Synthesis of Dual Target CPT-Ala-Nor Conjugates and Their Biological Activity Evaluation.

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.

Design, synthesis, and biological activity evaluation of campthothecin-HAA-Norcantharidin conjugates as antitumor agents in vitro.

Three components of Camptothecin, hydroxyacetic acid, and functionalized norcantharidins were constructed together to form a novel series of camptothecin derivatives in a good yield. The synthesized campthothecin-HAA-norcantharidin conjugate pro-drugs could suppress cancer cell growth in vitro. These conjugated pro-drug molecules possess therapeutic potential as novel bi-functional conjugates platforms for cancer treatment.

The regio-selective synthesis of 10-hydroxy camptothecin norcantharidin conjugates and their biological activity evaluation in vitro.

A series of conjugates of 10-hydroxy camptothecin (HCPT) with functionalized norcantharidin derivatives were regio-selectively synthesized in the condition of (3-dimethylaminopropyl) ethyl-carbodiimide monohydrochloride in a moderate yield. The synthesized conjugate HCPT pro-drugs can also suppress cancer cell growth in vitro. These conjugated pro-drug constructs possess therapeutic potential as novel bi-functional conjugate platforms for cancer treatment.