Hansch analysis of antitumor 4β-( arylamino )-4-desoxypodophyllotoxins and their 4' -demethyl analogs

Division of Pharmaceutical Chemistry, Seemanta Institute of Pharmaceutical Sciences, Jharpokharia,

Mayurbhanj-757 086, India

QSAR Lab, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology,

Jadavpur University, Calcutta-700 032, India

Antitumor activities (in vitro KB cell cytotoxicity and cellular protein-linked DNA damage data) of 4-arylamino derivatives (P1-P16) of epipodophyllotoxin and 4'-demethylepipodophyllotoxin are subjected to Hansch analysis with various physicochemical parameters [electronic (σ), hydrophobicity (π) and steric (MR)] of the phenyl ring suhstituents (R₁) alongwith some indicator variables. The best relation [EV = 75.9%, R = 0.898, F = 16.7 (df = 3, 12), PRESS : r = 0.808] relating KB cell cytotoxicity data with physicochemical/indicator parameters suggests that bulkier substituents at ortho and meta positions on the phenyl ring reduce the activity while an electron-withdrawing para-substituent increases the activity. Further, 4'-demethylation does not alter the activity significantly. The best relation [EV = 84.6%, R = 0.936, F = 28.4 (df = 3, 12), PRESS : r = 0.890] involving cellular protein-DNA complex formation data shows that 4cdeinethyl derivatives have higher activity. The equation also suggests that size of ortho-sub­stituent and lipophilicity of meta and para substituents (R₁) on the phenyl ring have negative contributions. Poor correlation (r = 0.396) is found between the two types of activity data. The hypothesis that DNA-breakage is insufficient to cause cell death may explain the lack of correlation between the activity parameters.