Drug development of cucurbitacins requires derivatives that have lower cytotoxicity. Therefore, the effect of structural modification on in vitro cytotoxicity has been investigated. Lipophilicity or chromatographic hydrophobicity index (CHI) was chosen as molecular property. CHI was determined by RP-HPLC in both aqueous acetonitrile and aqueous methanol. Compounds CHI range was wide and better defined in acetonitrile (CHI(ACN)=46-88 and 38-102) than in methanol (CHI(MeOH)=56-78). Higher resolution was achieved in acetonitrile, and higher precision on the shorter C18 column. Cucurbitacins cytotoxicity (IC(50)) was measured on the hepatocyte-derived HepG2 cells. Strong relationship between CHI and logarithmic IC(50) was found. As a result, cytotoxicity increased linearly with increasing hydrophobicity (r>/=0.90). Other lipophilicity parameters, such as logP and ClogP were also estimated. Cytotoxicity correlated well with logP (r=0.95) and slightly with ClogP (r=0.74). The logP and ClogP data showed good correlation with CHI (r>0.92). Overall, alkylation of C1 hydroxyl, unsaturation of C1C2 bond, and acetylation of C25 hydroxyl increased both lipophilicity and cytotoxicity. This assay should prove useful for monitoring cucurbitacin homologues or other drug candidates for their cytotoxicity.
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