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Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay

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Published on: February 9, 2021

Synthesis, Cytotoxic Evaluation, and Structure-Activity Relationship of Substituted Quinazolinones as

Hamad M Alkahtani¹, Amer Alhaj Zen², Ahmad J Obaidullah¹

¹Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

Molecules (Basel, Switzerland)

|January 8, 2023

Abstract:

Cyclin-dependent kinase 9 (CDK9) plays a critical role in transcriptional elongation, through which short-lived antiapoptotic proteins are overexpressed and make cancer cells resistant to apoptosis. Therefore, CDK9 inhibition depletes antiapoptotic proteins, which in turn leads to the reinstatement of apoptosis in cancer cells. Twenty-seven compounds were synthesized, and their CDK9 inhibitory and cytotoxic activities were evaluated. Compounds 7, 9, and 25 were the most potent CDK9 inhibitors, with IC₅₀ values of 0.115, 0.131, and 0.142 μM, respectively. The binding modes of these molecules were studied via molecular docking, which shows that they occupy the adenosine triphosphate binding site of CDK9. Of these three molecules, compound 25 shows good drug-like properties, as it does not violate Lipinski's rule of five. In addition, this molecule shows promising ligand and lipophilic efficiency values and is an ideal candidate for further optimization.

Insights

Targeting cyclin-dependent kinase 9 (CDK9) with novel inhibitors can restore apoptosis in cancer cells. Compounds 7, 9, and 25 show potent CDK9 inhibition, with compound 25 being a promising candidate for further drug development.

Area of Science:

Medicinal Chemistry
Molecular Biology
Cancer Research

Background:

Cyclin-dependent kinase 9 (CDK9) is crucial for transcriptional elongation.
Overexpression of antiapoptotic proteins due to CDK9 activity confers cancer cell resistance to apoptosis.
CDK9 inhibition offers a therapeutic strategy to re-sensitize cancer cells to apoptosis.

Purpose of the Study:

To synthesize and evaluate novel compounds as inhibitors of CDK9.
To identify potent CDK9 inhibitors with potential anticancer activity.
To assess the drug-like properties and optimization potential of lead compounds.

Main Methods:

Synthesis of 27 novel chemical compounds.
In vitro evaluation of CDK9 inhibitory and cytotoxic activities.
Molecular docking studies to elucidate binding modes within the CDK9 ATP-binding site.

Main Results:

Compounds 7, 9, and 25 emerged as the most potent CDK9 inhibitors, with IC50 values below 0.15 μM.
Molecular docking confirmed that these compounds bind to the ATP-binding site of CDK9.
Compound 25 demonstrated favorable drug-like properties, adhering to Lipinski's rule of five, and exhibited promising ligand and lipophilic efficiency.

Conclusions:

The synthesized compounds, particularly 7, 9, and 25, effectively inhibit CDK9.
Compound 25 represents a promising lead molecule for further optimization in anticancer drug discovery due to its potency and drug-like characteristics.

Read full analysis

Keywords:

CDK9 cytotoxic agents molecular docking quinazolinones

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