Synthesis and characterization of a fluorescent analog of methotrexate

Journal of Medicinal Chemistry
1983.0

Abstract

The lysine analogue (4) of methotrexate (1) was treated with 5-(dimethylamino)naphthalene-1-sulfonyl chloride to give the corresponding dansyl analogue 5. The product isolated by preparative TLC was further purified on a preparative HPLC column. Analogue 5 exhibited fluorescence properties characteristic of the dansyl moiety and was a potent inhibitor of dihydrofolate reductase purified from Lactobacillus casei, chicken liver, and a human lymphoblastoid cell line. 1-Alkyl-4-chloro-2-(2,6-dichloro-4-hydroxyphenyl)-6-hydroxyindoles (4, alkyl = CH3, C2H5, C3H7) were synthesized by thermolysis of the corresponding N,N'-dialkyl-1,2-diphenylethylenediamines and subsequent ether cleavage. They showed an affinity for the estrogen receptor (1% of 17β-estradiol) and inhibited the growth of the 9,10-dimethyl-1,2-benz[a]anthracene (DMBA) induced mammary carcinoma of the Sprague-Dawley (SD) rat. The best result was obtained by the ethyl compound (4b), which reduced the original tumor area by 50% after 4 weeks administration of 6 × 18 (mg/kg)/week. Since 4a and 4b show uterotrophic activity and cytostatic effects against hormone-independent cells, a dual mode of action has to be considered for the tumor inhibition.

Knowledge Graph

Similar Paper

Synthesis and characterization of a fluorescent analog of methotrexate
Journal of Medicinal Chemistry 1983.0
N,N'-Dialkyl-1,2-bis(hydroxyphenyl)ethylenediamines and N,N'-dialkyl-4,5-bis(4-hydroxyphenyl)imidazolidines. Syntheses and evaluation of their mammary tumor inhibiting activity
Journal of Medicinal Chemistry 1982.0
Methotrexate analogs. 9. Synthesis and biological properties of some 8-alkyl-7,8-dihydro analogs
Journal of Medicinal Chemistry 1977.0
Potential antiestrogens. Synthesis and evaluation of mammary tumor inhibiting activity of 1,2-dialkyl-1,2-bis(3'-hydroxyphenyl)ethanes
Journal of Medicinal Chemistry 1981.0
Methotrexate analogs. 12. Synthesis and biological properties of some aza homologs
Journal of Medicinal Chemistry 1979.0
2-Phenylindoles. Effect of N-benzylation on estrogen receptor affinity, estrogenic properties, and mammary tumor inhibiting activity
Journal of Medicinal Chemistry 1987.0
Methotrexate analogs. 22. Synthesis, dihydrofolate reductase affinity, cytotoxicity, and in vivo antitumor activity of some putative degradation products of methotrexate-poly(L-lysine) conjugates
Journal of Medicinal Chemistry 1984.0
Analogs of methotrexate
Journal of Medicinal Chemistry 1979.0
Chemistry and antitumor evaluation of selected classical 2,4-diaminoquinazoline analogs of folic acid
Journal of Medicinal Chemistry 1985.0
Methotrexate analogs. 14. Synthesis of new .gamma.-substituted derivatives as dihydrofolate reductase inhibitors and potential anticancer agents
Journal of Medicinal Chemistry 1981.0