On the Solubility and Lipophilicity of Metallacarborane Pharmacophores

Abstract

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 (Pow) as a lipophilicity descriptor. Pow weakly correlates with the water solubility of metallacarboranes, whereas the ability of HSA to increase the solubility of metallacarboranes correlates well with their Pow values. Because metallacarboranes are known inhibitors of HIV protease, the possible correlation between Pow 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.

Organotin Dyes Bearing Anionic Boron Clusters as Cell‐Staining Fluorescent Probes

“…[28,29] COSANh as ad ispersed negative charget hat gives rise to electrostatic interactions, [30] and ah ydrophobic surface that can engagei nn onbondingi ntermolecular interactions through its weakly polarized BÀHa nd CÀHb onds. [31,32] These inorganic anions have been shown to possesse xceptional chemicala nd thermals tability, [33][34][35] amphiphilicity, [36][37][38][39][40][41][42] as well as unusual physicochemical properties in water that confer an ability to self-assemble into micelles and monolayer vesicles. [36,41,43] The visualization of lipidic membranes by COSAN-containingf luoresceinp robes has also been reported.…”

Classical Amphiphilic Behavior of Nonclassical Amphiphiles: A Comparison of Metallacarborane Self‐Assembly with SDS Micellization

“…[6][7][8][9] As aresult of the presence of hydridic BÀHv ertices and charge delocalization, the [CoD] À anion exhibits surface activity [10][11][12] and has an amphiphilic character.Asaresult, it accumulates at interfaces and is soluble in both oil and water. [13] With this in mind, it is not surprising that metallacarboranes selfassemble in water in spite of their unusual molecular structure. [14][15][16][17][18][19][20][21] In this Communication, we compare the association behavior of Na [CoD] with the most studied ionic surfactant-sodium dodecylsulfate (SDS;F igure 1B).…”

GRL-04810 and GRL-05010, Difluoride-Containing Nonpeptidic HIV-1 Protease Inhibitors (PIs) That Inhibit the Replication of Multi-PI-Resistant HIV-1 In Vitro and Possess Favorable Lipophilicity That May Allow Blood-Brain Barrier Penetration

“…Of note, GRL-04810 reached the highest concentration in the octanol lipid interface (72 M) versus 14.09 M for GRL-05010 and 11.89 M for DRV (Table 4). GRL-04810 appeared the most lipophilic, with a log D value of Ϫ0.29, representing a 4-fold greater log D value than that of DRV (Ϫ1.03), since the assumption is that the more negative the log D value is, the less lipophilic the substance is estimated to be (40). GRL-05010 was found to have a log D value (Ϫ1.01) comparable to that of DRV.…”

“…1-Octanol, organic alcohol, and water were used for log P determination, while Trisbuffered saline (pH 7.4) and water were utilized for log D determination. Prior to obtaining the actual values, a standard curve was generated as a reference, and drug concentrations attained for each compartment (1-octanol, water, and Tris-buffered saline) were measured on a light spectrophotometer (at an absorbance of 230 nm) as previously described by Rak et al (40). Of note, GRL-04810 reached the highest concentration in the octanol lipid interface (72 M) versus 14.09 M for GRL-05010 and 11.89 M for DRV (Table 4).…”