- En Route to a Heterogeneous Catalytic Direct Peptide Bond Formation by Zr-Based Metal-Organic Framework Catalysts
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Peptide bond formation is a challenging, environmentally and economically demanding transformation. Catalysis is key to circumvent current bottlenecks. To date, many homogeneous catalysts able to provide synthetically useful methods have been developed, while heterogeneous catalysts remain largely restricted to the studies addressing the prebiotic formation of peptides. Here, the catalytic activity of Zr6-based metal-organic frameworks (Zr-MOFs) toward peptide bond formation is investigated using dipeptide cyclization as a model reaction. Unlike previous catalysts, Zr-MOFs largely tolerate water, and reactions are carried out under ambient conditions. Notably, the catalyst is recyclable and no additives to activate the COOH group are necessary, which are common limitations of previous methods. In addition, a broad reaction scope tolerates substrates with bulky and Lewis basic groups. The reaction mechanism was assessed by detailed mechanistic and computational studies and features a Lewis acid activation of carboxylate groups by Zr centers toward amine addition in which an alkoxy ligand on adjacent Zr sites assists in lowering the barrier of key proton transfers. The proposed concepts were also used to study the formation of intermolecular peptide bond formation. While intrinsic challenges associated with the catalyst structure and water removal limit a more general intermolecular reaction scope under current conditions, the results suggest that further design of Zr-MOF catalysts could render these materials broadly useful as heterogeneous catalysts for this challenging transformation.
- Conic, Dragan,De Azambuja, Francisco,Harvey, Jeremy N.,Loosen, Alexandra,Parac-Vogt, Tatjana N.,Van Den Besselaar, Maxime
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p. 7647 - 7658
(2021/06/30)
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- Design, synthesis and antitumor activity evaluation of Chrysamide B derivatives
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Marine natural products derived from special or extreme environment provide an important source for the development of anti-tumor drugs due to their special skeletons and functional groups. In this study, based on our previous work on the total synthesis and structure revision of the novel marine natural product Chrysamide B, a group of its derivatives were designed, synthesized, and subsequently of which the anti-cancer activity, structure-activity relationships and cellular mechanism were explored for the first time. Compared with Chrysamide B, better anti-cancer performance of some derivatives against five human cancer cell lines (SGC-7901, MGC-803, HepG2, HCT-116, MCF-7) was observed, especially for compound b-9 on MGC-803 and SGC-7901 cells with the IC 50 values of 7.88 ± 0.81 and 10.08 ± 1.08 μM, respectively. Subsequently, cellular mechanism study suggested that compound b-9 treatment could inhibit the cellular proliferation, reduce the migration and invasion ability of cells, and induce mitochondrial-dependent apoptosis in gastric cancer MGC-803 and SGC-7901 cells. Furthermore, the mitochondrial-dependent apoptosis induced by compound b-9 is related with the JAK2/STAT3/Bcl-2 signaling pathway. To conclude, our results offer a new structure for the discovery of anti-tumor lead compounds from marine natural products.
- Zhu, Longqing,Li, Junfang,Fan, Xiaohong,Hu, Xiaoling,Chen, Jinhong,Liu, Yonghong,Hao, Xiangyong,Shi, Tao,Wang, Zhen,Zhao, Quanyi
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- Discovery of a novel inhibitor of nitric oxide production with potential therapeutic effect on acute inflammation
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Inflammation as a host's excessive immune response to stimulation, is involved in the development of numerous diseases. To discover novel anti-inflammatory agents and based on our previous synthetic work on marine natural product Chrysamide B, it and a series of derivatives were synthesized and evaluated for their anti-inflammatory activity on inhibition of LPS-induced NO production. Then the preliminary structure–activity relationships were conducted. Among them, Chrysamide B is the most potent anti-inflammatory agent with low cytotoxicity and strong inhibition on the production of NO (IC50 = 0.010 μM) and the activity of iNOS (IC50 = 0.082 μM) in LPS-stimulated RAW 264.7 cells. Primary studies suggested that the mechanism of action may be that it interfered the formation of active dimeric iNOS but not affected transcription and translation. Furthermore, its good performance of anti-inflammatory effect on LPS-induced multiple inflammatory cytokines production, carrageenan-induced paw edema, and endotoxin-induced septic mice, was observed. We believe that these findings would provide an idea for the further modification and research of these analogs in the future.
