Synthesis, Biological Evaluation and In Silico Studies of Certain Oxindole–Indole Conjugates as Anticancer CDK Inhibitors

Abstract

On account of their overexpression in a wide range of human malignancies, cyclin-dependent kinases (CDKs) are among the most validated cancer targets, and their inhibition has been featured as a valuable strategy for anticancer drug discovery. In this study, a hybrid pharmacophore approach was adopted to develop two series of oxindole–indole conjugates (6a–i and 9a–f) and carbocycle–indole conjugates (11a,b) as efficient antitumor agents with potential inhibitory action toward CDK4. All oxindole–indole conjugates, except 6i, 9b, and 9c efficiently affected the growth of the human breast cancer MCF-7 (IC50: 0.39 ± 0.05–21.40 ± 1.58 μM) and/or MDA-MB-231 (IC50: 1.03 ± 0.04–22.54 ± 1.67 μM) cell lines, whereas bioisosteric replacement of the oxindole nucleus with indane or tetralin rings (compounds 11a,b) diminished the anti-proliferative activity. In addition, hybrids 6e and 6f displayed effective cell cycle disturbance and proapoptotic capabilities in MCF-7 cells. Furthermore, the efficient anti-proliferative agents towards MCF-7 and/or MDA-MB-231 cell lines (6a–h, 9a, and 9e) were investigated for their potential inhibitory action toward CDK4. Hybrids 6a and 6e displayed good CDK4 inhibitory activity with IC50s equal 1.82 and 1.26 µM, respectively. The molecular docking study revealed that oxindole moiety is implicated in two H-bonding interactions via both (NH) and (C=O) groups with the key amino acids Glu94 and Val96, respectively, whereas the indole framework is stably accommodated in a hydrophobic sub-pocket establishing hydrophobic interactions with the amino acid residues of Ile12, Val20, and Gln98 lining this sub-pocket. Collectively, these results highlighted hybrids 6a and 6e as good leads for further optimization as promising antitumor drugs toward breast malignancy and CDK inhibitors.

A New CDK2 Inhibitor with 3-Hydrazonoindolin-2-One Scaffold Endowed with Anti-Breast Cancer Activity: Design, Synthesis, Biological Evaluation, and In Silico Insights

“…The ester compound 3 was reacted with hydrazine hydrate to afford hydrazide 4 . 5-methoxyindole 2,3-dione condensed in anhydrous condition with 4 to produce the target HI 5 ( Scheme 1 ) using previously described methods for reported compounds ( 2 – 4 ) [ 32 , 33 ].…”

Discovery of New Coumarin-Based Lead with Potential Anticancer, CDK4 Inhibition and Selective Radiotheranostic Effect: Synthesis, 2D & 3D QSAR, Molecular Dynamics, In Vitro Cytotoxicity, Radioiodination, and Biodistribution Studies

“…The molecular hybridization of two or more bioactive pharmacophores is considered to be an optimistic strategy for the design and discovery of novel anticancer drugs [ 45 , 46 ]. This study has been focused on the development of two new sets of hybridized compounds to be evaluated as potential anticancer agents against some cancer cell lines with possible CDK4 kinase inhibitory activity.…”

Novel oxindole/benzofuran hybrids as potential dual CDK2/GSK-3β inhibitors targeting breast cancer: design, synthesis, biological evaluation, and in silico studies

“…1H-indole-2,3-dione (isatin) is a privileged scaffold that emerged as a promising nucleus in medicinal chemistry demonstrating a broad range of pharmacological activities including antibacterial, anticonvulsant, antifungal, antiviral, as well as anticancer activity [76][77][78] . Isatin derivatives exert their anticancer activity through several mechanisms such as inhibition and/or modulation of proteases, translation initiation, angiogenesis or tubulin polymerisation, moreover, PK inhibition is one of the key anticancer mechanisms of isatin derivatives [76][77][78] . Several oxindole-based multikinase inhibitors ( Figure 2) have been approved for cancer treatment such as sunitinib (2006) for gastrointestinal stromal tumour and renal cell carcinoma as PDGFR and VEGFR inhibitor 79 , and nintedanib (2014) for idiopathic pulmonary fibrosis as FGFR, PDGFR and VEGFR inhibitor 80 .…”

“…Several oxindole-based multikinase inhibitors ( Figure 2 ) have been approved for cancer treatment such as sunitinib (2006) for gastrointestinal stromal tumour and renal cell carcinoma as PDGFR and VEGFR inhibitor 79 , and nintedanib (2014) for idiopathic pulmonary fibrosis as FGFR, PDGFR and VEGFR inhibitor 80 . Moreover, several oxindole derivatives have been designed and synthesised as inhibitors for diverse PKs such as FLT3 kinase 81 , VEGFR 82–83 , polo-like kinase 4 (PLK4) 84 , aurora B kinase 85 , p90 ribosomal S6 protein kinase 2 (RSK2) 86 , microtubule affinity-regulating kinase 4 (MARK4) 87 as well as CDKs 78 , 88 , and GSK-3β 59 .…”