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Published on: July 21, 2018
(R)-6-[N-(3-(4-chlorophenyl) propyl] derivative of (R)-roscovitine inhibits lung carcinoma progression via
Jie Guo1, Jianshe Chen2, Weijie Li3
1School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, PR China; College of Pharmacy, Shenzhen Technology University, Shenzhen, PR China.
Abstract:
Cyclin-dependent kinases (CDKs) are crucial regulators of cell cycle checkpoints, capable of phosphorylating proteins and thereby governing essential cellular functions such as differentiation, proliferation, and apoptosis. Although various CDK inhibitors (CDKIs), including (R)-roscovitine, also known as seliciclib, have demonstrated promising outcomes in preclinical models, their clinical translation has been limited. This study aimed to design and synthesize (R)-roscovitine derivatives with improved pharmacological profiles. A series of compounds (4a-4q) was synthesized, structurally validated and evaluated against cancerous cells, including lung carcinoma (A549), triple-negative breast cancer (MDA-MB-231), and malignant melanoma (A375) cells and normal human epithelial (BEAS-2B) and embryonic lung fibroblasts (MRC-5) cells. Furthermore, the compound was assessed for its inhibitory potential against a broad panel of CDKs. Among these, the (R)-6-[N-(3-(4-chlorophenyl) propyl)] analogue (4 g) showed the highest inhibition of CDK2 and CDK13, along with potent antiproliferative activity (IC50 = 0.61 ± 0.06 μM) against A549 cells compared to (R)-roscovitine (13.30 ± 1.05 μM). Similarly, Compound 4 g showed an IC50 value of 1.437 ± 0.17 μM and 1.280 ± 0.37 μM in BEAS-2B and MRC-5 cells, which is 2 to 2.35 folds of the IC50 value in A549 cells. Compound 4 g significantly (p < 0.0001) induced S-phase cell cycle arrest and suppressed cellular migration and invasion of A549 cells. In silico docking studies revealed a strong and stable interaction with CDK13, with a binding affinity of -8.0 kcal/mol. Compound 4 g demonstrates promising anticancer potential, likely mediated by CDK inhibition with comparatively lower toxicity toward normal cells, however, it requires further toxicological assessment and preclinical studies.
Insights
Researchers developed novel (R)-roscovitine derivatives to improve cancer treatment. Compound 4g showed potent anticancer activity against lung cancer cells by inhibiting cyclin-dependent kinases (CDKs), with reduced toxicity to normal cells.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Cancer Research
Background:
- Cyclin-dependent kinases (CDKs) regulate cell cycle checkpoints and are crucial for cellular functions.
- Existing CDK inhibitors like (R)-roscovitine show promise but face clinical translation challenges.
- There is a need for CDK inhibitors with improved pharmacological profiles and reduced toxicity.
Purpose of the Study:
- To design and synthesize novel (R)-roscovitine derivatives.
- To evaluate the antiproliferative and inhibitory potential of these derivatives against various cancer cell lines and CDKs.
- To investigate the mechanism of action and preliminary toxicity profile of the most promising compound.
Main Methods:
- Synthesis and structural validation of (R)-roscovitine derivatives (compounds 4a-4q).
- In vitro evaluation of antiproliferative activity against lung carcinoma (A549), triple-negative breast cancer (MDA-MB-231), and malignant melanoma (A375) cells.
- Assessment of CDK inhibitory potential and selectivity.
- In silico docking studies to predict binding interactions with target CDKs.
Main Results:
- Compound 4g exhibited potent antiproliferative activity against A549 cells (IC50 = 0.61 μM), significantly outperforming (R)-roscovitine.
- Compound 4g demonstrated strong inhibition against CDK2 and CDK13.
- The compound induced S-phase cell cycle arrest and suppressed migration and invasion in A549 cells, with a favorable toxicity profile compared to cancer cells.
- In silico studies showed strong binding affinity (-8.0 kcal/mol) of compound 4g to CDK13.
Conclusions:
- Compound 4g represents a promising (R)-roscovitine derivative with significant anticancer potential.
- Its efficacy is likely mediated through CDK inhibition, offering a potential therapeutic strategy for lung cancer.
- Further toxicological assessment and preclinical studies are warranted to explore its clinical applicability.
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