- Zhu, Long-Qing,Fan, Xiao-Hong,Li, Jun-Fang,Chen, Jin-Hong,Liang, Yan,Hu, Xiao-Ling,Ma, Shu-Meng,Hao, Xiang-Yong,Shi, Tao,Wang, Zhen
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supporting information
(2021/05/26)
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- Novel piperazine compound as well as preparation method and application thereof
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The structural general formula of a novel piperazine compound is shown in the specification. The invention aims to provide a novel anti-inflammatory drug with high efficiency and low side effect. Because typical marine characteristic skeleton molecules ri
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Paragraph 0078-0080; 0084-0085
(2020/04/22)
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- Chrysamide B derivative with anti-tumor activity and preparation and application of Chrysamide B derivative
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The invention belongs to the field of medicinal chemistry, and particularly relates to a marine natural product Chrysamide B and a derivative thereof. The marine natural product Chrysamide B comprisesstereoisomers or pharmaceutically acceptable salts, solvates and prodrugs of the marine natural product Chrysamide B, general formulas are shown in a formula (I), a formula (II) and a formula (III).The invention also provides preparation and application of the compound. The compound has an anti-cancer effect; the compound has good inhibitory activity on digestive system cancers, leukemia, livertumors, non-small cell lung cancers, cervical cancers, breast cancers and the like and has the effects of inducing tumor cell apoptosis, activating apoptosis protein expression, retarding cycle, inhibiting proliferation and the like and is a potential antitumor drug.
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Paragraph 0061-0063; 0065
(2020/08/02)
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- Investigation of permeation of theophylline through skin using selected piperazine-2,5-diones
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Transdermal administration of drugs that penetrate, in this case directly into the blood circulation, has many advantages and is promising for many drugs thanks to its easy application and good patient compliance. (S)-8-Methyl-6,9-diazaspiro[4.5]decan-7,10-dione (alaptide), has been studied as a potential chemical permeation enhancer. Based on its structure, four selected piperazine-2,5-diones were synthesized by means of multi-step synthetic pathways. All the compounds were investigated on their ability to enhance the permeation of the model drug theophylline from the hydrophilic medium propylene glycol:water (1:1). In vitro experiments were performed using vertical Franz diffusion cells at constant temperature 34 ± 0.5 ?C and using full-thickness pig (Sus scrofa f. domestica) ear skin. Withdrawn samples were analyzed by RP-HPLC for determination of the permeated amount of theophylline. All the compounds were applied in ratio 1:10 (w/w) relative to the amount of theophylline. One hour after application, the permeated amount of theophylline from formulations with alaptide and (3S,6S)-3,6-dimethylpiperazine-2,5-dione, was ca. 15- and 12-fold higher, respectively, than from the formulation without the tested compounds. Despite the enhancement ratio of both enhancers in a steady state was ca. 2.3, the pseudo-enhancement ratio in the time range from 1 to 3 h was 4.4. These enhancement ratios indicate that the compounds are able to enhance the permeation of agents through the skin; however, the short-term application of both compound formulations seems to be more advantageous. In addition, the screening of the cytotoxicity of all the prepared compounds was performed using three cell lines, and the compounds did not show any significant toxic effect.
- Pokorna, Aneta,Bobal, Pavel,Oravec, Michal,Rarova, Lucie,Bobalova, Janette,Jampilek, Josef
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- Anti-biofilm and anti-adherence properties of novel cyclic dipeptides against oral pathogens
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Microorganisms embedded in a biofilm are significantly more resistant to antimicrobial agents and the defences of the human immune system, than their planktonic counterpart. Consequently, compounds that can inhibit biofilm formation are of great interest for novel therapeutics. In this study, a screening approach was used to identify novel cyclic dipeptides that have anti-biofilm activity against oral pathogens. Five new active compounds were identified that prevent biofilm formation by the cariogenic bacterium Streptococcus mutans and the pathogenic fungus Candida albicans. These compounds also inhibit the adherence of microorganisms to a hydroxylapatite surface. Further investigations were conducted on these compounds to establish the structure–activity relationship, and it was deduced that the common cleft pattern is required for these molecules to act effectively against biofilms.
