Synthesis of 2,4‐diamino‐5,10‐dideaza nonclassical antifolates

Gangjee, Aleem; Devraj, Rajesh; Lin, Fu-Tyan

doi:10.1002/jhet.5570280717

Cited by 26 publications

(22 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MS: m/e 268 and 270 ( + 1)+. NMR (Me2SO-d6): <5 2.77 (s, 3 H, 5-CH3), 4.93 (s, 2 H, CH2Br), 8.25 (br s, 2 H, 4-NH2), 8.86 (s, 1 , 7-H), 9.40 (br s, 2 H, 2-NH2).…”

Section: Methodsmentioning

confidence: 99%

6-Substituted 2,4-Diamino-5-methylpyrido[2,3-d]pyrimidines as Inhibitors of Dihydrofolate Reductases from Pneumocystis carinii and Toxoplasma gondii and as Antitumor Agents

Gangjee¹,

Vasudevan²,

Queener³

et al. 1995

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

The synthesis and biological activity of 15 6-substituted 2,4-diamino-5-methylpyrido[2,3-d]-pyrimidines are reported. These compounds were synthesized in improved yields by modifications of procedures previously reported by us. Specifically, dimethoxyphenyl-substituted compounds with H and CH3 at the N-10 position and trimethoxyphenyl-substituted compounds with N-10 ethyl, isopropyl, and propargyl moieties were synthesized. These compounds were evaluated as inhibitors of dihydrofolate reductases (DHFR) from Pneumocystis carinii, Toxoplasma gondii, and rat liver, and selected analogues were evaluated as inhibitors of the growth of T. gondii and tumor cells in culture. All the compounds showed increased selectivity (vs rat liver DHFR) for T. gondii DHFR compared to trimetrexate. In general, for the trimethoxy-substituted analogues, increasing the size of the N-10 substituent from a methyl group to larger groups resulted in a decrease in selectivity and potency for both P. carinii and T. gondii DHFR. For the dimethoxy-substituted analogues, N-10 methylation in general decreased potency but increased selectivity for T. gondii DHFR. In an attempt to improve the cell penetration of these analogues, the N-10 naphthyl-substituted analogues were also synthesized. These analogues displayed excellent cell penetration and inhibition of T. gondii cells in culture. Further, these analogues were potent inhibitors of the growth of tumor cells in the preclinical in-vitro screening program of the National Cancer Institute with IC50s in the nanomolar range.

show abstract

“…MS: m/e 268 and 270 ( + 1)+. NMR (Me2SO-d6): <5 2.77 (s, 3 H, 5-CH3), 4.93 (s, 2 H, CH2Br), 8.25 (br s, 2 H, 4-NH2), 8.86 (s, 1 , 7-H), 9.40 (br s, 2 H, 2-NH2).…”

Section: Methodsmentioning

confidence: 99%

6-Substituted 2,4-Diamino-5-methylpyrido[2,3-d]pyrimidines as Inhibitors of Dihydrofolate Reductases from Pneumocystis carinii and Toxoplasma gondii and as Antitumor Agents

Gangjee¹,

Vasudevan²,

Queener³

et al. 1995

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…In order to elucidate the importance of the 10-nitrogen atom on DHFR inhibitory potency and selectivity in this class, we also synthesized a series of 5,10-dideaza lipophilic antifolates in which the 10-nitrogen is replaced by a carbon atom. The synthesis of the 3,4-dimethoxyphenyl-substituted 5,10-dideaza analogs 7 , 10 , and 13 was reported by us in a preliminary communication . This report describes the biological activity of analogs 7 , 10 , and 13 and the synthesis and biological activity of additional 5,10-dideaza lipophilic antifolates which varied in the number of methoxy substituents in the 3-, 4-, and 5-positions on the phenyl ring.…”

Section: Introductionmentioning

confidence: 86%

“…The synthesis of all the analogs utilized the common intermediate 2,4-bis(pivaloylamino)-6-bromopyrido[2,3- d ]pyrimidine ( 17 ). This critical intermediate 17 was synthesized via reaction of 2,4,6-triaminopyrimidine ( 14 ) and bromomalonaldehyde ( 15 ) under acidic conditions to afford the cyclized compound 16 followed by protection of the 2- and 4-amino groups with pivaloyl anhydride and pyridine . The synthesis of the 5-deaza analogs 2 − 5 is shown in Scheme .…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Dihydrofolate Reductase Inhibitory Activities of 2,4-Diamino-5-deaza and 2,4-Diamino-5,10-dideaza Lipophilic Antifolates

1997

Self Cite

View full text Add to dashboard Cite

Two series of nonclassical antifolates (2,4-diamino-5-deaza compounds 2-5 and 5,10-dideaza compounds 6-13) were synthesized as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (pc) and Toxoplasma gondii (tg) organisms that are responsible for fatal opportunistic infections in AIDS patients. Rat liver (rl) DHFR served as the mammalian reference enzyme to determine selectivity. Syntheses of the target 5-deaza compounds were achieved by initial construction of the pivaloyl-protected 2,4-diamino-6-bromopyrido[2,3-d]-pyrimidine 17 via a cyclocondensation of 2,4,6-triaminopyrimidine with bromomalonaldehyde. Sequential Heck coupling of 17 with styrene followed by ozonolysis afforded the 6-formyl derivative 19. Reductive amination of 19 with 3,4,5-trimethoxyaniline afforded the N10-H analog. The N10-Me and N10-Et analogs were synthesized by nucleophilic displacement of the 6-bromomethyl derivative 22 (obtained from the 6-formyl derivative 19 by reduction and bromination) with the appropriate N-alkylaniline. The trans-5,10-dideaza analogs 6-8 were synthesized via a Heck coupling of the appropriate methoxystyrene with 17, and selective reduction of the resulting 9,10-double bond afforded target compounds 9-11. Further reduction to the tetrahydro derivatives afforded analogs 12 and 13. The 5-deaza N10-Me 3,4,5-trimethoxy analog 3 maintained the best balance of potency and selectivity against both tgDHFR and pcDHFR. Compared to trimethoprim, compound 3 was only slightly less selective but was 300-fold more potent against tgDHFR. The 5,10-dideaza analogs were generally less potent and selective than the 5-deaza compounds.

show abstract

“…This novel derivative was not more potent than PTX 158 but had an excellent potency against P carinii DHFR (IC 50 ¼ 1.2 nM) [59]. Other DHFR inhibitors are also under investigation [13,60]. 166 which is a potent inhibitor of DHFR from P. jirovecii (Ki ¼ 2.7 nM).…”

Section: Antiviral Agentsmentioning

confidence: 96%