From norbornane-based nucleotide analogs locked in South conformation to novel inhibitors of feline herpes virus

Dejmek, Milan; Hřebabecký, Hubert; Šála, Michal; Dračínský, Martin; Procházková, Eliška; Leyssen, Pieter; Neyts, Johan; Balzarini, Jan; Nencka, Radim

doi:10.1016/j.bmc.2014.04.004

Cited by 17 publications

(11 citation statements)

References 17 publications

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“…by the landmark report from Bartlett and Knox 12 in which bridgehead-substituted 1-apocamphanes (7,7-dimethylnorbornanes) were used as negative controls for S N 2 reactivity supporting the Walden inversion mechanism. [13][14][15] These classical accounts, [16][17][18][19][20] as well as more recent approaches, [21][22][23][24] largely generate the bridgehead amine via Hofmann or Curtius rearrangements of C1-CO 2 H motifs within terpene derivatives or from downstream products of cyclopentadiene-based Diels-Alder reactions. One radical-based closure exists from Della and Knill, 25 cyclizing a C7-radical into an oxime after traditional tin-based initiation conditions.…”

Section: As Illustratedmentioning

confidence: 99%

Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonorbornanes

Staveness

Sodano

et al. 2019

Chem

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The chemistry provided herein details an efficient and flexible route toward architecturally distinctive 1-aminonorbornanes through the use of visible-light photoredox catalysis. The incorporation of readily diversifiable functional handles (e.g., -OH, -CO 2 Me, -NHBoc, -NHCbz) illustrates the potential utility of these 1aminonorbornanes within drug-discovery programs. Additionally, these motifs offer improved metabolic stability relative to that of their aniline congeners (as demonstrated through microsomal stability assays and metabolite identification efforts), indicating applicability of 1-aminonorbornanes as aniline bioisosteres. HIGHLIGHTSStrain-driven homolysis initiates radical cyclization sequence toward norbornane core Robust functional-group tolerance provides readily modifiable building blocks Unique modes of diastereocontrol afford enantiopure 1aminonorbornanes 1-Aminonorbornanes are shown to offer improved metabolic stability over anilines Staveness et al., Chem 5,[215][216][217][218][219][220][221][222][223][224][225][226] January 10, SUMMARYThis report describes the photochemical conversion of aminocyclopropanes into 1-aminonorbornanes via formal [3 + 2] cycloadditions initiated by homolytic fragmentation of amine radical cation intermediates. Aligning with the modern movement toward sp 3 -rich motifs in drug discovery, this strategy provides access to a diverse array of substitution patterns on this saturated carbocyclic framework while offering the robust functional-group tolerance (e.g., -OH, -NHBoc) necessary for further derivatization. Evaluating the metabolic stability of selected morpholine-based 1-aminonorbornanes demonstrated a low propensity for oxidative processing and no proclivity toward reactive metabolite formation, suggesting a potential bioisosteric role for 1-aminonorbornanes. Continuous-flow processing allowed for efficient operation on the gram scale, providing promise for translation to industrially relevant scales. This methodology only requires low loadings of a commercially available, visible-light-active photocatalyst and a simple salt; thus, it stays true to sustainability goals while readily delivering saturated building blocks that can reduce metabolic susceptibility within drug development programs.

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Section: As Illustratedmentioning

confidence: 99%

Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonorbornanes

Staveness

Sodano

et al. 2019

Chem

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“…This work also represents ar are prior example of a1 -aminoNB in the literature;o fn ote,t he majority of prior 1-aminoNB preparations generate the bridgehead amine via aH ofmann or aC urtius rearrangement of terpene-based materials [43][44][45][46] or from downstream products of cyclopentadiene-acrylate Diels-Alder reactions [47][48][49][50] (only one radicalbased closure [51] existed before our work [18] ).…”

Section: Introductionmentioning

confidence: 95%

“…One example of an imine‐specific rearrangement is the photo‐racemization of dihydropyrazine (−)‐ 3 (see Figure A), facilitated by the non‐classical bond structure available to [2.2.1] bicyclic systems with open‐shell character adjacent to the bridgehead position. This work also represents a rare prior example of a 1‐aminoNB in the literature; of note, the majority of prior 1‐aminoNB preparations generate the bridgehead amine via a Hofmann or a Curtius rearrangement of terpene‐based materials or from downstream products of cyclopentadiene‐acrylate Diels–Alder reactions (only one radical‐based closure existed before our work).…”

Section: Introductionmentioning

confidence: 99%

Exploiting Imine Photochemistry for Masked N‐Centered Radical Reactivity

et al. 2019

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This report details the development of a masked N‐centered radical strategy that harvests the energy of light to drive the conversion of cyclopropylimines to 1‐aminonorbornanes. This process employs the N‐centered radical character of a photoexcited imine to facilitate the homolytic fragmentation of the cyclopropane ring and the subsequent radical cyclization sequence that forms two new C−C bonds en route to the norbornane core. Achieving bond‐forming reactivity as a function of the N‐centered radical character of an excited state Schiff base is unique, requiring only violet light in this instance. This methodology operates in continuous flow, enhancing the potential to translate beyond the academic sector. The operational simplicity of this photochemical process and the structural novelty of the (hetero)aryl‐fused 1‐aminonorbornane products are anticipated to provide a valuable addition to discovery efforts in pharmaceutical and agrochemical industries.

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“…13 Hypoxanthine derivative 16b and guanine derivative 16c were prepared using the nucleobase assembly approach adopted from ref. 16 (employing 4,6-dichloro-5-formamidopyrimidine (32) and 2-amino-4,6-dichloro-5-formamidopyrimidine (33) respectively) followed by bromotrimethylsilane promoted iso- propyl ester group removal. The reaction of amino derivative 31 with 32 and 33 did not lead to purine ring closure so additional treatment with diethoxymethyl acetate in DMF at elevated temperatures was required.…”

Section: Synthesismentioning

confidence: 99%

Synthesis, conformational studies, and biological properties of phosphonomethoxyethyl derivatives of nucleobases with a locked conformation via a pyrrolidine ring

et al. 2015

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Systematic structure-activity studies on a diverse family of nucleoside phosphonic acids has led to the development of potent antiviral drugs such as HPMPC (CidofovirTM), PMEA (AdefovirTM), and PMPA (TenofovirTM), which are used in the treatment of CMV-induced retinitis, hepatitis B, and HIV, respectively. Here, we present the synthesis of a novel class of acyclic phosphonate nucleotides that have a locked conformation via a pyrrolidine ring. NMR analysis of these compounds revealed that the pyrrolidine ring has a constrained conformation when in the cis-form at pD < 10 via hydrogen bonding. Four of these compounds were tested as inhibitors of the human and Plasmodium falciparum 6-oxopurine phosphoribosyltransferases. The most potent has a Ki of 0.6 μM for Plasmodium falciparum HGXPRT.

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From norbornane-based nucleotide analogs locked in South conformation to novel inhibitors of feline herpes virus

Cited by 17 publications

References 17 publications

Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonorbornanes

Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonorbornanes

Exploiting Imine Photochemistry for Masked N‐Centered Radical Reactivity

Synthesis, conformational studies, and biological properties of phosphonomethoxyethyl derivatives of nucleobases with a locked conformation via a pyrrolidine ring

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