- Simon, Ga?lle,Bérubé, Christopher,Voyer, Normand,Grenier, Daniel
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p. 2323 - 2331
(2018/12/11)
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- Synthesis method for nitro group-containing natural product chrysamides B and diastereoisomer-compound thereof
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The invention belongs to the technical fields of medicinal chemistry and organic synthesis, and relates to a synthesis method for a nitro group-containing natural product chrysamides B, a chrysamidesB diastereoisomer-compound and a synthesis method and application thereof. According to the invention, a convergent synthesis method is adopted to condense chiral epoxy carboxylic acid and chiral dimethylpiperazine ring, and thereby the nitro group-containing natural product chrysamides B with a symmetrical structure and the chrysamides B diastereoisomer-compound are easily and efficiently synthesized. By three-step continuous oxidation, chiral epoxy carboxylic acid is prepared from p-nitrobenzaldehyde which is easy to obtain commercially, and dimethylpiperazine ring is prepared by reduction after alanine dimerization. The compound shows inhibitory activity on pasteurella multocida. Such a convergent synthesis route can be applied to the chemical synthesis of compounds with the similar structure and related derivatives, opening up a broad development space for novel antibiotic drugs.
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Paragraph 0042; 0043
(2018/11/22)
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- Interfacial supramolecular biomimetic epoxidation catalysed by cyclic dipeptides
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We synthesised a library of cis- and trans-cyclic dipeptides and evaluated their efficacy as catalysts in the asymmetric Weitz-Scheffer epoxidation of trans-chalcone. A thorough investigation relying on structure-activity studies and computational studies provided insights into the mechanism of the process. Our results revealed some structural features required for efficient conversion and for introduction of chirality into the product. The cyclic dipeptide acts as a catalyst by templating a supramolecular arrangement at the aqueous-organic interface required for efficient transformations to occur. Among all cyclic dipeptides investigated, cyclo(Leu-Leu) was the most efficient supramolecular catalyst.
- Bérubé, Christopher,Barbeau, Xavier,Cardinal, Sébastien,Boudreault, Pierre-Luc,Bouchard, Corinne,Delcey, Nicolas,Lagüe, Patrick,Voyer, Normand
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p. 330 - 349
(2017/03/15)
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- AGRICULTURAL CHEMICAL CONTAINING 2,5-DIKETOPIPERAZINE DERIVATIVE AS ACTIVE INGREDIENT
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Disclosed herein is an agricultural agent containing a 2,5-diketopiperazine derivative capable of controlling plant diseases and promoting plant growth or an agriculturally acceptable salt thereof as an active ingredient.
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Paragraph 0033
(2013/06/05)
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- Oligomerization of glycine and alanine on metal(II) octacynaomolybdate(IV): Role of double metal cyanides in prebiotic chemistry
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Condensation reactions of amino acid (glycine and alanine) on the surface of metal(II) octacyanomolybdate( IV) (MOCMo) complexes are investigated using highperformance liquid chromatography (HPLC) and electron spray ionizations-mass spectroscopy (ESI-MS). The series of MOCMo have been synthesized and the effect of outer sphere metal ions present in the MOCMo on the oligomerization of glycine and alanine at different temperature and time found out. Formation of peptides was observed to start after 7 days at 60°C. Maximum yield of peptides was found after 35 days at 90°C. It has been found that zinc(II) octacyanomolybdate( IV) and cobalt(II) were the most effective metal cations present in outer sphere of the MOCMo for the production of high yield of oligomerized products. Surface area of MOCMo seems to play dominating parameter for the oligomerization of alanine and glycine. The results of the present study reveal the role of MOCMo in chemical evolution for the oligomerization of biomolecules. Springer-Verlag 2012.
- Kumar, Anand,Kamaluddin
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p. 2417 - 2429
(2013/03/28)
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- An efficient green synthesis of proline-based cyclic dipeptides under water-mediated catalyst-free conditions
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l-Proline-based cyclic dipeptides were synthesized from N-Boc-protected dipeptide methyl esters under catalyst-free condition using water as a solvent. One-pot deprotection and cyclization have been used as the key steps, providing an efficient and environmentally friendly approach. Clean reaction conditions, easy isolation, and good yields of cyclic dipeptides are the salient features of the proposed methodology.
