101375-08-0Relevant articles and documents
Synthesis and Biological Activities of 5-Deaza Analogues of Aminopterin and Folic Acid
Su, Tsann-Long,Huang, Jai-Tung,Burchenal, Joseph H.,Watanabe, Kyoichi A.,Fox, Jack J.
, p. 709 - 715 (2007/10/02)
N-pyrimidin-6-yl)methyl>amino>benzoyl>-L-glutamic acid (1a, 5-deazaaminopterin) and the 5-methyl analogue (1b) were synthesized in 14 steps from 5-cyanouracil (4a) and 5-cyano-6-methyluracil (4b), respectively, by exploitation of the novel pyrimidine to pyridopyrimidine ring transformation reaction.The 5-cyanouracils 4 were treated with chloromethyl methyl ether to the 1,3-bis(methoxymethyl)uracils (5, which were treated with malononitrile in NaOEt/EtOH to give the pyridopyrimidines 6.Diazotization of 6 in concentrated HCl afforded the 7-chloro derivatives 8 in high yield.After reduction of 8, the 7-unsubstituted products 9 were reduced in the presence of Ac2O and the products, 6-(acetamidomethyl)pyridopyrimidines 10, were converted into the 6-acetoxymethyl derivatives 12 via nitrosation.After removal of the N-methoxymethyl groups from 12, the 6-(acetoxymethyl)pyridopyrimidine 2,4(1H,3H)-diones 14 were converted into 2,4-diamino-6-(hydroxymethyl)pyridopyrimidine (15a) and its 5-methyl analogue 15b by the silylation-amination procedure.Compounds 15 were brominated to the 6-bromomethyl derivatives 16, which were treated with diethyl (p-aminobenzoyl)-L-glutamate, and the products 17 were saponified to afford 5-deazaaminopterin (1a) and its 5-methyl analogue 1b.Compopund 1b was also prepared by an alternative procedure in 10 steps from cyanothioacetamide and ethyl β-(ethoxymethylene)acetoacetate via 2,4-diamino-6-(hydroxymethyl)-5-methylpyridopyrimidine (15b). 5-Deaza-5-methylfolic acid (2) was also prepared in four steps from 15b.The aminopterine analogues 1 showed significant anticancer activity in vitro and in vivo, whereas thefolic acid analogue 2 did not exhibit any significant toxicity.