A 2-nitroimidazole carbamate prodrug of 5-amimo-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbony l]-1,2-dihydro-3H--benz[E]indole (amino-seco-CBI-TMI) for use with ADEPT and GDEPT.
The synthesis of a 2-nitroimidazol-5-ylmethyl carbamate prodrug 10 of the potent minor groove alkylating agent amino-seco-CBI-TMI 3 is described. Chemical, radiolytic, and enzymic reductions of a model 2-nitroimidazol-5-yl carbamate 8 show release of the amine effector upon reduction. Prodrug 10 gives a ten fold increase in cytotoxicity against human ovarian carcinoma SKOV3 cells in the presence of E. coli B nitroreductase (NTR) and a 21-fold increase in cytotoxicity against a SKOV3 cell line (SC3.2) transfected with the gene for NTR. The cytotoxicity of 10 increased 15- to 40-fold under hypoxia. Prodrug 10 has significant potential as a prodrug for use in ADEPT and GDEPT applications, and as a hypoxia-selective cytotoxin.
Hay
M P
MP
Auckland Cancer Society Research Centre, University of Auckland School of Medicine, New Zealand.
Sykes
B M
BM
Denny
W A
WA
Wilson
W R
WR
D000477:Alkylating Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D015316:Genetic Therapy; D006801:Humans; D007167:Immunotherapy; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
C400305:5-amino-1-(chloromethyl)-3-((5,6,7-trimethoxyindol-2-yl)carbonyl)-1,2-dihydro-3H-benz(e)indole; D000477:Alkylating Agents; D018906:Antineoplastic Agents, Alkylating; D007211:Indoles; D011355:Prodrugs