ABSTRACT
To develop hemoglobin (Hb) derivatives with an increased circulatory half-life, Hb was chemically modified with long chain fatty acid analogs. One compound, sodium 1-hexadecyl 6-(2-iodoacetamido)hexyl phosphate, specifically modified the Cys-93 beta residues of human hemoglobin (HbA) as determined by sulfhydryl titration analysis. The resulting modified Hb derivative, FAHbA, was isolated and was shown to have a two-fold longer circulatory half-life than native HbA in a rat low-dose acute transfusion model.
Subject(s)
Fatty Acids/chemistry , Hemoglobins/chemistry , Hemoglobins/pharmacokinetics , Animals , Blood Transfusion , Blood Vessels , Cysteine/chemistry , Half-Life , Male , Molecular Structure , Rats , Rats, Sprague-Dawley , Sulfhydryl Compounds/blood , Time Factors , TitrimetryABSTRACT
Thirty-eight 2-(aryl or heteroaryl)quinolin-4-amines, N,N-disubstituted, N-monosubstituted, and without a substituent at the amino group have been synthesized with use of novel chemistries developed by us recently. Some of these derivatives show anti-HIV-1 activity at a concentration level of 1 microM and low cell toxicity in vitro. The most active and least toxic compounds are derivatives of 2-(3-pyridyl)quinoline. The results of the quantitative structure-activity relationship analyses, including several classical, linear regression correlations and a Free-Wilson approach of de novo model, provide guidelines for the design of new active compounds of this class.
