title: Calculation of lipophilicity of a large, diverse dataset of anticancer platinum complexes and the relation to cellular uptake.
abstract: A quantitative structure--property relationship (QPSR) for the octanol--water partition of platinum complexes was constructed using molecular descriptors derived from density functional (DFT) calculations. A dataset of partition data for 64 complexes, consisting of 43 square-planar platinum(II) and 21 octahedral platinum(IV) complexes, was drawn from literature sources. Not only does this dataset include considerable structural diversity of complexes considered but also a variety of techniques for the measurement of partition coefficients. These data were modeled using descriptors drawn from electrostatic potentials and hardness/softness indices projected onto molecular surfaces. This required initial descriptor selection using a genetic algorithm approach, followed by partial least-squares regression against log Po/w data. In this way, a statistically robust model was constructed, with errors of similar size to the variation in log Po/w from multiple experimental measurements. Implications of lipophilicity for cellular accumulation of Pt-based drugs, and hence for design of new drugs, are discussed, as is the uptake of metabolites of cisplatin.
authors: School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, U.K.
authors: Steven P
authors: SP
authors: Oldfield
authors: Matthew D
authors: MD
authors: Hall
authors: James A
authors: JA
authors: Platts
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D001693:Biological Transport, Active; D004058:Diffusion; D016018:Least-Squares Analysis; D008954:Models, Biological; D000442:Octanols; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity; D014867:Water
chemical_list: D000970:Antineoplastic Agents; D000442:Octanols; D009944:Organoplatinum Compounds; D014867:Water