title: 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.
abstract: 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2c; ethyleneamino, 2d; the N-methyl- and N-ethyl derivatives of 2d, 2e, f) and those in which the benzene ring of 1 has been replaced by heterocyclic isosters (indole, 2g; indoline, 2h; thiophene, 2i).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.
authors.affiliation: Research and Development Division, Eisai Company, Ltd., Ibaraki, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kotake
authors.forename: T
authors.initials: T
authors.lastname: Okauchi
authors.forename: A
authors.initials: A
authors.lastname: Iijima
authors.forename: K
authors.initials: K
authors.lastname: Yoshimatsu
authors.forename: H
authors.initials: H
authors.lastname: Nomura
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007624:KB Cells; D007941:Leukemia P388 / Q000188:drug therapy; D008727:Methotrexate / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D005493:Folic Acid Antagonists; D011725:Pyridines; D008727:Methotrexate