On the Solubility and Lipophilicity of Metallacarborane Pharmacophores

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• 作者：Jakub Rak ; Barbora Dejlov谩 ; Hana Lampov谩 ; Robert Kapl谩nek ; Pavel Mat臎j铆膷ek ; Petr C铆gler ; Vladim铆r Kr谩l
• 刊名：Molecular Pharmaceutics
• 出版年：2013
• 出版时间：May 6, 2013
• 年：2013
• 卷：10
• 期：5
• 页码：1751-1759
• 全文大小：544K
• 年卷期：v.10,no.5(May 6, 2013)
• ISSN：1543-8392

文摘

Metallacarborane moieties have been identified as promising pharmacophores. The pharmaceutical use of such compounds is, however, complicated by their low solubility and tendency to self-assemble in aqueous solution. In this work, we estimated the solubilities of a vast series of metallacarboranes [cobalt bis(dicarbollide) derivatives] in pure water, saline, and saline with human serum albumin as a model of blood plasma. In addition, we determined the octanol鈥搘ater partition coefficients (P_ow) as a lipophilicity descriptor. P_ow weakly correlates with the water solubility of metallacarboranes, whereas the ability of HSA to increase the solubility of metallacarboranes correlates well with their P_ow values. Because metallacarboranes are known inhibitors of HIV protease, the possible correlation between P_ow and the ability to inhibit HIV protease was investigated. Results from this study indicate that interaction of metallacarborane inhibitors with HIV protease is driven by specific binding rather than by promiscuous lipophilic interactions. The most promising candidates for further drug development were identified by ligand lipophilicity efficiency analysis.

Keywords:

metallacarborane; cobalt bis(dicarbollide); serum albumin; HIV protease; inhibitor; lipophilicity; P_ow; solubility