Synthesis and in vitro antitumor activity of new deaza analogues of the nonpolyglutamatable antifolate N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine (PT523).
Details are disclosed for the synthesis of N(alpha)-[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]-N(delta)-hemiphthaloyl-L-ornithine (2) and N(alpha)-[4-[5-(2,4-diaminoteridin-6-yl)pent-1-yn-4-yl]benzoyl]-N(delta)-hemiphthaloyl-L-ornithine (6) as analogues of N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine (1, PT523), a nonpolyglutamatable antifolate currently in advanced preclinical development. In a 72 h growth inhibition assay against cultures of CCRF-CEM human leukemic lymphoblasts, the IC(50) of 2 and 6 was 0.69 +/- 0.044 nM and 1.3 +/- 0.35 nM, respectively, as compared with previously reported values 4.4 +/- 0.10 nM for aminopterin (AMT) and 1.5 +/- 0.39 nM for PT523. In a spectrophotometric assay of dihydrofolate reductase (DHFR) inhibition using dihydrofolate and NADPH as the cosubstrates, the previously unreported compounds 2 and the mixed 10R and 10S diastereomers of 6 had K(i) values of 0.21 +/- 0.05 pM and 0.60 +/- 0.02 pM, respectively, as compared with previously reported values of 3.70 +/- 0.35 pM for AMT and 0.33 +/- 0.04 pM for PT523. Thus, while they were comparable to 1 and several of its previously studied analogues in their ability to bind to DHFR and inhibit the growth of CCRF-CEM cells, 2 and the mixed diastereomers of 6 were several times more active than AMT despite the fact that they cannot form gamma-polyglutamylated metabolites of the type formed in cells from AMT and other classical antifolates with a glutamate side chain.
Vaidya
Chitra M
CM
Dana-Farber Cancer Institute and the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Wright
Joel E
JE
Rosowsky
Andre
A
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009952:Ornithine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D011621:Pteridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011622:Pterins / Q000737:chemistry* / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; C453484:N(alpha)-(4-(2-(2,4-diaminoquinazolin-6-yl)ethyl)benzoyl)-N(delta)-hemiphthaloylornithine; C453485:N(alpha)-(4-(5-(2,4-diaminopteridin-6-yl)pent-1-yn-4-yl)benzoyl)-N(delta)-hemiphthaloylornithine; D011621:Pteridines; D011622:Pterins; D011799:Quinazolines; C085590:N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine; D009952:Ornithine; D013762:Tetrahydrofolate Dehydrogenase