Synthesis of Ureidopeptides and Peptidyl Ureas Employing Bsmoc Chemistry

This work describes the utility of Bsmoc group in the synthesis of ureidopeptides and peptidyl ureas. The reaction of isocyanates derived from Bsmoc-α-amino acids with amino acid ester has yielded the ureidopeptides in good yields. The isocyanates were obtained by subjecting Bsmoc-amino acid azides to Curtius rearrangement. Bsmoc protected ureidopeptides have been isolated as solids and characterized by ¹H NMR, ¹³C NMR and mass spectrum.     

新型氮杂多肽酰肼类衍生物的设计、合成和抗肿瘤活性研究

目的:新型氮杂多肽酰肼类衍生物的设计和合成及其抗肿瘤活性研究。方法:以脯氨酸甲酯盐酸盐为原料,通过与苄氧羰基丙氨酸反应,在肼中肼解,得到所需中间体,进而与富马酸单酯反应得到目标化合物;和溴乙酸叔丁酯反应,三氟乙酸中脱去叔丁氧基,再与取代胺或氨水反应得到目标化合物。用MTT法测试合成的氮杂多肽酰肼类衍生物对肿瘤细胞的抑制活性。结果:合成了10个氮杂多肽酰肼类衍生物,其中有6个化合物对肿瘤细胞表现出抑制活性。结论:初步建立了氮杂多肽酰肼类衍生物的合成方法及其对肿瘤细胞抑制活性的构效关系。     

Hydrolase-catalyzed Michael addition of imidazoles to acrylic monomers in organic medium

Hydrolase-catalyzed Michael addition of imidazole derivatives to acrylic monomers in organic medium was described. A serial of N-substituted imidazole derivatives were successfully synthesized in moderate yields by the catalysis of hydrolases in organic medium. Nine commercially available hydrolases from different sources were screened and all of them were found to be able to catalyze this type of addition reaction. The reaction yields depended on the solvent properties and the solvents with higher log P value supported this enzyme-catalyzed reaction to give higher conversion. Influence of the structure of the Michael acceptor and donor on the enzymatic Michael addition was also investigated. The acceptor with shorter alcohol chain afforded a higher yield. A more rapid conversion was observed when the donor had an electron-withdrawing group. This hydrolase-catalyzed Michael addition reaction has widened the applicability of biocatalysts in organic and bioorganic synthesis.     

Inhibition of protein phosphatases by Michael adducts of ascorbic acid analogues with alpha,beta-unsaturated carbonyl compounds

By investigating the stereospecific Michael reaction of derivatives of ascorbic acid with acrolein we obtained a novel class of protein Ser/Thr phosphatase inhibitors. The inhibitory effect of the Michael adducts was examined using the canonical protein phosphatases type 1, 2A and 2B. Of the isozymes examined the type 1 isoform was strongly inhibited.     

Coupling of iminodiacetic acid with amino acid derivatives in solution and solid phase

Summary The IR studies for the preactivation step of N-protected iminodiacetic acid with different coupling reagents (TCFH, TFFH, HATU, HBTU, HSTU) were reported here and showed the formation of an anhydride as an active intermediate in case of TCFH and TFFH. The formation of a mixture of an anhydride and an active ester (-OBt,-OAt or-OSu) were observed for HBTU, HATU or HSTU coupling reagent. Dependent on the coupling conditions, acylation of N-protected iminodiacetic acid with amino acid ester or amide derivatives in solution phase gave monoor di-substituted iminodiacetic acid derivatives. Coupling of N-protected iminodiacetic acid with an amino acid or peptide attached to a solid support (PAL-PEG-PS or Wang resin) gave only the monosubstituted iminodiacetic acid derivatives. Abbreviations: HBTU, N-[(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate N-oxide; Boc,t-butyloxycarbonyl; DCC, N,N′-dicyclohexylcarbodiimide; DIC, N,N′-diisopropylcarbodiimide; DIEA, diisopropylethylamine; HATU, N-[(dimethylamino)-1H-1,2,3,-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate N-oxide; DMF, N,N-dimethylformamide; Bsmoc, 1,1-dioxobenzo[b]thiophene-2-ylmethoxycarbonyl; Fmoc, 9-fluorenylmethyloxycarbonyl; HOAt, l-hydroxy-7-azabenzotriazole; HOBt, l-hydroxybenzotriazol; IDA, iminodiacetic acid; HSTU, O-(succinimidyl)-tetramethyluronium hexafluorophosphate; TCFH; 1,1,3,3-tetramethyl-2-chloroformamidinium hexafluorophosphate; TFFH, 1,1,3,3-tetramethyl-2-fluoroformamidinium hexafluorophosphate; TMS-Cl, trimethylchlorosilane. Amino acids and peptides are abbreviated and designated following the rules of the IUPAC-IUB Commission of Biochemical Nomenclature (J. Biol. Chem., 247 (1972) 997).     

