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Synthesis of Dual Target CPT-Ala-Nor Conjugates and Their Biological Activity Evaluation
Chang K Zhao1, Lang Xu1, Xian H Wang1
1School of Pharmacy, Zunyi Medical University, No.6 Xue Fu West Road, Zunyi City, 563003, China.
Background:
Target therapy has been one of the important strategies in new drug discovery and the resulting drug resistance has also been a serious problem for concern. At the same time, there are several cancer genes or pathways operating within a given cancer. Given these two things, the combination therapy will be needed for optimal therapeutic effect.
Objective:
Camptothecin and norcantharidin were thus chosen to construct a dual anticancer drugs assemblies mainly because CPT was the DNA-topoisomerase I inhibitor and norcantharidin could also suppress the cancer cell growth by inhibiting protein phosphatase. The designed conjugate of camptothecin and norcantharidin linked by alanine was expected to have dual target drug properties.
Methods:
EDCI/DMAP was chosen as a coupling agent for the coupling of CPT with substituted norcantharidin derivatives and CCK-8 method was used to test the cytotoxicity and intensity on human hepatoma cell line HepG2. Two kinds of enzymes, Top I and CDC 25B were selected to screen the binding affinity in molecular level.
Results:
Nine of dual targets camptothecin derivatives were smoothly synthesized by twice coupling in the condition of EDCI/DMAP in moderate yield. All of the synthesized compounds were characterized by 1HNMR and 13CNMR spectrum and exhibited strong potent inhibition against Hep G2, SW480, BGC803, and PANC-1 cell line in vitro. The newly synthesized camptothecin compounds, such as 3j and 3i have strengthened inhibition activity compared to camptothecin and norcantharidin.
Conclusion:
We have successfully synthesized a series of novel camptothecin derivatives constructed from three components of camptothecin, alanine and norcantharidin. These compounds not only preserved strong activity against several cancer cell lines in vitro, but also exhibited potential binding affinity to target Top I and CDC 25B. Therefore, these conjugates linked by alanine could suppress cancer cell growth by inhibiting Top I and protein phosphatase simultaneously, which makes it much valuable as a novel bi-functional target drug candidate to develop in vivo.
Insights
Novel dual-target anticancer drugs combining camptothecin and norcantharidin were synthesized. These new compounds show potent inhibition against cancer cells by targeting DNA topoisomerase I and protein phosphatase simultaneously.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Targeted therapy is crucial for cancer drug discovery, but drug resistance remains a significant challenge.
- Multiple cancer genes and pathways necessitate combination therapies for optimal efficacy.
- Developing novel bifunctional drugs addresses the complexity of cancer treatment.
Purpose of the Study:
- To synthesize novel dual-target anticancer drug conjugates.
- To combine camptothecin (CPT), a DNA-topoisomerase I inhibitor, with norcantharidin, a protein phosphatase inhibitor.
- To evaluate the in vitro efficacy and binding affinity of these novel conjugates.
Main Methods:
- Synthesized nine camptothecin derivatives conjugated with norcantharidin via alanine using EDCI/DMAP coupling.
- Assessed cytotoxicity against human cancer cell lines (HepG2, SW480, BGC803, PANC-1) using the CCK-8 assay.
- Screened binding affinity to target enzymes, Topoisomerase I and CDC 25B, at the molecular level.
Main Results:
- Successfully synthesized nine novel dual-target camptothecin derivatives with moderate yields.
- All synthesized compounds demonstrated potent in vitro inhibition against multiple cancer cell lines.
- Compounds 3j and 3i exhibited enhanced inhibition compared to parent drugs camptothecin and norcantharidin.
Conclusions:
- A series of novel camptothecin-alanine-norcantharidin conjugates were successfully synthesized.
- These compounds retain strong in vitro anticancer activity and show potential binding to Top I and CDC 25B.
- These bifunctional conjugates offer a promising strategy for simultaneous inhibition of Top I and protein phosphatase, representing valuable novel drug candidates.
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