On the Solubility and Lipophilicity of Metallacarborane Pharmacophores

0394143 - ÚOCHB 2014 RIV US eng J - Článek v odborném periodiku
Rak, J. - Dejlová, B. - Lampová, H. - Kaplánek, R. - Matějíček, P. - Cígler, Petr - Král, V.
On the Solubility and Lipophilicity of Metallacarborane Pharmacophores.
Molecular Pharmaceutics. Roč. 10, č. 5 (2013), s. 1751-1759. ISSN 1543-8384. E-ISSN 1543-8392
Grant CEP: GA MŠMT(CZ) LH11027; GA TA ČR(CZ) TE01020028; GA AV ČR IAAX00320901
Grant ostatní: GA ČR(CZ) GAP303/11/1291; Biomedreg Project(XE) CZ.1.05/2.1.00/01.0030
Program: GA
Institucionální podpora: RVO:61388963
Klíčová slova: metallacarborane * cobalt bis(dicarbollide) * serum albumin * HIV protease * inhibitor * lipophilicity * P-ow * solubility
Kód oboru RIV: CC - Organická chemie
Impakt faktor: 4.787, rok: 2013

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-water partition coefficients (P-ow) as a lipophilicity descriptor. P-ow 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.
Trvalý link: http://hdl.handle.net/11104/0222446