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, 51 (1), 68-76

Design, Synthesis, and Biological Evaluation of Classical and Nonclassical 2-amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors

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Design, Synthesis, and Biological Evaluation of Classical and Nonclassical 2-amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors

Aleem Gangjee et al. J Med Chem.

Abstract

We designed and synthesized a classical antifolate N-{4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5 H-pyrrolo[3,2- d]pyrimidin-5-yl)methyl]benzoyl}- l-glutamic acid 4 and 11 nonclassical analogues 5- 15 as potential dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors. The key intermediate in the synthesis was N-(4-chloro-6-methyl-5 H-pyrrolo[3,2- d]pyrimidin-2-yl)-2,2-dimethylpropanamide, 29, to which various 5-benzyl substituents were attached. For the classical analogue 4, the ester obtained from the N-benzylation reaction was deprotected and coupled with diethyl l-glutamate followed by saponification. Compound 4 was a potent dual inhibitor of human TS (IC 50 = 46 nM, about 206-fold more potent than pemetrexed) and DHFR (IC 50 = 120 nM, about 55-fold more potent than pemetrexed). The nonclassical analogues were marginal inhibitors of human TS, but four analogues showed potent T. gondii DHFR inhibition along with >100-fold selectivity compared to human DHFR.

Figures

Figure 1
Figure 1
Figure 2
Figure 2
Stereoview of compound 4 superimposed on SRI 9662 in human DHFR (PDB code 1KMV). The hydrophobic interaction between C7 and Phe31 is shown.
Scheme 1<sup><i>a</i></sup>
Scheme 1a
a Reagents and conditions: (a) NaOEt, EtOH, 0 °C, 1 h; (b) AcOH, diethyl aminomalonate hydrochloride, room temp, 24 h; (c) MeOH, room temp, 5 h; (d) NaOEt, EtOH, 60 °C, 6 h; (e) NaH, DMF, benzyl bromides, room temp, 4 h; (f) (1) 1,3-bis(methoxycarbonyl)-2-methylthiopseudourea, AcOH, MeOH, room temp, 12 h; (2) NaOMe, MeOH, room temp, 12 h; (g) 1 N NaOH, 55 °C, 3 h.
Scheme 2<sup><i>a</i></sup>
Scheme 2a
a Reagents and conditions: (h) l-glutamic acid diethyl ester hydrochloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine, N-methylmorpholine, DMF, room temp, 5 h; (i) (1) 1 N NaOH, room temp, 4 h; (2) 3 N HCl.
Scheme 3<sup><i>a</i></sup>
Scheme 3a
a Reagents and conditions: (j) (1) 1,3-bis(methoxycarbonyl)-2-methylthiopseudourea, AcOH, MeOH, room temp, 12 h; (2) NaOMe, MeOH, room temp, 2 h; (k) 1 N NaOH, 55 °C, 3 h; (l) PivCl, DMAP, TEA, dichloroethane, 50 °C, 12 h; (m) POCl3, reflux, 3 h; (n) NaH, benzyl bromides, DMF, 0 °C, 3 h; (o) 2 N NaOH, 1,4-dioxane, reflux, 24 h.

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