Synthesis and In Vitro Anti-HCV and Antitumor Evaluation of Schisan-dronic acid derivatives

Background: Schisandronic acid (SA), a triterpenoid from fruits of Schisandra sphenanthera, inhibited pan-genotypic HCV entry into human hepatocytes by interfering with virion-cell membrane fusion. It was a promising lead compound for development of novel HCV entry inhibition agents Objective: To search for compounds with more potent anti-HCV and antitumor activities and explore SARs, a series of nov-el derivatives of SA were designed and synthesized and evaluated for in vitro their anti-HCV and antitumor activities.

Methods: SA derivatives were synthesized by reduction, condensation, esterification or amidation. The anti-HCV activity of title compounds was tested by inhibition on HCVcc infection of Huh7 cells, and preliminary MOA study was conducted by determining inhibition on HCVpp entry into Huh7 cells. The antitumor activity in vitro was determined by MTT methods.

Results: Totally 24 novel derivatives were synthesized. Most of the compounds inhibited HCVcc infection. Compounds 5hand 6 showed most potent anti-HCVcc activities and inhibition of HCVpp entry into Huh7 cells without obvious cytotoxici-ty. Most of title compounds showed potent in vitro antitumor activities against Bel7404 and SMMC7721 tumor cell lines. Compounds 5j and 6 exhibited more potent antitumor activity than positive controlSA and DOX.

Conclusion: Structural modification of SA could lead to the discovery of potent anti-HCV or antitumor agents. Compounds 5h, 5j and 6 werepromising lead compounds development of novel HCV entry inhibition or antitumor agents.

Keywords: SAR; Triterpenoids; anti-HCV activity; antitumor activity; schisandronic acid; synthesis.