Cyclopropamitosenes, novel bioreductive anticancer agents. Synthesis, electrochemistry, and biological activity of 7-substituted cyclopropamitosenes and related indolequinones.
The synthesis of the indolequinones 8 and 9 starting from methyl 4-(benzyloxy)-5-methoxy-indole-2-carboxylate (10) is described. The methoxy group in the indolequinones 1, 2, 4, 5, and 7-9 can be displaced by various nitrogen nucleophiles (ammonia, 2-methoxyethylamine, aziridine, 2-methylaziridine, pyrrolidine) in 22-88% yield. The resulting amino-substituted quinones, together with their methoxy precursors, were studied by cyclic voltammetry to determine their reduction potentials, which, in DMF solution, lie in the range -1.355 to -1.597 V (vs ferrocene). The cytotoxicity of the compounds towards aerobic and hypoxic mammalian cells was also determined; in general, under aerobic conditions, the cyclopropamitosenes are more toxic than the corresponding pyrrolo[1,2-a]indolequinones, which are in turn more toxic than the simple 1,2-dimethylindolequinones, with many of the compounds in each series showing greater toxicity toward hypoxic cells.
Cotterill
A S
AS
Department of Chemistry, Loughborough University of Technology, Leicestershire, U.K.
Moody
C J
CJ
Mortimer
R J
RJ
Norton
C L
CL
O'Sullivan
N
N
Stephens
M A
MA
Stradiotto
N R
NR
Swann
E
E
Stratford
I J
IJ
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004563:Electrochemistry; D007211:Indoles / Q000737:chemistry*; D008937:Mitomycins / Q000138:chemical synthesis* / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011809:Quinones / Q000138:chemical synthesis* / Q000494:pharmacology
D007211:Indoles; D008937:Mitomycins; D011809:Quinones