title: Synthesis and biological activity of open-chain analogues of 5,6,7,8-tetrahydrofolic acid--potential antitumor agents.
abstract: This study describes the synthesis and in vitro antitumor activity of inhibitors of purine de novo biosynthesis that are analogues of N-[4-[[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl) propyl]amino]benzoyl-L-glutamic acid (5-DACTHF). Benzene ring substituted analogues were synthesized from a protected pyrimidinyl propionaldehyde and a substituted benzoyl glutamate moiety by a key reductive amination step. Pyrimidine and linking chain substituted analogues were built up stepwise from p-aminobenzoic acid or analogues. The compounds were tested as inhibitors of methotrexate uptake as a measure of binding to the reduced folate transport system, as inhibitors of glycinamide ribonucleotide transformylase, as substrates for folylpolyglutamate synthetase, and as inhibitors of tumor cell growth in cell culture. With the exception of 2'-F substituent, the ring-substituted analogues are less active than the parent compound. Replacement of the 10-nitrogen by carbon, sulfur, or oxygen produced less than 2-fold changes to biological activity in vitro. A four-atom linking chain and an amino group at the 2-position on the pyrimidine ring are important for good activity.
authors.affiliation: Wellcome Research Laboratories, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709.
authors.forename: E C
authors.initials: EC
authors.lastname: Bigham
authors.forename: S J
authors.initials: SJ
authors.lastname: Hodson
authors.forename: W R
authors.initials: WR
authors.lastname: Mallory
authors.forename: D
authors.initials: D
authors.lastname: Wilson
authors.forename: D S
authors.initials: DS
authors.lastname: Duch
authors.forename: G K
authors.initials: GK
authors.lastname: Smith
authors.forename: R
authors.initials: R
authors.lastname: Ferone
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D001943:Breast Neoplasms / Q000188:drug therapy; D006801:Humans; D013329:Structure-Activity Relationship; D013552:Swine; D013763:Tetrahydrofolates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D013763:Tetrahydrofolates