ABSTRACT
The 6-maleimidocaproylhydrazone derivatives of highly potent antitumor agents 5-Diacetoxypentyldoxorubicin and Morpholinodoxorubicin were synthesized and conjugated to monoclonal antibody BR96 and control IgG. Immunoconjugate molar ratios were generally 7.5-8.5, and dimer aggregate levels were low. The linkers released parent drug at lysosomal pH 5, while they remained stable at neutral pH. BR96 conjugates were highly potent and antigen specific in vitro. The BR96-DAPDOX conjugate demonstrated an IC(50) of 0.03 micrometer and was at least 300-fold more potent than a non-binding IgG-DAPDOX control conjugate.
Subject(s)
Anthracyclines/chemical synthesis , Anthracyclines/pharmacology , Antibiotics, Antineoplastic/chemical synthesis , Antibiotics, Antineoplastic/pharmacology , Antibodies, Monoclonal/chemistry , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Hydrazones/chemical synthesis , Hydrazones/pharmacology , Hydrolysis , Indicators and Reagents , KineticsABSTRACT
Screening of a diverse set of bisbenzimidazoles for inhibition of the hepatitis C virus (HCV) serine protease NS3/NS4A led to the identification of a potent Zn(2+)-dependent inhibitor (1). Optimization of this screening hit afforded a 10-fold more potent inhibitor (46) under Zn(2+) conditions (K(i)=27nM). This compound (46) binds also to NS3/NS4A in a Zn(2+) independent fashion (K(i)=1microM). The SAR of this class of compounds under Zn(2+) conditions is highly divergent compared to the SAR in the absence of Zn(2+), suggesting two distinct binding modes.
