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
This study summarizes the antitumor properties of a number of sulofenur thiophene analogs against subcutaneously implanted 6C3HED lymphosarcoma with structural modification of the aryl moiety of the sulfonamide portion of the diarylsulfonylureas. The spectrum of activity of N-(p-chlorophenyl)-N'- [(5-methoxy-2-thienyl)sulfonyl]urea in the HXGC3, VRC5, CX-1, and LX-1 cell lines is also presented.
