Activity Trends in Desoxy Anthrapyrazoles: The Influence of Molar Volume, Polarizability and Lipophilicity of N₂ C₅ Side Chains on Their Anticancer Response

Abstract

QSAR methodology was used to assess the effects of lipophilicity (logP), molar volume (MV) and polarizability (pl) of the side chains at N₂ and C₅ of 20 known desoxy anthrapyrazoles on their in vitro anticancer activity expressed as the negative logarithm of the inhibitory concentration of 50% of L1210 murine leukemia cell line (1/logIC₅₀). The main data set shows poor correlations between biological response and the descriptors with exception of MV of the C₅ side chain, where a moderate correlation was discerned ( =0.60, n = 18, two outliers). To extract more information regarding mechanism, the main data set was visually classified to three clusters depending on N₂ side chain. Cluster 1 containing six 5-substituted 2-[(2-hydroxyethyl) amino] ethyl anthrapyrazoles; cluster 2 contains ten 5-subsitutes 2-(diethyl amino) ethyl anthrapyrazoles and cluster 3 contains four anthrapyrazoles with miscellaneous substituents at both N₂ and C₅. For cluster 1, MV and pl of C₅ show high correlation with biological response (R²’s = 0.75 and 0.72 respectively) while logP gives a weak correlation (R² = 0.44). For cluster 2, the correlations of logP and pl of C₂side chain are higher (=0.66 and 0.62 respectively) compared with MV (=0.16). Cluster 3 shows very poor correlation with all descriptors (~0.3). This indicates mechanistic distinction between the three clusters. Derived descriptors which represent the difference between the descriptors of N₂ and C₅ side chains where used to explore the presence of interplay between these descriptors in affecting variability of the biological response.