Solid-Phase Synthesis and Chemical Properties of 2-(2-Amino/hydroxyethyl)-1-aryl-3,4-dihydropyrazino[1, 2-<i>b</i>]indazol-2-iums

Kočí, Jaromír; Krchňák, Viktor

doi:10.1021/cc9001422

Cited by 14 publications

(3 citation statements)

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“…Since synthesis of tetrahydropyrazines through the agency of cyclic N ‐alkyliminiums has not been reported, we describe the synthesis and full characterization of 2‐substituted‐1,2,3,4‐tetrahydropyrazines. To prepare the acyclic precursor, we applied a synthetic route used recently for the preparation of2‐(2‐amino/hydroxyethyl)‐1‐aryl‐3,4‐dihydropyrazino[1,2‐ b ]indazol‐2‐iums33 (Scheme ). Resin‐bound acyclic precursors 31 were treated with TFA to yield tetrahydropyrazines 33 .…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Piperazinones, Piperazines, Tetrahydropyrazines, and Dihydropyrazinones from Polymer‐Supported Acyclic Intermediates via N‐Alkyl‐ and N‐Acyliminiums

Vaňková

Brulíková

et al. 2012

Eur J Org Chem

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Trisubstituted piperazinones, piperazines, tetrahydropyrazines, and dihydropyrazinones were prepared in a one‐step procedure from easily accessible polymer‐supported acyclic precursors containing either a masked aldehyde or ketone group. Acid‐mediated unmasking of the aldehyde triggered cyclic iminium formation followed by reduction with triethylsilane present in the cleavage cocktail. The effect of the substituent at the iminium‐forming nitrogen was evaluated: whereas complete conversion to the target compounds was observed with N‐alkyl, aryl, and phenylsulfonamido derivatives, the N‐acyl compound suffered from a partial reduction of the aldehyde to an alcohol. Similarly, ketones readily provided cyclic iminiums with N‐alkyl compounds, whereas their cyclization with N‐acyl precursors proceeded unwillingly. Interestingly, cleavage of the resin‐bound acyclic precursor at 60 °C in the presence of triethylsilane resulted in the decomposition of the amide bond and formation of a lactone. An analogous synthetic route was also successfully used for the preparation of piperazines and tested as an alternative route for the synthesis of diazepanones.

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Section: Resultsmentioning

confidence: 99%

Synthesis of Piperazinones, Piperazines, Tetrahydropyrazines, and Dihydropyrazinones from Polymer‐Supported Acyclic Intermediates via N‐Alkyl‐ and N‐Acyliminiums

Vaňková

Brulíková

et al. 2012

Eur J Org Chem

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“…Cleavage of peptide−PEG from the resin was done with hydrazine monohydrate, as described previously. 24 Purification of the synthesized peptides was achieved by reverse-phase high-performance liquid chromatography (Thermo Scientific Dionex UltiMate 3000, Sunnyvale, CA). 19 For the conjugation of PEG to fatty acids [myristic acid (Ma) (C14)], the acyl chloride form of fatty acids was used by the previously reported modified method.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

Integrin α₂β₁-Targeted Self-Assembled Nanocarriers for Tumor Bioimaging

Fluksman

Steinberg

Orehov

et al. 2020

ACS Appl. Bio Mater.

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Recent developments in near-infrared (NIR) dyes and imaging modalities enable tumor fluorescent images in preclinical and clinical settings. However, NIR dyes have several drawbacks, and therefore, there is an unmet diagnostic need for NIR dye encapsulation in appropriate pharmaceutical nanocarriers with targeting abilities for the purpose of achieving effective diagnosis and image-guided surgeries. Because integrin receptors are established diagnostic targets, the cyclic Arg-Gly-Asp (RGD) peptides, recognizing the αVβ3 integrin, have been extensively investigated for radiology and bioimaging of tumors. However, the Lys(Arg)-Thr-Ser [K(R)TS] cyclic peptides, selective for collagen receptors α1β1/α2β1 integrins, which are overexpressed in many tumors, were not yet investigated and therefore used here for tumor bioimaging with a unique α2β1-integrin-targeted nanocarrier, encapsulating the indocyanine green NIR dye. We synthesized three kinds of peptides: two cyclic RTS peptides functional only in the cyclic conformation and a linear peptide lacking the cyclic cysteine constrained RTS loop. We used them for the preparation of integrin-targeted self-assembled nanocarriers (ITNCs), referred to as OF5 and OF27, and a nontargeted control nanocarrier, referred to as OF70. Their selective association was demonstrated with α2β1 integrin expressing cell cultures and three-dimensional tumor spheroids and by competition with a α2β1 selective disintegrin. Cytotoxicity experiments in vitro demonstrated the safety of the ITNCs. The targeting potential and the biodistribution of the ITNCs, applied intravenously in A431 tumor-bearing nude mice, were evaluated in vivo using NIR bioimaging. Time-dependent biodistributions indicated that the ITNC OF27 showed higher fluorescent signals in main tissues, with no cytotoxic effects to major organs, and presented higher accumulation in tumors. Cumulatively, these results highlight the potential of the ITNC OF27 as an optical and innovative pharmaceutical bioimaging system, suitable for integrin α2β1 receptor in vivo tumor targeting and visualization in the NIR region.

