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

Tarfah Al-Warhi¹, Ahmed M El Kerdawy^2,3, Nada Aljaeed¹

¹Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 12271, Saudi Arabia.

Molecules (Basel, Switzerland)

|May 1, 2020

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.

Insights

New oxindole-indole conjugates show potent antitumor activity by inhibiting cyclin-dependent kinase 4 (CDK4). Compounds 6a and 6e are promising leads for developing novel breast cancer therapeutics.

Area of Science:

Medicinal Chemistry
Oncology
Drug Discovery

Background:

Cyclin-dependent kinases (CDKs) are crucial regulators of the cell cycle and are frequently overexpressed in human cancers.
CDK inhibition is a validated strategy for anticancer drug development.
Targeting CDK4 is particularly relevant for certain malignancies.

Purpose of the Study:

To design and synthesize novel oxindole-indole and carbocycle-indole conjugates as potential antitumor agents.
To evaluate the antiproliferative activity of these compounds against human breast cancer cell lines.
To investigate the inhibitory potential against CDK4 and explore the mechanism of action.

Main Methods:

Hybrid pharmacophore approach for compound design.
Synthesis of oxindole-indole and carbocycle-indole conjugates.
In vitro antiproliferative assays against MCF-7 and MDA-MB-231 cell lines.
Cell cycle analysis and apoptosis assays.
Enzyme inhibition assays against CDK4.
Molecular docking studies.

Main Results:

Several oxindole-indole conjugates (e.g., 6a-h, 9a, 9e) exhibited significant antiproliferative effects on breast cancer cells.
Compounds 6e and 6f induced cell cycle arrest and apoptosis in MCF-7 cells.
Hybrids 6a and 6e demonstrated potent CDK4 inhibitory activity (IC50s of 1.82 and 1.26 µM, respectively).
Molecular docking revealed key interactions of the oxindole and indole moieties with CDK4 active site residues.

Conclusions:

Oxindole-indole conjugates represent a promising class of antitumor agents.
Compounds 6a and 6e are identified as potent CDK4 inhibitors and potential drug leads for breast cancer.
The study provides a foundation for further optimization of these hybrids as anticancer therapeutics.

Read full analysis

Keywords:

CDK4 inhibitors anti-proliferative activity apoptosis breast cancer oxindole

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