Facile Synthesis of 9-Substituted 9-Deazapurines as Potential Purine Nucleoside Phosphorylase Inhibitors.

Shih, Hsiencheng; Cottam, Howard B.; Carson, Dennis A.

doi:10.1248/cpb.50.364

Cited by 17 publications

(5 citation statements)

References 16 publications

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“…1f Scheme 29-Alkyl-9-deazapurines have been synthesized by time-consuming construction of the bicyclic ring system via pyrroles 6 or pyrimidines, 7 and alkyl-or acyl substituents have been introduced at C-9 in 6-oxo-9-deazapurines be Friedel-Craft alkylation or acylation, but the yields are generally quite modest. 8 Instead, we evaluated several routes for the synthesis of our target 9-deazapurines 16 and 17 (Scheme 3), starting from 6-chloro-9-deazapurine (4-chloropyrrolo [3,2-d]pyrimidine) (10). The 4,7-dihalopyrrolo [3,2-d]pyrimidine 13a were available be N-methylation and halogenation of compound 10.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis of non-purine analogs of 6-aryl-9-benzylpurines, and their antimycobacterial activities. Compounds modified in the imidazole ring

Khoje

Kulendrn

Charnock

et al. 2010

Bioorganic & Medicinal Chemistry

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Purine analogs modified in the five-membered ring have been synthesized and examined for antibacterial activity against Mycobacterium tuberculosis H(37)Rv in vitro employing the microplate alamar blue assay (MABA). The 9-deaza analogs were only found to be weak inhibitors, but the 8-aza-, 7-deaza- and 8-aza-7-deazapurine analogs studied displayed excellent antimycobacterial activities, some even substantially better than the parent purine. In the 7-deazapurine series, MIC values between 0.08 and 0.35 μM, values comparable or better than the reference drugs used in the study (MIC rifampicin 0.09 μM, MIC isoniazid 0.28 μM and MIC PA-824 0.44 μM). The five most active compounds were also examined against a panel of drug-resistant Mtb strain, and they all retained their activity. The compounds examined were significantly less active against M. tuberculosis in a state of non-replicating persistence (NRP). MIC in the low-oxygen-recovery assay (LORA) ≥ 60 μM. The 7-deazapurines were somewhat more toxic towards mammalian cells, but still the selectivity indexes were excellent. The non-purine analogs exhibit a selective antimycobacterial activity. They were essentially inactive against Staphylococcus aureus and Escherichia coli.

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Section: Chemistrymentioning

confidence: 99%

Synthesis of non-purine analogs of 6-aryl-9-benzylpurines, and their antimycobacterial activities. Compounds modified in the imidazole ring

Khoje

Kulendrn

Charnock

et al. 2010

Bioorganic & Medicinal Chemistry

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“…For related preparation and biological activity, see: Shih et al (2002); Niwas et al (1994). For related literature, see: Ding et al (2004).…”

Section: Related Literaturementioning

confidence: 99%

3-(4-Fluorophenyl)-2-(4-methoxyphenoxy)-4-oxo-5-phenyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile

Guo-ping

Yan

2008

Acta Cryst E

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Key indicators: single-crystal X-ray study; T = 298 K; mean (C-C) = 0.009 Å; R factor = 0.055; wR factor = 0.088; data-to-parameter ratio = 7.6.There are two crystallographically independent molecules in the asymmetric unit of the title compound, C 26 H 17 FN 4 O 3 , which differ in the dihedral angles between the aromatic rings (fluorophenyl, phenyl) and the pyrrolopyrimidine rings [0.6 (3)/76.3 and 73.7 (3)/64.6 , respectively]. The crystal structure is mainly stabilized by C-HÁ Á ÁO and C-HÁ Á ÁF interactions. Related literatureFor related preparation and biological activity, see: Shih et al.

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“…Pyrrolo[3,2- d ]pyrimidines, or 9-deazapurines, represent a class of compounds that are sterically and electronically similar to the naturally occurring purine nucleobases, with the exception of a hydrogen-bond donating moiety at N5 (Figure 1) [1,2,3]. These compounds have seen widespread biological activity and have been extensively utilized in the design of small molecule inhibitors of purine nucleoside phosphorylase (PNP) [4,5,6,7,8,9], dihydrofolate reductase (DHFR) [3], the transient receptor potential channel family [10], and various kinases [11,12,13]. In addition, pyrrolo[3,2- d ]pyrimidines have shown promise in the development of antitumor agents [1,14,15,16].…”

Section: Introductionmentioning

confidence: 99%

Structural and Biological Investigations for a Series of N-5 Substituted Pyrrolo[3,2-d]pyrimidines as Potential Anti-Cancer Therapeutics

et al. 2019

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Pyrrolo[3,2-d]pyrimidines have been studied for many years as potential lead compounds for the development of antiproliferative agents. Much of the focus has been on modifications to the pyrimidine ring, with enzymatic recognition often modulated by C2 and C4 substituents. In contrast, this work focuses on the N5 of the pyrrole ring by means of a series of novel N5-substituted pyrrolo[3,2-d]pyrimidines. The compounds were screened against the NCI-60 Human Tumor Cell Line panel, and the results were analyzed using the COMPARE algorithm to elucidate potential mechanisms of action. COMPARE analysis returned strong correlation to known DNA alkylators and groove binders, corroborating the hypothesis that these pyrrolo[3,2-d]pyrimidines act as DNA or RNA alkylators. In addition, N5 substitution reduced the EC50 against CCRF-CEM leukemia cells by up to 7-fold, indicating that this position is of interest in the development of antiproliferative lead compounds based on the pyrrolo[3,2-d]pyrimidine scaffold.

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Facile Synthesis of 9-Substituted 9-Deazapurines as Potential Purine Nucleoside Phosphorylase Inhibitors.

Cited by 17 publications

References 16 publications

Synthesis of non-purine analogs of 6-aryl-9-benzylpurines, and their antimycobacterial activities. Compounds modified in the imidazole ring

Synthesis of non-purine analogs of 6-aryl-9-benzylpurines, and their antimycobacterial activities. Compounds modified in the imidazole ring

3-(4-Fluorophenyl)-2-(4-methoxyphenoxy)-4-oxo-5-phenyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile

Structural and Biological Investigations for a Series of N-5 Substituted Pyrrolo[3,2-d]pyrimidines as Potential Anti-Cancer Therapeutics

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