l-Prolinol as a highly enantioselective catalyst for Michael addition of cyclohexanone to nitroolefins

Though many chiral amines such as l-proline and its derivatives have proven to be versatile catalysts in many reactions, l-prolinol was seldom used as organocatalyst for reactions. Herein, we report the first l-prolinol catalyzed asymmetric Michael addition of cyclohexanone to nitroolefins in the presence of benzoic acid to afford Michael adducts with high diastereoselectivities (87:13–>99:1) and enantioselectivities (82–96%).     

Synthesis of 1-(2-naphthylsulfonyl)pyrazole-C-glycosides

2-Naphthylsulfonylhydrazine was reacted with aromatic aldehydes or aldehydo sugars to give the corresponding hydrazones which undergo Michael addition reactions with malononitrile or ethyl cyanoacetate to form pyrazole derivatives.     

Two-step sequential synthesis of pyrimidine derivatives containing a sugar branch via combining of enzymatic Michael addition/acylation

A new strategy for the enzymatic synthesis of pyrimidine derivatives containing a sugar branch was developed via combining of Michael addition and acylation. The first-step reaction of pyrimidines and vinyl 3-propionyloxy propionate was catalyzed by Amano lipase M from Mucor javanicus in DMSO. The initial reaction rates of different pyrimidines decreased in the order of fluorouracil, uracil, thymine, in agreement with their nucleophilicity. The succeeding regioselective acylation of d-glucose and d-mannose with the Michael adducts was catalyzed by alkaline protease from Bacillus subtilis in pyridine. The d-glucose and d-mannose were all acylated at C-6 position. Moderate yield was obtained for each step.     

Michael reaction of chitosan with various acryl reagents in water

A Michael reaction of chitosan was conducted in water containing acetic acid with various acryl reagents. The degree of substitution could be controlled by temperature, reaction time, and the amount of acryl reagents. Although the modified chitosan derivatives with acrylic acid esters showed water-solubility, that with poly(ethylene glycol) acrylate, however, turned to water-insoluble material by lyophilization. Good biodegradation was observed in modified chitosan derivatives by standard activated sludge.     

Design and synthesis of a novel series of HIV-1 protease inhibitors.

The synthesis and the SAR study of novel pseudo symmetric inhibitors of HIV-1 protease are described. Michael addition of amino acid derivatives to vinyl ketones was utilized to derive a potent (nM) series of HIV-1 protease inhibitors.     

Inhibition of human cytomegalovirus protease by enedione derivatives of thieno[2,3-d]oxazinones through a novel dual acylation/alkylation mechanism

Enedione derivatives of thieno[2,3-d]oxazinones are nanomolar inhibitors of CMV protease which act through a novel dual acylation of the catalytic serine and alkylation of the protease cysteine 161 via a Michael addition to the enedione moiety of the inhibitor.     

Chemical structures critical for the induction of FMN-dependent NADH-quinone reductase in Escherichia coli.

