Total synthesis and biological properties of novel antineoplastic (chloromethyl)furanoindolines: an asymmetric hydroboration mediated synthesis of the alkylation subunits.
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.
Mohamadi
F
F
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
Spees
M M
MM
Staten
G S
GS
Marder
P
P
Kipka
J K
JK
Johnson
D A
DA
Boger
D L
DL
Zarrinmayeh
H
H
D000478:Alkylation; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001483:Base Sequence; D001572:Benzofurans; D001896:Boron Compounds / Q000737:chemistry*; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D003509:Cyclohexanecarboxylic Acids / Q000737:chemistry; D053138:Cyclohexenes; D004247:DNA / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D000080890:Duocarmycins; D005260:Female; D005663:Furans / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007933:Leucomycins / Q000737:chemistry* / Q000494:pharmacology; D008175:Lung Neoplasms / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001572:Benzofurans; D001896:Boron Compounds; D003509:Cyclohexanecarboxylic Acids; D053138:Cyclohexenes; D000080890:Duocarmycins; D005663:Furans; D007211:Indoles; D007933:Leucomycins; C054483:U 71184; C085523:1,2-dihydro-1-(chloromethyl)-5-hydroxy-8-methyl-3H-furano(3,2-e)indole; C018782:CC 1065; C060090:adozelesin; D004247:DNA