Biological Screening of Novel Derivatives of Valproic Acid for Anticancer and Antiangiogenic Properties

Background: Valproic acid (VPA) is a potent anticancer and antiangiogenic agent. However, design andsynthesis of chemical derivatives with improved antiangiogenic and anticancer activities are still necessary. Inthis study a library of novel derivatives of VPA was synthesized and tested.
Methods: A human liver cancer cellline (HepG2) and a human normal embryonic kidney cell line (HEK 293) were exposed to various concentrationsof VPA derivatives for 24 hours and cell viability was checked by MTT colorimetric assay. Anti-angiogenicproperties were evaluated in transgenic zebrafish embryos.
Results: N-valproylglycine derivatives suppressedsurvival almost 70% (p value 0.001) in HepG2 cells but only 10-12% in HEK 293 cells (p value 0.133). Theyalso suppressed angiogenic blood vessel formation by 80% when used between 2-20 μM in zebrafish embryos.Valproic acid hydrazides showed moderate level of anticancer activity by affecting 30-50% (p value 0.001) of cellviability in HepG2 cells and 8-10% in HEK293 cells (p value 0.034).
Conclusion: The majority of compounds inthis study showed potent and stronger antiangiogenic and anticancer activity than VPA. They proved selectivelytoxic to cancer cells and safer for normal cells. Moreover, these compounds inhibited developmental angiogenesisin zebrafish embryos. Based on the fact that liver is a highly vascularized organ, in case of liver carcinoma thesecompounds have the potential to target the pathological angiogenesis and could be an effective strategy to treathepatocellular carcinoma.