Novel 6-5 fused ring heterocycle antifolates with potent antitumor activity: bridge modifications and heterocyclic benzoyl isosters of 2,4-diamino-6,7-dihydro-5H-cyclopenta[d]pyrimidine antifolate
| Autor: | Tatsuo Okauchi, Kentaro Yoshimatsu, Atsumi Iijima, Yoshihiko Kotake, Hiroaki Nomura |
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| Rok vydání: | 1995 |
| Předmět: |
Pyrimidine
Stereochemistry Pyridines Drug Resistance Chemical synthesis KB Cells chemistry.chemical_compound Structure-Activity Relationship Drug Discovery Dihydrofolate reductase Tumor Cells Cultured Structure–activity relationship Animals Humans Indole test biology Bicyclic molecule Leukemia P388 General Chemistry General Medicine Methotrexate chemistry Indoline Antifolate biology.protein Folic Acid Antagonists Drug Screening Assays Antitumor Colorectal Neoplasms Cell Division |
| Zdroj: | Chemicalpharmaceutical bulletin. 43(5) |
| ISSN: | 0009-2363 |
| Popis: | Structural modifications of an extremely potent inhibitor of dihydrofolate reductase (DHFR) activity and tumor cell growth, N-[4-[3-(2,4-diamino-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5- yl)propyl]benzoyl]-L-glutamic acid (1), have led to the synthesis of new cyclopenta[d]pyrimidine-based antifolates, including those with low alkyl substituted trimethylene bridges (2a, b) and isosterically modified bridges (ethyleneoxa, 2c; ethyleneamino, 2d; the N-methyl- and N-ethyl derivatives of 2d, 2e, f) and those in which the benzene ring of 1 has been replaced by heterocyclic isosters (indole, 2g; indoline, 2h; thiophene, 2i). These new analogs are highly potent as DHFR and cell growth inhibitors, and most of them are more potent than methotrexate (MTX) and 10-ethyl-10-deazapterin (10-EDAM) in inhibiting tumor cell growth (P388 MTX-sensitive and MTX-resistant, colon 26 and KB) on 72 h drug exposure. Among them, 2a (the 10-methyl derivative of 1) and 2i were most potent, being 2- to 3-fold more potent than 10-EDAM. On 4 h drug exposure, the growth-inhibitory activity of these analogs was radically influenced by even minor structural changes. Compounds 1, 2a--e, g--i were much more cytotoxic in colon 26 cell line than were MTX and 10-EDAM, with 2d and 2i being most potent, followed by 2a. Structure-activity relationships and their possible significance are discussed. |
| Databáze: | OpenAIRE |
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