Synthesis of potential dual-acting radiation sensitizer antineoplastic agents: 2,2-dimethylphosphoraziridines containing 2-nitroimidazoles or other electron-affinic moieties

Journal Article · Mon Apr 01 04:00:00 EST 1991 · Journal of Medicinal Chemistry; (USA)

DOI:https://doi.org/10.1021/jm00108a024· OSTI ID:5639476

Perlman, M E; Dunn, J A; Piscitelli, T A; Earle, J; Rose, W C; Wampler, G L; MacDiarmid, J E; Bardos, T J ^[1]

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1. State University of New York at Buffalo, Amherst (USA)

In view of the in vivo demonstrated radiation-potentiating activities of several previously studied 2,2-dimethylphosphoraziridines, six new compounds incorporating the bis(2,2-dimethyl-1-aziridinyl)phosphinyl moiety, together with an electron-affinic group such as 2-nitroimidazole or nitrobenzyl, have been synthesized and tested (1) in vitro for ability to increase the effect of X-irradiation under hypoxic conditions on V-79 Chinese hamster lung fibroblast cells, (2) in vivo for antitumor activity in the absence of radiation against P388 leukemia in mice, and (3) in a preliminary experiment with compound 10 only, in combination with whole-body gamma-radiation, using the P388 leukemia mouse model for in vivo radiation-potentiating activity. The chemical-alkylating activities and hydrolytic behavior of these compounds, as well as their antitumor activities without radiation, were found to be comparable to those of other 2,2-dimethylphosphoraziridines, while their in vitro radiosensitizing activities were at low concentrations generally comparable to that of misonidazole, with compound 8 showing superior activity. At higher concentrations, only compound 10 was sufficiently soluble and nontoxic to the cells for evaluation in this assay. Thus, the bis(2,2-dimethyl-1-aziridinyl) phosphinyl moiety does not seem to have contributed to the hypoxic radiosensitizing activities (only to the cytotoxicities) of the electron-affinic moieties in this in vitro assay. In comparison, the prototype 2,2-dimethylphosphoraziridine, ethyl (bis(2,2-dimethyl-1-aziridinyl) phosphinyl)carbamate (AB-132), showed at nontoxic doses no radiosensitizing activity in this assay, and at cytotoxic doses increased the cell-killing effect of each given dose of X-radiation additively under both hypoxic and oxic conditions.

• OSTI ID: 5639476
• Journal Information: Journal of Medicinal Chemistry; (USA), Journal Name: Journal of Medicinal Chemistry; (USA) Vol. 34:4; ISSN JMCMA; ISSN 0022-2623
• Country of Publication: United States
• Language: English

Related Subjects

560120* -- Radiation Effects on Biochemicals
Cells
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560152 -- Radiation Effects on Animals-- Animals
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMAL CELLS
ANIMALS
ANOXIA
ANTINEOPLASTIC DRUGS
BODY
CHEMICAL PREPARATION
CONNECTIVE TISSUE CELLS
DISEASES
DRUGS
ELECTROMAGNETIC RADIATION
EXPERIMENTAL NEOPLASMS
EXTERNAL IRRADIATION
FIBROBLASTS
GAMMA RADIATION
IMMUNE SYSTEM DISEASES
IN VITRO
IN VIVO
IONIZING RADIATIONS
IRRADIATION
LEUKEMIA
LUNGS
MAMMALS
MICE
MOLECULAR STRUCTURE
NEOPLASMS
ORGANS
RADIATIONS
RADIOSENSITIZERS
RESPIRATORY SYSTEM
RODENTS
SOMATIC CELLS
STRUCTURE-ACTIVITY RELATIONSHIPS
SYNTHESIS
VERTEBRATES
WHOLE-BODY IRRADIATION
X RADIATION