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Calculation of lipophilicity of a large, diverse dataset of anticancer platinum complexes and the relation to cellular uptake

Oldfield, Steven Peter, Hall, Matthew D. and Platts, James Alexis 2007. Calculation of lipophilicity of a large, diverse dataset of anticancer platinum complexes and the relation to cellular uptake. Journal of Medicinal Chemistry 50 (21) , pp. 5227-5237. 10.1021/jm0708275

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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.

Item Type: Article
Status: Published
Schools: Chemistry
Subjects: Q Science > QD Chemistry
Publisher: ACS
ISSN: 0022-2623
Last Modified: 20 Oct 2017 19:58
URI: http://orca-mwe.cf.ac.uk/id/eprint/12531

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