Microwave-assisted protocols for the expedited synthesis of pyrazolo[1,5-a] and [3,4-d]pyrimidines

Daniels, R. Nathan; Kim, Kwang‐Ho; Lebois, Evan P.; Muchalski, Hubert; Hughes, Mary; Lindsley, Craig W.

doi:10.1016/j.tetlet.2007.11.054

Cited by 68 publications

(31 citation statements)

References 9 publications

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“…Our effort was concentrated on varying two aspects of the dorsomorphin structure: the R 1 group (C-3 of the core structure) and the R 2 group (4-phenyl group on the C-6 of the core structure) (Figure 1d; Tables S1, S2)(25). The parallel library synthesis, as detailed in supplementary methods, led to the synthesis and isolation of 63 distinct compounds (Tables S1, S2).…”

Section: Resultsmentioning

confidence: 99%

In Vivo Structure−Activity Relationship Study of Dorsomorphin Analogues Identifies Selective VEGF and BMP Inhibitors

Hao¹,

Ho²,

Lewis³

et al. 2010

ACS Chem. Biol.

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356

357

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The therapeutic potential of small molecule signaling inhibitors is often limited by off-target effects. Recently, in a screen for compounds that perturb zebrafish embryonic dorsoventral axis, we identified dorsomorphin, the first selective inhibitor of bone morphogenetic protein (BMP) signaling. Here we show that dorsomorphin has significant “off-target” effects against the VEGF (vascular endothelial growth factor) type-2 receptor (Flk1/KDR) and disrupts zebrafish angiogenesis. Since both BMP and VEGF signals are known to be involved in vascular development, we sought to determine whether dorsomorphin’s anti-angiogenic effects are due to its impact on the BMP or VEGF signals through the development of analogs that target BMP but not VEGF signaling, and vise versa. In a structure activity relationship (SAR) study of dorsomorphin analogs based primarily on their effects on live zebrafish embryos, we identified highly selective and potent BMP inhibitors as well as selective VEGF inhibitors. One of the BMP inhibitors, DMH1, which exclusively targets the BMP, but not VEGF, pathway, dorsalized the embryonic axis without disrupting angiogenic process, demonstrating that BMP signaling was not involved in angiogenic process. This is one of the first full-scale SAR study performed in vertebrates, and demonstrates the potential of zebrafish as an attractive complementary platform for drug development that incorporates an assessment of in vivo bioactivity and selectivity in the context of a living organism.

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Section: Resultsmentioning

confidence: 99%

In Vivo Structure−Activity Relationship Study of Dorsomorphin Analogues Identifies Selective VEGF and BMP Inhibitors

Hao¹,

Ho²,

Lewis³

et al. 2010

ACS Chem. Biol.

Self Cite

356

357

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“…9 To our knowledge the first microwave-accelerated decomposition of formamide has been described in 2003 by a Swedish group in Uppsala University, 10 where formamide was used as combined ammonia (NH 3 ) synthon and carbon monoxide (CO) source in palladium-catalyzed aminocarbonylations of aryl halides. Since this date, and in connection with microwave-assisted methodologies, it has been recently exploited as both a surrogate for carbon monoxide in the synthesis of pyrazolo [1,5-a] and [3,4-d] pyrimidines 11 and for ammonia in the synthesis of pyrimido [1,2-a] pyrimidines. 12 In 2008, Negrete and his group described the one-pot reductive N-heterocyclization of various 2-nitrobenzoic acid derivatives with formamide, in the presence of a molar equivalent amount of indium(III) (chloride or acetate) or bismuth(III) acetate salts.…”

Section: Introductionmentioning

confidence: 99%

Microwave-assisted thermal decomposition of formamide: a tool for coupling a pyrimidine ring with an aromatic partner

Loidreau

Besson

2011

Tetrahedron

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“…Literature survey reveals that they have antibacterial [5,6], antiproliferative [7, 8], CNS modulating [9], antiviral [10], antifungal [11], anticancer [12] and anti-inflammatory [13] activities. These molecules have shown affinity towards adenosine receptors [14] and 5HT-6 and CRF-1 [15] receptors.Further, it has been found that substitution of the pyrazole 1-NH proton of the pyrazolo[3,4-d]pyrimidine ring system with other bioactive moieties leads to interesting pharmacological properties probably by increasing the π-stacking [16][17][18][19][20][21]. In view of the above-mentioned facts and in continuation of an ongoing program aimed at finding new structural leads with potential chemotherapeutic activities [22][23][24], we report herein the synthesis and antioxidant activity of some novel structure hybrids incorporating the pyrazolo[3,4-d]-pyrimidin-4-one moiety joined with the thiazole, tetrazole, thiophene, chromene, pyridine or pyrazole ring systems through different linkages.…”

mentioning

confidence: 99%

Synthesis and Antioxidant Activity of Some New Heterocycles Incorporating the Pyrazolo-[3,4-D]Pyrimidin-4-One Moiety

El‐Mekabaty

2015

Chem Heterocycl Comp

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moiety. Representative compounds of the synthesized series were tested and evaluated as antioxidants. Two of the tested compounds (pyrazole and thiophene derivatives) showed antioxidant activity nearly equal to that of ascorbic acid.Pyrazole derivatives are both important synthetic intermediates and compounds with interesting biological and pharmacological activities [1,2]. They are useful as starting materials for the synthesis of several polysubstituted fused pyrazoles [2,3]. For instance, 5-aminopyrazoles have been extensively used as precursors in the preparation of other fused heterocyclic systems like pyrazolotriazinones, pyrazolotriazepinones, and pyrazolopyrimidinones [2, 3]. We have recently reviewed the methods for preparation and the chemical reactivity of 5-amino-1-phenyl-1H-pyrazole-4-carboxamide as a building block for the synthesis of polyfunctionalized heterocyclic compounds with pharmacological interest [4].Pyrazolopyrimidinones, being purine analogs, are of considerable chemical and pharmacological importance. Literature survey reveals that they have antibacterial [5,6], antiproliferative [7, 8], CNS modulating [9], antiviral [10], antifungal [11], anticancer [12] and anti-inflammatory [13] activities. These molecules have shown affinity towards adenosine receptors [14] and 5HT-6 and CRF-1 [15] receptors.Further, it has been found that substitution of the pyrazole 1-NH proton of the pyrazolo[3,4-d]pyrimidine ring system with other bioactive moieties leads to interesting pharmacological properties probably by increasing the π-stacking [16][17][18][19][20][21]. In view of the above-mentioned facts and in continuation of an ongoing program aimed at finding new structural leads with potential chemotherapeutic activities [22][23][24], we report herein the synthesis and antioxidant activity of some novel structure hybrids incorporating the pyrazolo[3,4-d]-pyrimidin-4-one moiety joined with the thiazole, tetrazole, thiophene, chromene, pyridine or pyrazole ring systems through different linkages. This combination was suggested as a means of discovering a new lead structure that would have a significant antioxidant activity.

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Microwave-assisted protocols for the expedited synthesis of pyrazolo[1,5-a] and [3,4-d]pyrimidines

Cited by 68 publications

References 9 publications

In Vivo Structure−Activity Relationship Study of Dorsomorphin Analogues Identifies Selective VEGF and BMP Inhibitors

In Vivo Structure−Activity Relationship Study of Dorsomorphin Analogues Identifies Selective VEGF and BMP Inhibitors

Microwave-assisted thermal decomposition of formamide: a tool for coupling a pyrimidine ring with an aromatic partner

Synthesis and Antioxidant Activity of Some New Heterocycles Incorporating the Pyrazolo-[3,4-D]Pyrimidin-4-One Moiety

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