Synthesis and antitumor activity of 10-alkyl-10-deazaminopterins. A convenient synthesis of 10-deazaminopterin

Abstract

Requirements for large-scale synthesis of the potent antitumor drug 10-deazaminopterin have led to development of a facile synthesis of this compound and its 10-alkyl analogues. The lithium diisopropyl amide generated dianions of appropriate p-alkylbenzoic acids were alkylated with 3-methoxyallyl chloride. The resulting 4-(p-carboxyphenyl)-1-methoxy-1-butenes were brominated at pH 7-8 to afford the 2-bromo-4-(p-carboxyphenyl)butyraldehydes. Condensation with 2,4,5,6-tetraminopyrimidine and subsequent in situ oxidation of the resulting dihydropteridines yielded crystalline 10-alkyl-10-deaza-4-amino-4-deoxypteroic acids. The pteroic acids were coupled with diethyl glutamate via the mixed anhydride method, followed by saponification at room temperature, to give the target 10-deazaminopterins. The 10-alkyl compounds were approximately equipotent to 10-deazaminopterin as growth inhibitors of folate-dependent bacteria. Their abilities to inhibit Lactobacillus casei and L1210 derived dihydrofolate reductases were also similar. Transport properties in vitro were suggestive of an improved therapeutic index for the 10-alkyl analogues. Against L1210 in mice, the percent increase in life span at the LD10 dosage was +151% (methotrexate), +178% (10-deazaminopterin), +235% (10-methyl analogue), and +211% (10-ethyl analogue). 10,10-Dimethyl-10-deazaminopterin was less effective at an equimolar dosage, but the ILS at the maximum dose tested (72 mg/kg) was +135%. It was far less toxic than the other analogues possibly because of enhanced clearance.

Biological and biochemical properties of new anticancer folate antagonists

“…Previous work [20] shows that the Nl°-alkyl derivatives of aminopterin are transported much less efficiently in normal tissues, such as gut, than in tumor tissue and therefore have the potential for greater selectivity and perhaps an enhanced therapeutic index. The results of an initial study [10] comparing in vivo antitumor properties in L1210 leukemia, inhibition of dihydrofolate reductase, and the transport characteristics in L1210, of methotrexate, aminopterin 10-dAM and 10-EdAM are consistent with these predictions. Although there were only minor differences in K i for inhibition of dihydrofolate reductase between these analogs, 10-EdAM extended the life span of tumor-bearing mice to a greater extent.…”

“…lO-Ethyl-lO-deaza-aminopterin (IO-EdAM) is one of several derivatives synthesized by DeGraw et al [10] in which the Nl°-amine of aminopterin is replaced by a methylene group. The initial compound produced in this series, 10-deaza-aminopterin (10-dAM) [16], is clearly superior to methotrexate in several murine tumor models [17,18] and eventually went to clinical trial [19].…”

“…The structures of MTX and of the five novel folate antagonists discussed in this review are shown in Figure 1.10-Ethyl-10-deazaaminopterin is a classical antifolate synthesized by DeGraw et al [10]. Trimetrexate is one of a series of quinazoline antifolates synthesized in the Parke-Davis labora- tories [11,12].…”

Inhibition of the Neutrophil Nrdph Oxidase by Folic Acid and Antagonists of the Folic Acid Metabolism

“…Antagonists of folate metabolism were synthesized in our laboratory and their purity was greater than 99% as determined by HPLC and by mass spectrometry [6,15,26,29]. Antagonists of folate metabolism were synthesized in our laboratory and their purity was greater than 99% as determined by HPLC and by mass spectrometry [6,15,26,29].…”

Phase II study of 10-ethyl-10-deaza-aminopterin (10-EdAM; CGP 30 694) for stage IIIB or IV non-small cell lung cancer

“…10-Ethyl-10-deaza-aminopterin (10-EdAM; C GP 30 694) is one of the analogues of methotrexate developed by collaborative research efforts between Memorial Sloan-Kettering Cancer Center and the Stanford Research Institute International [8][9][10][11][12][13][14]. Preclinical studies demonstrated that 10-EdAM has greater antitumor activity than methotrexate against many ascitic and solid murine tumors [10] and human tumor xenografts (MX-1, LX-1, CX-1) [12].…”