Synthesis and antifolate evaluation of the aminopterin analogue with a bicyclo[2.2.2]octane ring in place of the benzene ring Journal Article
| Authors: | Reynolds, R. C.; Johnson, C. A.; Piper, J. R.; Sirotnak, F. M. |
| Article Title: | Synthesis and antifolate evaluation of the aminopterin analogue with a bicyclo[2.2.2]octane ring in place of the benzene ring |
| Abstract: | N-[4-[[2,4-diamino-6-pteridinyl)methyl]amino]bicyclo[2.2.2]octane-1- carbonyl]-L-glutamic acid (1) was synthesized and tested for antifolate activity. N-(4-Aminobicyclo[2.2.2]octane-1-carbonyl-L-glutamic acid dimethyl ester (6), the side chain precursor to subject compound 1, was synthesized readily via reported bicyclo[2.2.2]octane-1,4-dicarboxylic acid monoethyl ester (2). The side chain precursor 6 was alkylated by 6-(bromomethyl)-2,4-pteridinediamine (7). Subsequent ester hydrolysis then afforded 1. Antifolate and antitumor evaluation of 1 verses L1210 dihydrofolate reductase (DHFR) and three tumor cell lines (L1210, S180, and HL60) showed it to be ineffective. Although compound 1 was very similar to aminopterin structurally, the bicyclo[2.2.2]octane ring system in place of the phenyl ring in the p-aminobenzoate moiety effectively negates the stoichiometric binding displayed by many classical DHFR inhibitors bearing appropriate aromatic ring systems in the side chain. © 2001 Éditions scientifiques et médicales Elsevier SAS. |
| Keywords: | controlled study; unclassified drug; human cell; nonhuman; animal cell; mouse; cell division; antineoplastic activity; drug structure; tumor cells, cultured; drug synthesis; structure-activity relationship; enzyme inhibitors; alkylation; dihydrofolate reductase inhibitor; dihydrofolate reductase; folic acid antagonist; structure analysis; folic acid antagonists; tetrahydrofolate dehydrogenase; hydrolysis; aminopterin; stoichiometry; cell strain hl 60; aminopterin derivative; humans; human; article; 6-bromomethyl-2,4-pteridinediamine; antifolate evaluation; curtius rearrangement; n-(4-aminobicyclo[2.2.2]octane-1-carbonyl)-l-glutamic acid dimethyl ester; n [4 [[(2,4 diamino 6 pteridinyl)methyl]amino]bicyclo[2.2.2]octane 1 carbonyl]glutamic acid; leukemia l 1210 |
| Journal Title: | European Journal of Medicinal Chemistry |
| Volume: | 36 |
| Issue: | 3 |
| ISSN: | 0223-5234 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2001-03-01 |
| Start Page: | 237 |
| End Page: | 242 |
| Language: | English |
| DOI: | 10.1016/s0223-5234(01)01224-7 |
| PUBMED: | 11337102 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 21 May 2015 -- Source: Scopus |
