Synthesis of Classical and Nonclassical, Partially Restricted, Linear, Tricyclic 5-Deaza Antifolates

Abstract

Seven novel 2,4-diamino-5-deaza-6,7,8,9-tetrahydropyrido[3,4-g]pteridine derivatives 3-9 with different benzyl and a benzoyl substitution at the N7 position were designed and synthesized, as classical and nonclassical, partially restricted, linear tricyclic 5-deaza antifolates. The purpose was to investigate the effect of conformational restriction of the C6-C9 (tau(1)) and C9-N10 (tau(2)) bonds via an ethyl bridge from the N10 to the C7 position of 5-deaza methotrexate (MTX) on the inhibitory potency against dihydrofolate reductase (DHFR) from different sources and on antitumor activity. The synthetic methodology for most of the target compounds was a concise five-step total synthesis to construct the tricyclic nucleus, 2,4-diamino-5-deaza-7H-6,7,8,9-tetrahydropyrido[3,4-g]pteridine (23), followed by regioselective alkylation of the N7 nitrogen. Biological results indicated that this partial conformational modification for the classical analogue N-[4-[(2,4-diamino-5-deaza-6,7,8,9-tetrahydropyrido[3,4-g]pteridin-7-yl)methyl]benzoyl]-L-glutamic acid 3 was detrimental to DHFR inhibitory activity as well as to antitumor activity compared to MTX or 5-deaza MTX. However, the classical analogue 3 was a better substrate for folypolyglutamate synthetase (FPGS) than MTX. These results show that a classical 5-deaza folate partially restricted via a bridge between the N10 and C7 positions retains FPGS substrate activity and that the antitumor activity of classical tricyclic analogues such as 3 would be influenced by FPGS levels in tumor systems. Interestingly, the nonclassical analogues 4-9 showed moderate to good selectivity against DHFR from pathogenic microbes compared to recombinant human DHFR. These results support the idea that removal of the 5-methyl group of piritrexim along with restriction of tau(1) and tau(2) can translate into selectivity for DHFR from pathogens.

2,4-Diaminopteridine-Based Compounds as Precursors for De Novo Synthesis of Antifolates: a Novel Class of Antimalarials

“…In mammalian cells, methotrexate is polyglutamated in vivo by the enzyme FPGS, and this increases the activity of methotrexate against DHFR (7,15,22). Moreover, polyglutamation converts methotrexate into a potent inhibitor of other enzymes in the folate pathways, such as thymidylate synthase, and enzymes that use folate derivatives in the purine synthesis pathway (1,5).…”

Dihydrofolate Reductase as a Target for Chemotherapy in Parasites

“…Gangjee et al [123] designed linear, conformationally restricted, tricyclic compounds 33a-f (Fig. 21) as inhibitors of pcDHFR and tgDHFR by introducing conformational restriction in the C6-C9 and C9-N10 bonds of 5-deaza PTX by incorporating the atoms in a third ring via an ethyl bridge from the N10 to the C7 position.…”

Magnetic Graphene Oxide Anchored Sulfonic Acid as a Novel Nanocatalyst for the Synthesis of N‐aryl‐2‐amino‐1,6‐naphthyridines

“…Over the past few years, naphthyridine derivatives have received considerable attention because of their wide range of biological and pharmaceutical activities, such as antitumor, anti-inflammatory, and antifungal properties. [9][10][11] These compounds are very useful in the treatment of hypertension, myocardial infarction, hyperlipidemia, cardiac arrhythmia, and rheumatoid arthritis. [12][13][14] In view of these useful properties, and since we were interested in the synthesis of N-aryl-2-amino-1,6-naphthyridine derivatives, a literature survey revealed that there are only a few reports for the synthesis of these compounds.…”