ABSTRACT
1,2-Dihydro-1-(chloromethyl)-5-hydroxy-8-methyl-3H-furano[3,2-e]in dole (CFI) as a novel replacement of the cyclopropylpyrroloindoline (CPI) alkylation subunit of CC-1065, U-71184, and U-73975 (adozelesin) has been synthesized and incorporated into a series of efficacious antineoplastic agents. A partial solution to an asymmetric synthesis of the CFI alkylation subunit has been achieved by the implementation of an asymmetric hydroboration reaction of an intermediate 3-methyleneindoline (13). Extension to the asymmetric synthesis of the CBI and CI alkylation subunits is presented. The demonstration and comparative study of the sequence-selective DNA alkylation properties of the CFI-based agents are detailed, and the preliminary in vitro and in vivo antineoplastic properties of these agents in the human epidermoid cell lung carcinoma (T222) are described.
Subject(s)
Antineoplastic Agents/chemical synthesis , Boron Compounds/chemistry , Furans/chemical synthesis , Indoles/chemical synthesis , Leucomycins/chemistry , Alkylation , Animals , Antineoplastic Agents/pharmacology , Base Sequence , Benzofurans , Carcinoma, Squamous Cell/pathology , Cyclohexanecarboxylic Acids/chemistry , Cyclohexenes , DNA/drug effects , Drug Screening Assays, Antitumor , Duocarmycins , Female , Furans/pharmacology , Humans , Indoles/chemistry , Indoles/pharmacology , Leucomycins/pharmacology , Lung Neoplasms/pathology , Mice , Mice, Nude , Molecular Sequence Data , Tumor Cells, CulturedABSTRACT
A series of hydroxyacetophenones was prepared for evaluation as leukotriene B4 (LTB4) receptor antagonists, culminating in 1-[5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5- yl)heptyl]oxy]phenyl]ethanone (compound 35, LY255283). Using an assay for inhibition of specific [3H]LTB4 binding to human PMN, we found that substitution of a nonpolar substituent in the 5-position was required for activity. Best activity was realized with hydrogen in the 3-position, hydroxyl in the 2-position, short chain alkyl ketone in the 1-position, and a six- or eight-carbon chain linking the oxygen in the 4-position with an unsaturated terminal function. Compound 35, having an IC50 of 87 nM in the binding assay, was chosen for further preclinical evaluation.