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“…Cleavage of Vipegitide-PEG2 peptide from the resin first was done with hydrazine monohydrate, as described previously. 21 Briefly, a solution of hydrazine monohydrate (41.2 mM, 2 mL) in 10 mL methanol/tetrahydrofuran (1:1) was added to the resin and reaction slurry was shaken for 6 hours. The resin was washed with methanol (5×) and with dichloromethane (3×).…”

Section: Methodsmentioning

confidence: 99%

Vipegitide: a folded peptidomimetic partial antagonist of α2β1 integrin with antiplatelet aggregation activity

Momić¹,

Katzhendler²,

Shai³

et al. 2015

DDDT

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Linear peptides containing the sequence WKTSRTSHY were used as lead compounds to synthesize a novel peptidomimetic antagonist of α2β1 integrin, with platelet aggregation-inhibiting activity, named Vipegitide. Vipegitide is a 13-amino acid, folded peptidomimetic molecule, containing two α-aminoisobutyric acid residues at positions 6 and 8 and not stable in human serum. Substitution of glycine and tryptophan residues at positions 1 and 2, respectively, with a unit of two polyethylene glycol (PEG) molecules yielded peptidomimetic Vipegitide-PEG2, stable in human serum for over 3 hours. Vipegitide and Vipegitide-PEG2 showed high potency (7×10−10 M and 1.5×10−10 M, respectively) and intermediate efficacy (40% and 35%, respectively) as well as selectivity toward α2 integrin in inhibition of adhesion of α1/α2 integrin overexpressing cells toward respective collagens. Interaction of both peptidomimetics with extracellular active domain of α2 integrin was confirmed in cell-free binding assay with recombinant α2 A-domain. Integrin α2β1 receptor is found on the platelet membrane and triggers collagen-induced platelet aggregation. Vipegitide and Vipegitide-PEG2 inhibited α2β1 integrin-mediated adhesion of human and murine platelets under the flow condition, by 50%. They efficiently blocked adenosine diphosphate- and collagen I-induced platelet aggregation in platelet rich plasma and whole human blood. Higher potency of Vipegitide than Vipegitide-PEG2 is consistent with results of computer modeling of the molecules in water. These peptidomimetic molecules were acutely tolerated in mice upon intravenous bolus injection of 50 mg/kg. These results underline the potency of Vipegitide and Vipegitide-PEG2 molecules as platelet aggregation-inhibiting drug lead compounds in antithrombotic therapy.

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Solid-Phase Synthesis and Chemical Properties of 2-(2-Amino/hydroxyethyl)-1-aryl-3,4-dihydropyrazino[1, 2-b]indazol-2-iums

Cited by 14 publications

References 28 publications

Synthesis of Piperazinones, Piperazines, Tetrahydropyrazines, and Dihydropyrazinones from Polymer‐Supported Acyclic Intermediates via N‐Alkyl‐ and N‐Acyliminiums

Synthesis of Piperazinones, Piperazines, Tetrahydropyrazines, and Dihydropyrazinones from Polymer‐Supported Acyclic Intermediates via N‐Alkyl‐ and N‐Acyliminiums

Integrin α₂β₁-Targeted Self-Assembled Nanocarriers for Tumor Bioimaging

Vipegitide: a folded peptidomimetic partial antagonist of α2β1 integrin with antiplatelet aggregation activity

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Solid-Phase Synthesis and Chemical Properties of 2-(2-Amino/hydroxyethyl)-1-aryl-3,4-dihydropyrazino[1, 2-b]indazol-2-iums

Cited by 14 publications

References 28 publications

Synthesis of Piperazinones, Piperazines, Tetrahydropyrazines, and Dihydropyrazinones from Polymer‐Supported Acyclic Intermediates via N‐Alkyl‐ and N‐Acyl­iminiums

Synthesis of Piperazinones, Piperazines, Tetrahydropyrazines, and Dihydropyrazinones from Polymer‐Supported Acyclic Intermediates via N‐Alkyl‐ and N‐Acyl­iminiums

Integrin α2β1-Targeted Self-Assembled Nanocarriers for Tumor Bioimaging

Vipegitide: a folded peptidomimetic partial antagonist of &alpha;2&beta;1 integrin with antiplatelet aggregation activity

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Synthesis of Piperazinones, Piperazines, Tetrahydropyrazines, and Dihydropyrazinones from Polymer‐Supported Acyclic Intermediates via N‐Alkyl‐ and N‐Acyliminiums

Synthesis of Piperazinones, Piperazines, Tetrahydropyrazines, and Dihydropyrazinones from Polymer‐Supported Acyclic Intermediates via N‐Alkyl‐ and N‐Acyliminiums

Integrin α₂β₁-Targeted Self-Assembled Nanocarriers for Tumor Bioimaging

Vipegitide: a folded peptidomimetic partial antagonist of α2β1 integrin with antiplatelet aggregation activity