An examination of O-2-isocephems as orally absorbable antibiotics

Mastalerz, Harold; Ménard, Marcel; Vinet, V.; Desiderio, J. V.; Fung‐Tomc, Joan; Kessler, R E; Tsai, Yuan-Hwang

doi:10.1021/jm00401a020

Cited by 28 publications

(6 citation statements)

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“…The mixture was cooled to -78 °C and treated dropwise with 3-(phenylseleno)propionyl chloride (9.11 g, 0.037 mmol). 12 The mixture was stirred for 90 min at -78 °C, poured onto dilute hydrochloric acid/ice, and filtered. The collected solid was dissolved in dichloromethane, washed with water, and dried (MgSO4) and the solvent removed in vacuo.…”

Section: Methods a 2-cyano-3-cyclopropyl-3-hydroxy-n-[3′methyl-4′-(tr...mentioning

confidence: 99%

“…The preparation of 3-acetylenic derivatives was carried out using acyl fluorides for the acylation, whilefor the preparation of the 3-olefinic derivative 4 , the acylation using propenoyl chloride afforded only very poor yields of the required product. The acylation was best performed by method C (Scheme ) in which the acid chloride is substituted with a potential leaving group, phenylseleno, thus allowing the generation of the carbon−carbon double bond as a last step in the synthesis.…”

Section: Chemistrymentioning

confidence: 99%

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Synthesis, Structure−Activity Relationships, and Pharmacokinetic Properties of Dihydroorotate Dehydrogenase Inhibitors: 2-Cyano-3-cyclopropyl-3-hydroxy- N-[3‘-methyl-4‘-(trifluoromethyl)phenyl]propenamide and Related Compounds

et al. 1996

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The active metabolite (2) of the novel immunosuppressive agent leflunomide (1) has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. A series of analogues of the active metabolite 2 have been synthesized. Their in vivo biological activity determined in rat and mouse delayed type hypersensitivity has been found to correlate well with their in vitro DHODH potency. The most promising compound (3) has shown activity in rat and mouse collagen (II)-induced arthritis models (ED50 = 2 and 31 mg/kg, respectively) and has shown a shorter half-life in man when compared with leflunomide. Clinical studies in rheumatoid arthritis are in progress.

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Section: Methods a 2-cyano-3-cyclopropyl-3-hydroxy-n-[3′methyl-4′-(tr...mentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Synthesis, Structure−Activity Relationships, and Pharmacokinetic Properties of Dihydroorotate Dehydrogenase Inhibitors: 2-Cyano-3-cyclopropyl-3-hydroxy- N-[3‘-methyl-4‘-(trifluoromethyl)phenyl]propenamide and Related Compounds

et al. 1996

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“…Next, we have attempted to deprotect N-1 via oxidative cleavage of the dimethoxybenzyl protecting group. Several procedures using persulfate salts (e.g., potassium and/or ammonium persulfate, under various conditions including heating and acid addition [ 40 , 41 ]), which are known to be strong oxidizing agents, provided poor yields and numerous side products, making the isolation of the desired product by column chromatography extremely challenging.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of 3-Amino-4-substituted Monocyclic ß-Lactams—Important Structural Motifs in Medicinal Chemistry

Grabrijan

Strašek

Gobec

2021

IJMS

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Monocyclic ß-lactams (azetidin-2-ones) exhibit a wide range of biological activities, the most important of which are antibacterial, anticancer, and cholesterol absorption inhibitory activities. The synthesis of decorated monocyclic ß-lactams is challenging because their ring is highly constrained and consequently reactive, which is also an important determinant of their biological activity. We present the optimized synthesis of orthogonally protected 3-amino-4-substituted monocyclic ß-lactams. Among several possible synthetic approaches, Staudinger cycloaddition proved to be the most promising method for initial ring formation, yielding monocyclic ß-lactams with different substituents at the C-4 position, a phthalimido-protected 3-amino group, and a (dimethoxy)benzyl protected ring nitrogen. Challenging deprotection methods were then investigated. Oxidative cleavage with cerium ammonium nitrate and ammonia-free Birch reduction was found to be most effective for selective removal of ring nitrogen protection. Hydrazine hydrate was used for deprotection of the phthalimido group, and the procedure had to be modified by the addition of HCl in the case of aromatic substituents at the C-4 position. The presented methods and the synthesized 3-amino-4-substituted monocyclic ß-lactam derivatives are an important step toward new ß-lactams with potential pharmacological activities.

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“…Hydrogen peroxide‐induced oxidation of ethoxyselenide 7 , followed by syn ‐elimination of the in situ formed selenoxide, gave enol ether 8 as a separable mixture of E ‐/ Z ‐isomers (Scheme ). Starting from the single diastereoisomer of ethoxyselenide 7 , this sequence was expected to deliver only the E ‐isomer (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

Aruncin B: Synthetic Studies, Structural Reassignment and Biological Evaluation

Ribaucourt

Towers

Josa-Culleré

et al. 2017

Chemistry A European J

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A ring‐closing alkene metathesis (RCM)/ oxyselenation‐selenoxide elimination sequence was established to the sodium salts E‐ and Z‐25 of the originally proposed structure for the recently isolated cytotoxin aruncin B (1), as well as to the sodium salt Z‐34 of a related ethyl ether regioisomer; however, none of their corresponding free acids could be obtained. Their acid sensitivity, together with detailed analysis of the spectroscopic data indicated that profound structural revision was necessary. This led to reassignment of aruncin B as a Z‐γ‐alkylidenebutenolide Z‐36. Although a related RCM/ oxyselenation‐selenoxide elimination sequence was used to confirm the γ‐alkylidenebutenolide motif, a β‐iodo Morita‐Baylis–Hillman reaction/ Sonogashira cross‐coupling‐5‐exo‐dig lactonisation sequence was subsequently developed, due to its brevity and flexibility for diversification. Aruncin B (36), together with 14 γ‐alkylidenebutenolide analogues, were generated for biological evaluation.

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An examination of O-2-isocephems as orally absorbable antibiotics

Cited by 28 publications

References 0 publications

Synthesis, Structure−Activity Relationships, and Pharmacokinetic Properties of Dihydroorotate Dehydrogenase Inhibitors: 2-Cyano-3-cyclopropyl-3-hydroxy- N-[3‘-methyl-4‘-(trifluoromethyl)phenyl]propenamide and Related Compounds

Synthesis, Structure−Activity Relationships, and Pharmacokinetic Properties of Dihydroorotate Dehydrogenase Inhibitors: 2-Cyano-3-cyclopropyl-3-hydroxy- N-[3‘-methyl-4‘-(trifluoromethyl)phenyl]propenamide and Related Compounds

Synthesis of 3-Amino-4-substituted Monocyclic ß-Lactams—Important Structural Motifs in Medicinal Chemistry

Aruncin B: Synthetic Studies, Structural Reassignment and Biological Evaluation

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