Solubility, ionization, and partitioning behavior of unsymmetrical disulfide compounds: alkyl 2-imidazolyl disulfides.
Alkyl 2-imidazolyl disulfide compounds are novel antitumor agents, one of which is currently being evaluated in Phase I clinical trials. These molecules contain an unsymmetrical disulfide fragment, the lipophilic and electronic contributions of which are still not defined in the literature. Lipophilicity, ionization, and solubility of a number of alkyl 2-imidazolyl disulfides were studied. Based on the additivity of lipophilicity and ionization properties, the contribution of the unsymmetrical disulfide fragment to lipophilicity and ionization was elucidated. The unsymmetrical disulfide fragment contributed a Rekker's hydrophobic constant of 0.761 to the lipophilicity of these compounds and an approximated Hammett constant (sigma) of 0.30 to their ionization. The applicability of the general solubility equation (GSE) proposed by Jain and Yalkowsky in predicting the aqueous solubility of these analogs was evaluated. The GSE correctly ranked the aqueous solubilities of these compounds and estimated their log molar solubilities with an average absolute error of 0.35.
Graduate School of Pharmaceutical Sciences, Room 422B, 600 Forbes Avenue, Mellon Hall of Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, USA.
Ahmad
A
Hashash
D Lynn
DL
Kirkpatrick
John S
JS
Lazo
Lawrence H
LH
Block
D004220:Disulfides / Q000737:chemistry / Q000493:pharmacokinetics*; D005544:Forecasting; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D007477:Ions / Q000737:chemistry; D011199:Potentiometry; D012995:Solubility / Q000187:drug effects
D004220:Disulfides; D007093:Imidazoles; D007477:Ions