Solid-Phase Synthesis of Benzopiperazinones

Morales, Guillermo A.; Corbett, Jeffrey W.; DeGrado, William F.

doi:10.1021/jo971688+

Cited by 106 publications

(60 citation statements)

References 13 publications

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“…The choice of these scaffolds for the attachment of HN pharmacophoric elements was based on several criteria. The benzimidazole and o-phenylenediamine scaffolds were first selected on the basis of previous reports that indicated that these types of molecules could be used as effective nontoxic peptide mimics and/or activators of specific membrane receptors (Kubo et al, 1993;Khan et al, 1996;Morales et al, 1998;Zarrinmayeh et al, 1999;Wu and Ede, 2001;Balboni et al, 2002;Heitsch, 2002). The next criteria was based on the principle that these molecules contain sites on which guanidino and phenolic hydroxy groups can be attached and still conserve enough freedom for proper orientation and interaction with the HN receptor(s).…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, the less rigid molecule of o-phenylenediamine, which possesses a hydrophilic skeleton, can also be used as a linker of pharmacophoric elements via attachment on adjacent free amino groups. Ortho-phenylenediamine has been successfully used as a precursor for the synthesis of tetrahydroquinoxaline-2-ones (Lee et al, 1997), benzopiperazinones (Morales et al, 1998), benzimidazoles, and quinoxalines (Wu and Ede, 2001).…”

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confidence: 99%

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Histogranin-Like Antinociceptive and Anti-Inflammatory Derivatives ofo-Phenylenediamine and Benzimidazole

Le¹,

Lemaire²,

Gilbert³

et al. 2004

J Pharmacol Exp Ther

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Histogranin (HN)-like nonpeptides were designed and synthesized using benzimidazole (compound 1) and o-phenylenediamine (compounds 2-7) as scaffolds for the attachment of phenolic hydroxyl and basic guanidino pharmacophoric elements present in HN. The benzimidazole derivative N-5- (2) were more potent analgesics than HN in both the mouse writhing (5.5 and 3.5 as potent as HN, respectively) and tail-flick (11.8 and 8.0 as potent as HN, respectively) pain assays. Improvements in the potencies and times of action of compound 2 in the mouse writhing test were obtained by attaching carboxyl (6) or p-Cl-benzoyl (7) groups at position 4 of the (2R) o-phenylenediamine derivative (5). In rats, compounds 2 (80 nmol i.t.), 6 (36 nmol i.t.), and 7 (18 nmol i.t.) were effective in blocking both persistent inflammatory pain in the formalin test and hyperalgesia in the complete Freund adjuvant assay. Compounds 2, 6, and 7, but not compound 1 at 10 nmol (i.c.v.) also mimicked the HN (60 nmol i.c.v.) blockade of N-methyl-D-aspartate (NMDA)-induced convulsions in mice. Finally, in primary cultures of rat alveolar macrophages, HN and compounds 1, 2, 6, and 7 (10 Ϫ8 M) significantly blocked lipopolysaccharide-induced cyclooxygenase-2 induction and prostaglandin E 2 secretion. These studies indicate that both derivatives of benzimidazole and o-phenylenediamine mimic the in vivo antinociceptive and in vitro anti-inflammatory effects of HN, but the HN protection of mice against NMDA-induced convulsions is mimicked only by the o-phenylenediamine derivatives.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Histogranin-Like Antinociceptive and Anti-Inflammatory Derivatives ofo-Phenylenediamine and Benzimidazole

Le¹,

Lemaire²,

Gilbert³

et al. 2004

J Pharmacol Exp Ther

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“…Note: method based on the procedure of Morales and co-workers (Morales, Corbett & DeGrado, 1998) where it is reported at larger scales. We exemplify here the procedure on a 76 µmol scale, which is routinely carried out in our laboratory.…”

Section: Equipment Setupmentioning

confidence: 99%

Solid Phase Synthesis of Helically Folded Aromatic Oligoamides

Dawson¹,

Hu²,

Claerhout³

et al. 2016

Methods in Enzymology

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Aromatic amide foldamers constitute a growing class of oligomers that adopt remarkably stable folded conformations. The folded structures possess largely predictable shapes and open the way towards the design of synthetic mimics of proteins. Important examples of aromatic amide foldamers include oligomers of 7-or 8-amino-2-quinoline carboxylic acid that have been shown to exist predominantly as well-defined helices, including when they are combine with -amino acids to which they may impose their folding behavior. To rapidly iterate their synthesis, solid phase synthesis protocols have been developed and optimized for overcoming synthetic difficulties inherent to these backbones such as low nucleophilicity of amine groups on electron poor aromatic rings and a strong propensity of even short sequences to fold on the solid phase during synthesis. For example, acid chloride activation and the use of microwaves are required to bring coupling at aromatic amines to completion. Here, we report detailed solid phase synthesis protocols for the rapid production of: 1) oligomers of 8-amino-2-quinolinecarboxylic acid; 2) 2 oligomers containing 7-amino-8-fluoro-2-quinolinecarboxylic acid; 3) heteromeric oligomers of 8-amino-2-quinolinecarboxylic acid and -amino acids. Solid phase synthesis brings the advantage to quickly produce sequences having varied main chain or side chain components without having to purify multiple intermediates as in solution phase synthesis. With these protocols, an octamer could easily be synthesized and purified within one to two weeks from Fmoc protected amino acid monomer precursors.

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“…1,2 Further, the polymer-supported synthesis has also been applied in a variety of organic reactions including the synthesis of natural products, heterocycles and in medicinal chemistry. [3][4][5][6][7][8][9][10] Synthesis of 10-substituted isoalloxazines by the acidic cyclocondensation of 2-substituted aminoanilines with alloxan monohydrate in aqueous and organic solvents has been reported by us. [11][12][13][14][15] Now, we report an improved synthesis of selected novel 10-substituted isoalloxazine-7-carboxylic acids via polymer-support to examine the feasibility of polymer-support synthesis in the synthesis of biologically active isoalloxazines.…”

Section: Introductionmentioning

confidence: 99%

Solid-phase synthesis of isoalloxazines using merrifield resin

Singh

2006

J. Braz. Chem. Soc.

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A reação da resina de Merrifield ligada a compostos diamino com aloxan monohidrato, resultou em uma resina ligada a isoaloxazinas 10-substituídas, que foram caracterizadas por fluorescência em fase sólida e espectroscopia de IV. A resina foi segmentada por solução aquosa de HF/DMF a 40%, obtendo-se isoaloxazinas 7-carboxi-10-substituídas, que foram caracterizadas por UV-Vis., IV, 1 H RMN, fluorescência e análise elementar.The reaction of Merrifield resin bound diamino compounds with alloxan monohydrate gave 7-resin bound 10-substituted isoalloxazines that were characterized by solid phase fluorescence and IR spectroscopy. The resin was cleaved by 40% aqueous HF/DMF to give 7-carboxy-10-substituted isoalloxazines that were characterized by UV-vis., IR, 1 H NMR, fluorescence and elemental analysis.

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Solid-Phase Synthesis of Benzopiperazinones

Cited by 106 publications

References 13 publications

Histogranin-Like Antinociceptive and Anti-Inflammatory Derivatives ofo-Phenylenediamine and Benzimidazole

Histogranin-Like Antinociceptive and Anti-Inflammatory Derivatives ofo-Phenylenediamine and Benzimidazole

Solid Phase Synthesis of Helically Folded Aromatic Oligoamides

Solid-phase synthesis of isoalloxazines using merrifield resin

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