Molecules
Department of Pharmaceutical Chemistry, Pharmacy Program, Batterejee Medical College, Jeddah 6231, Saudi Arabia.
Published: April 2020
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 ( and ) and carbocycle-indole conjugates (, as efficient antitumor agents with potential inhibitory action toward CDK4. All oxindole-indole conjugates, except , , and efficiently affected the growth of the human breast cancer MCF-7 (IC: 0.39 ± 0.05-21.40 ± 1.58 μM) and/or MDA-MB-231 (IC: 1.03 ± 0.04-22.54 ± 1.67 μM) cell lines, whereas bioisosteric replacement of the oxindole nucleus with indane or tetralin rings (compounds ,) diminished the anti-proliferative activity. In addition, hybrids and 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 (, , and ) were investigated for their potential inhibitory action toward CDK4. Hybrids and displayed good CDK4 inhibitory activity with ICs 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 and as good leads for further optimization as promising antitumor drugs toward breast malignancy and CDK inhibitors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248897 | PMC |
http://dx.doi.org/10.3390/molecules25092031 | DOI Listing |
Molecules
April 2020
Department of Pharmaceutical Chemistry, Pharmacy Program, Batterejee Medical College, Jeddah 6231, Saudi Arabia.
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 ( and ) and carbocycle-indole conjugates (, as efficient antitumor agents with potential inhibitory action toward CDK4. All oxindole-indole conjugates, except , , and efficiently affected the growth of the human breast cancer MCF-7 (IC: 0.
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