for anticancer activity in this work by Abdelall et G1 cell accumulation and cell cycle arrest in S phase in MCF-7 cells. In addition, in the early and late phases of apoptosis, 11 generated a 7-and 63-fold increase in an apoptotic cell population.…”

“…The results demonstrated that 7 was not a cytotoxic candidate when compared to Dasatinib so the derivative was the best inhibitor in the cell‐free assay. The nitrogen atom of indolin‐2‐one ring formed hydrogen bond with Leu276 amino acid residue Src kinase [29] …”

Dual activity of indolin-2-ones containing an arylidene motif: DNA and BSA interaction

“…Thiazole-containing 3-(hetero) AINDs have been the most promising activity (IC 50 = 33 ± 2 μM). 33 Very good selectivity followed with inhibitory potency against FGFR1 enzyme was declared for AINDs that contain morpholine or piperazine moiety. 34 Furthermore, Senwar et al pointed out the importance of the presence of an additional heterocyclic motif that positively affects the anticancer activity of AINDs.…”