69827-84-5Relevant academic research and scientific papers
Synthesis and in Vitro Biological Activity of New Deaza Analogues of Folic Acid, Aminopterin, and Methotrexate with an L-Ornithine Side Chain
Rosowsky, Andre,Forsch, Ronald A.,Bader, Henry,Freisheim, James H.
, p. 1447 - 1454 (2007/10/02)
The 5-deaza and 5,8-dideaza analogues of Nα-pteroyl-L-ornithine (Pter-Orn), the 5-deaza, 8-deaza, and 5,8-dideaza analogues of Nα-(4-amino-4-deoxypteroyl)-L-ornithine (APA-Orn), and the Nδ-carboxymethyl derivative of Nα-(4-amino-4-deoxy-N10-methylpteroyl)-L-ornithine (m-APA-Orn) were synthesized and tested as inhibitors of dihydrofolate reductase (DHFR) and as inhibitors of tumor cell growth in culture.Reductive amination of 2-acetamido-6-formylpyridopyrimidin-4(3H)-one with methyl Nα-(4-aminobenzoyl)-Nδ-(benzyloxycarbonyl)-L-ornithinatefollowed by removal of the blocking groups afforded the 5-deaza analogue of Pter-Orn, whereas N-alkylation of methyl Nα-(4-aminobenzoyl)-Nδ-(benzyloxycarbonyl)-L-ornithinate with 2-amino-6-(bromomethyl)quinazolin-4(3H)-one and deprotection gave the corresponding 5,8-dideaza analogue.Reductive coupling of 2,4-diaminopyridopyrimidine-6-carbonitrile and 4-aminobenzoic acid followed by reaction with 96-97percent formic acid yielded 4-amino-4-deoxy-5-deaza-N10-formylpteroic acid, which on condensation with methyl Nδ-(benzyloxycarbonyl)-L-ornithinate and deprotection gave the 5-deaza analogue of APA-Orn.A similar sequence starting from 2,4-diaminoquinazoline-6-carbonitrile led to the corresponding 5,8-dideaza compound, whereas treatment of 2,4-diaminopyridopyrimidine-6-methanol with phosphorus tribromide followed by condensation with methyl Nα-(4-aminobenzoyl)-Nδ-(benzyloxycarbonyl)-L-ornithinate and deprotection afforded the 8-deaza analogue.For the preparation of the Nδ-carboxymethyl derivative of mAPA-Orn, Nα-(benzyloxycarbonyl)-L-ornithine was subjected to Nδ-monoalkylation with glyoxylic acid and sodium cyanoborohydride, followed by Nδ-acylation with ethyl trifluoroacetate, Nα-deprotection by hydrogenolysis, condensation with 4-amino-4-deoxy-N10-methylpteroic acid, and Nδ-deprotection by gentle treatment with ammonia.The 2,4-diamino derivatives all inhibited the growth of tumor cells in culture, with IC50 values of 0.2-2 μM, and inhibited purified DHFR with IC50 values of 0.02-0.08 μM.Deletion of ring nitrogens and Nδ-carboxymethylation both increased potency in the cell growth assay; however, the ornithine derivatives were less potent than aminopterin or methotrexate.
