Synthesis and Antitumor Evaluation of a Highly Potent Cytotoxic DNA Cross-Linking Polyamine Analogue, 1,12-Diaziridinyl-4,9-diazadodecane

A diaziridinylspermine analogue, 1,12-diaziridinyl-4,9-diazadodecane (NSC-667005), was synthesized as a bisalkylating agent with a polyamine backbone. DNA cross-linking was detected in the reaction of linearized pBR322 DNA with 1,12-diaziridinyl-4,9-diazadodecane at concentrations comparable with th...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1996-01, Vol.39 (1), p.339-341
Main Authors: Li, Yanlong, Eiseman, Julie L, Sentz, Dorothy L, Rogers, Faye A, Pan, Su-Shu, Hu, Li-Tai, Egorin, Merrill J, Callery, Patrick S
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Aziridines - administration & dosage
Aziridines - chemical synthesis
Aziridines - chemistry
Aziridines - pharmacology
Biological and medical sciences
Cross-Linking Reagents - chemical synthesis
Cross-Linking Reagents - pharmacology
Cross-Linking Reagents - toxicity
DNA - drug effects
Electrophoresis, Agar Gel
Female
General aspects
Leukemia L1210 - drug therapy
Mechlorethamine - pharmacology
Medical sciences
Melphalan - pharmacology
Mice
Mice, Inbred Strains
Pharmacology. Drug treatments
Spermine - administration & dosage
Spermine - analogs & derivatives
Spermine - chemical synthesis
Spermine - chemistry
Spermine - pharmacology
Thiotepa - pharmacology
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Summary:A diaziridinylspermine analogue, 1,12-diaziridinyl-4,9-diazadodecane (NSC-667005), was synthesized as a bisalkylating agent with a polyamine backbone. DNA cross-linking was detected in the reaction of linearized pBR322 DNA with 1,12-diaziridinyl-4,9-diazadodecane at concentrations comparable with that required for cross-linking by two nitrogen mustard drugs, mechlorethamine and melphalan. A significant increase in life span of female CD2F1 mice bearing L1210 murine leukemia was observed after intravenous administration of 1,12-diaziridinyl-4,9-diazadodecane in doses of less than 2.7 mg/kg, given on days 1, 5, and 9 of treatment.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm9500885