An FMN-dependent NADH-quinone reductase is induced in Escherichia coli by growing the cells in the presence of menadione (2-methyl-1,4-naphthoquinone). Since the properties of induced enzyme are very similar to those of NAD(P)H: (quinone-acceptor) oxidoreductase (EC 1.6.99.2), known as DT-diaphorase, from animal cells, structural requirements of quinone derivatives as an inducer of NADH-quinone reductase in E. coli were examined. Among quinone derivatives examined, it was found that 2-alkyl-1,4-quinone structure with C-3 unsubstituted or substituted with Br is critical as a common inductive signal. Michael reaction acceptors which have been reported to be strong inducers of DT-diaphorase in mouse hepatoma cells were not always effective inducers in E. coli. However, several compounds, such as 2-methylene-4-butyrolactone, methylacrylate and methyl vinyl ketone, showed a slight inductive activity. The efficient inducers of NADH-quinone reductase in E. coli contain 1,4-quinone structure as a part of the inductive signal. These compounds belong to Michael acceptors and are likely to conjugate with thiol compounds such as glutathione.     

Synthesis of alkenyl acyclonucleosides derivatives of 5-halogenouracil as antiviral and antitumoral agents.

Alkenyl acyclonucleosides derivatives of 5-halogenouracil have been synthesized via Michael addition reaction. These compounds were treated by allylbromide, propargylbromide or ethylbromoacetate to give the corresponding N-1,N-3-disubstituted 5-halogenouracil.     

Synthesis of diamine maleyl chitosans, and in vitro transfection studies

Three novel diamine-modified chitosan derivatives were synthesized from N-maleyl chitosan via Michael addition reaction with 1,2-diaminoethane, 1,4-diaminobutane, and 1,6-diaminohexane, respectively. These chitosan derivatives exhibited well binding ability of condensing plasmid DNA to form complexes with size ranging from 150 to 500 nm when the chitosan derivative/DNA weight ratios were above 10. The complexes observed by scanning electron microscopy (SEM) exhibited a compact and spherical morphology. The cytotoxicity of the chitosan derivatives presented a dependence on their side-chain structures. The gene transfection experiments were evaluated in 293 T and HeLa cells. The data obtained demonstrated that the gene transfection efficiencies of these chitosan derivatives were better than that of chitosan, suggesting these chitosan derivatives as potential gene vectors in vitro.     

Ring A structural modified derivatives of withaferin A and the evaluation of their cytotoxic potential

Regio-/stereoselective Michael addition to ring A of withaferin-A was performed using an optimized reaction procedure to synthesise a library of 2,3-dihydro,3-β-substituted withaferin-A derivatives. The analogues thus obtained were evaluated for in vitro cytotoxicity against various human cancer cell lines. 3-Azido analogue exhibited 35-fold increase (IC(50)=0.02-1.9 μM) in cytotoxicity against almost the entire cell lines tested when compared to the parent molecule. However, further modifications of 3-azido analogue with various alkynes under Husigen's cycloaddition conditions generated a variety of triazole derivatives with reduced cytotoxicity.     

One-pot synthesis of highly functionalized morphans from C-glycosides

Highly functionalized morphan derivatives were synthesized from nitroalkene 2′-(oxoalkyl)-C-glycosides by a tandem reaction that created three (two C–N and one C–C) new bonds and four stereogenic centers in a one-pot procedure under very mild conditions without the use of expensive reagents. The transformation was achieved from a β-elimination/Michael addition cascade, followed by Michael addition of the amine and intramolecular enamination. In the presence of sodium cyanoborohydride the iminium intermediate was reduced in situ to afford the desired morphans.     

SYNTHESIS OF 1-(2-NAPHTHYLSULFONYL)PYRAZOLE-C-GLYCOSIDES

ABSTRACT

2-Naphthylsulfonylhydrazine was reacted with aromatic aldehydes or aldehydo sugars to give the corresponding hydrazones which undergo Michael addition reactions with malononitrile or ethyl cyanoacetate to form pyrazole derivatives.     

Synthesis of Alkenyl Acyclonucleosides Derivatives of 5-Halogenouracil as Antiviral and Antitumoral Agents

Abstract

Alkenyl acyclonucleosides derivatives of 5-halogenouracil have been synthesized via Michael addition reaction. These compounds were treated by allylbromide, propargylbromide or ethylbromoacetate to give the corresponding N-1,N-3-disubstituted 5-halogenouracil.