- Synthesis and antifolate evaluation of 10-ethyl-5-methyl-5,10- dideazaaminopterin and an alternative synthesis of 10-ethyl-10- deazaaminopterin (edatrexate)
-
Previous findings suggesting that 5,10-dialkyl-substituted derivatives of 5,10-dideazaaminopterin warranted study as potential antifolates prompted synthesis of 10-ethyl-5-methyl-5,10-dideazaaminopterin (12a). The key step in the synthetic route to 12a was Wittig condensation of the tributylphosphorane derived from 6-(bromomethyl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine (7a) with methyl 4-propionylbenzoate. Reaction conditions for the Wittig condensation were developed using the tributylphosphorane prepared from 6- (bromomethyl)-2,4-pteridinediamine (7b) as a model. Each of the respective Wittig products 8a and 8b was obtained in 75-80% yield. Hydrogenation of 8a and 8b at their 9,10-double bond afforded 4-amino-4-deoxy-10-ethyl-5-methyl- 5,10-dideazapteroic acid methyl ester (9a) and 4-amino-4-deoxy-10-ethyl-10- deazapteroic acid methyl ester (9b). This route to 9b intersects reported synthetic approaches leading to 10-ethyl-10-deazaaminopterin (10-EDAM, edatrexate), an agent now in advanced clinical trials. Thus the Wittig approach affords an alternative synthetic route to 10-EDAM. Remaining steps were ester hydrolysis of 9a,b to give carboxylic acids 10a,b followed by standard peptide coupling with diethyl L-glutamate to produce diethyl esters 11a,b, which on hydrolysis gave 12a and 10-EDAM (12b), respectively. The relative influx of 12a was enhanced about 3.2-fold over MTX, but as an inhibitor of dihydrofolate reductase (DHFR) from L1210 cells and in the inhibition of L1210 cell growth in vitro, this compound was approximately 20- fold less effective than MTX (DHFR inhibition, K(i) = 4.82 ± 0.60 pM for MTX, 100 pM for 12a; cell growth, IC50 = 3.4 ± 1.0 nM for MTX, 65 ± 18 nM for 12a).
- Piper,Johnson,Otter,Sirotnak
-
p. 3002 - 3006
(2007/10/02)
-
- Folate Analogues. 24. Syntheses of the Antitumor Agents 10-Deazaaminopterin (10-DAAM) and 10-Ethyl-10-deazaaminopterin (10-EDAAM)
-
Methods have been developed for the chemical synthesis of two recently described potent antitumor agents.They are 10-deazaaminopterin (10-DAAM) (2) and 10-ethyl-10-deazaaminopterin (10-EDAAM) (3).The methods described in this paper have general applicability for the synthesis of a variety of hitherto difficulty accessible 10-substituted-10-deazafolic acids and analogues.Reaction of methyl p-formylbenzoate (7) with the Wittig reagent 6 derived from N-(3-bromo-2-oxopropyl)phtalimide (5) and triphenylphosphine gave the common intermediate 8, which was used for the synthesis of both 2 and 3.This enone was reduced with Zn/HOAc to 15 and was used for the synthesis of 2.Alternately 8 was reacted with ethylmagnesium bromide in the presence of cuprous bromide to obtain the conjugate addition product 16.Both 15 and 16 were converted to the masked α-amino ketones 20 and 21 reacted with 6-chloro-2,4-diamino-5-nitropyrimidine to obtain 22 and 23.These pyrimidine intermediates were subsequently elaborated to the pteroic acid analogues 26 and 27 by multistep procedures previously described from this laboratory.The target compounds 2 and 3 were prepared from 26 and 27 by standard coupling procedures involving isobutyl chloroformate and diethyl L-glutamate.
- Nair, M. G.
-
p. 1879 - 1884
(2007/10/02)
-