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Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents
Published on: May 28, 2014
Design and synthesis of some β-carboline derivatives as multi-target anticancer agents
Mohamed A Abdelsalam1, Omaima M AboulWafa1, El-Sayed Am Badawey1
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Aim:
Some anticancer β-carbolines exhibited dual inhibition of topo-I and KSP.
Methodology/Results:
Novel β-carbolines were synthesized and screened for their anticancer activity according to the NCI protocol. Five dose assays results indicated that compounds 9, 10, 12, 17 and 20 were potent and non selective anticancer agents; the sulfanyltriazole 12 was the most potent. Compounds 10, 12 and 20 showed dual topo-I and KSP inhibition with compound 12 being the most potent. Active compounds elicited Pre-G1 apoptosis and cell cycle arrest at G2/M phase of melanoma MDA-MB-435 cells. Docking results, in silico physicochemical and absorption, distribution, metabolism, excretion (ADME) properties were appropriate.
Conclusion:
Compounds 10, 12 and 20 are potent apoptosis-inducing multitarget anticancer agents that act via dual inhibition of topo-I and KSP-ATPase.
Insights
Novel anticancer beta-carbolines were developed, showing potent activity against cancer cells. Compounds 10, 12, and 20 effectively induce apoptosis via dual inhibition of topoisomerase I (topo-I) and KSP-ATPase.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Cancer Research
Background:
- Beta-carbolines are a class of compounds with known biological activities.
- Targeting topoisomerase I (topo-I) and Kinesin Spindle Protein (KSP)-ATPase are promising strategies for cancer therapy.
Purpose of the Study:
- To synthesize and evaluate novel beta-carbolines for anticancer properties.
- To investigate the mechanism of action, including dual inhibition of topo-I and KSP-ATPase.
Main Methods:
- Synthesis of novel beta-carboline derivatives.
- Anticancer activity screening using the NCI protocol.
- In vitro assays for topoisomerase I and KSP-ATPase inhibition.
- Apoptosis and cell cycle analysis in melanoma cells.
- In silico studies including docking and ADME property prediction.
Main Results:
- Five compounds (9, 10, 12, 17, 20) demonstrated potent, non-selective anticancer activity.
- Compound 12 (a sulfanyltriazole) was the most potent agent.
- Compounds 10, 12, and 20 exhibited dual inhibition of topo-I and KSP-ATPase.
- These active compounds induced Pre-G1 apoptosis and G2/M cell cycle arrest in MDA-MB-435 melanoma cells.
- In silico analyses confirmed favorable physicochemical and ADME profiles.
Conclusions:
- Compounds 10, 12, and 20 are effective multi-target anticancer agents.
- Their mechanism involves potent apoptosis induction through dual inhibition of topo-I and KSP-ATPase.
- These novel beta-carbolines represent promising candidates for further anticancer drug development.
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