Syntheses and evaluation as antifolates of MTX analogues derived from 2, ω-diaminoalkanoic acids Journal Article
| Authors: | Piper, J. R.; McCaleb, G. S.; Montgomery, J. A.; Schmid, F. A.; Sirotnak, F. M. |
| Article Title: | Syntheses and evaluation as antifolates of MTX analogues derived from 2, ω-diaminoalkanoic acids |
| Abstract: | Methotrexate (MTX) analogues 27a-c bearing 2, ω-diaminoalkanoic acids (ornithine and its two lower homologues) in place of glutamic acid were synthesized by routes proceeding through N2-[4-(methylamino)benzoyl]-Nω-[(1, 1-dime thylethoxy) carbonyl]-2, ω-diaminoalkanoic acid ethyl esters (12a, b) and N2-[4-(methylamino)benzoyl]-N5-[(1, 1-dimethylethoxy)carbonyl]-2, 5-diaminopentanoic acid (13) followed by alkylation with 6-(bromomethyl)-2, 4-pteridinediamine hydrobromide. Reactions at the terminal amino group of 27-type analogues or of appropriate precursors led to other MTX derivatives whose side chains terminate in ureido (23a, b), methylureido (24), N-methyl-N-nitrosoureido (30), N-(2-chloroethyl)-N-nitrosoureido (31), and 4-chlorobenzamido (28a-c) groups. Also prepared were unsymmetrically disubstituted ureido types resulting from addition of ethyl isocyanatoacetate and diethyl 2-isocyanatoglutarate to the ethyl esters of 27a, b. Of these ureido adducts (32a, b and 33a, b, respectively), only 33a was successfully hydrolyzed to the corresponding pure acid, in this instance the tricarboxylic acid 34, a pseudo-peptide analogue of the MTX metabolite MTX-7-Glu. Biological evaluations of the prepared compounds affirmed previous findings that the 7-carboxyl is not required for tight binding to dihydrofolate reductase (DHFR) but is operative in the carrier-mediated transport of classical antifolates through cell membranes. High tolerance levels observed in studies against L1210 leukemia in mice suggest the reduced potency may be due not only to lower transport efficacy but also to loss of the function of intracellular 7-polyglutamylation. The N-nitrosoureas 30 and 31 showed appreciable activity in vivo vs. L1210, but the activity did not appear to be due to antifolate action as evidenced by their poor inhibition of both L1210 DHFR and cell growth in vitro. © 1985, American Chemical Society. All rights reserved. |
| Keywords: | cancer chemotherapy; unclassified drug; drug activity; drug efficacy; nonhuman; methotrexate; mouse; animals; mice; cells, cultured; cell division; animal experiment; animal model; in vitro study; drug screening; drug synthesis; structure activity relation; structure-activity relationship; drug mechanism; leukemia cell; drug metabolism; drug cytotoxicity; dihydrofolate reductase; folic acid antagonists; tetrahydrofolate dehydrogenase; drug sensitivity; drug tolerance; therapy; synthesis; carboxylic acids; drug solubility; drug identification; intoxication; drug comparison; methotrexate derivative; leukemia l1210; new drug; priority journal; article; leukemia l 1210; sarcoma 180; blood and hemopoietic system; drug analysis; n [[[2 carboxy 2 [[4 [[(2,4 diamino 6 pteridinyl)methyl]methylamino]benzoyl]amino]ethyl]amino]carbonyl]glutamic acid; n2 [4 [[(2,4 diamino 6 pteridinyl)methyl]methylamino]benzoyl] 3 [[(methylamino)carbonyl]amino]propionic acid; ehrlich ascites tumor cell |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 28 |
| Issue: | 8 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 1985-08-01 |
| Start Page: | 1016 |
| End Page: | 1025 |
| Language: | English |
| DOI: | 10.1021/jm00146a008 |
| PROVIDER: | scopus |
| PUBMED: | 4020824 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 26 October 2021 -- Source: Scopus |
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