Abstract：
:A series of novel nitroheterocyclic phosphoramidates has been evaluated for antitumor activity in murine and xenograft tumor models and for toxicity in mice. Significant increases in lifespan and long-term survivors were noted in L1210 leukemia and B16 melanoma models, and both complete and partial tumor regressions were observed in the MX-1 breast cancer xenograft model. All compounds exhibited some degree of toxicity to granulocyte/macrophage progenitors in the bone marrow of mice. Two drugs were selected for further toxicologic, histopathologic, and pharmacokinetic evaluations. Toxicity of potential clinical significance was observed only in the bone marrow at the highest drug dose; otherwise no significant abnormalities in blood chemistries or organ histopathology were noted. The bone marrow lesions consisted of reduced numbers of progenitor cells in the myeloid and erythroid series; platelets were not affected. The compounds were eliminated rapidly by first-order kinetics, with half-lives in the 4-12 min range. The best of these compounds exhibits excellent antitumor activity and minimal toxicity at therapeutically effective doses in mice.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Borch RF,Liu J,Joswig C,Baggs RB,Dexter DL,Mangold GLdoi
10.1021/jm000359ykeywords:
subject
Has Abstractpub_date
2001-01-04 00:00:00pages
74-7issue
1eissn
0022-2623issn
1520-4804pii
jm000359yjournal_volume
44pub_type
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