- Thajudeen, Habeebullah,Park, Kyungseok,Moon, Surk-Sik,Hong, In Seok
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scheme or table
p. 1303 - 1305
(2010/04/29)
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- Fragmentation of deprotonated cyclic dipeptides by electrospray ionization mass spectrometry
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The fragmentation pathways of deprotonated cyclic dipeptides have been studied by electrospray ionization multi-stage mass spectrometry (ESI-MSn) in negative mode. The results showed that the fragmentation pathways of deprotonated cyclic dipeptides depend
- Guo, Yanchun,Cao, Shuxia,Wei, Donghui,Zong, Xiangkun,Yuan, Xingbo,Tang, Mingsheng,Zhao, Yufen
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experimental part
p. 1188 - 1194
(2010/07/03)
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- THE "GAS-SOLID-PHASE" 2,5-DIOXOPIPERAZINE SYNTHESIS. CYCLIZATION OF VAPOROUS DIPEPTIDES ON SILICA SURFACE
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The "gas-solid-phase" method is used for the preparation of both symmetric and asymmetric 2,5-dioxopiperazines via cyclization of vaporous linear dipeptides in the presence of silica.
- Basiuk, Vladimir,Gromovoy, Taras Yu.
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p. 461 - 466
(2007/10/02)
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- Enantioselective synthesis of hydroxy-substituted α-methyl-α-amino acids using Al and Mn derivatives of cyclo(L-Ala-L-Ala) bis-lactim ethers
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Aluminium and manganese derivatives of lithiated bis-lactim ethers of cyclo-(L-Ala-L-Ala) were used for the enantioselective synthesis of β-hydroxy and polyhydroxy α-amino acids of the 2-methylserine series.A new variant of the synthesis of these acids vi
- Tolstikov, G. A.,Kresteleva, I. V.,Spivak, A. Yu.,Fatykhov, A. A.,Sultanmuratova, V. R.
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p. 557 - 563
(2007/10/02)
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- Conformational effects in reversed-phase liquid chromatographic separation of diastereomers of cyclic dipeptides
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The capacity factors, k′, of 11 cyclic dipeptides (X-Y) including diastereomers have been determined on an RP-HPLC column in 30% and 50% methanol and 10%, 30%, and 50% acetonitrile solutions. These factors are roughly correlated with hydrophobic parameters, such as octanol-water partition coefficients estimated and k′ values for alcohols. For a pair of diastereomers of cyclic (L-X-L-Phe) and (L-X-D-Phe) derivatives k′LL is larger than k′LD and for cyclic (D-Ala-L-Trp) and (L-Ala-L-Trp) k′LL is smaller than k′DL, particularly in highly aqueous solutions. These elution orders can be well predicted by the holistic molecular surface area approach which takes into account the folded structures of cyclic dipeptides. The present results will be useful for prediction of the log k′ values of larger peptides and the hydrophobicity and related properties of peptides.
- Funasaki, Noriaki,Hada, Sakae,Neya, Saburo
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p. 1861 - 1867
(2007/10/02)
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- A novel approach to the synthesis of symmetric optically active 2,5-dioxopiperazines
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'Gas-solid-phase' method for the preparation of some cyclic dipeptides,2,5-dioxopiperazines (diketopiperazines), is described. The method implies cyclodimerization of vaporous aliphatic α-amino acids in the presence of silica at reduced pressure and yields optically active 2,5-dioxopiperazines.
- Basiuk,Gromovoy,Chuiko,Soloshonok,Kukhar
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p. 449 - 451
(2007/10/02)
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- A Mechanism for bitter Taste Sensibility in Peptides
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To estimate the steric distance between the bitter taste determinant sites in peptides, some cyclic dipeptides, amino acid anilides, amino acid cyclohexylamides, and benzoyl amino acids were synthesized and their tastes were evaluated.The diketopiperazine ring of cyclic dipeptides acted as a bitter taste determinant site due to its hydrophobicity.The steric distance between 2 sites was estimated as 4.1 Angstroem from the molecule models of cyclic dipeptides composed of typical amino acids in the bitter peptides.Due to the hypothesis of two bitter taste determinant sites, which bind with the bitter taste receptor via a "binding unit" and a "stimulating unit," a mechanism for the bitterness in peptides was postulated.
- Ishibashi, Norio,Kouge, Katsushige,Shinoda,Ichizo,Kanehisa, Hidenori,Okai, Hideo
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p. 819 - 828
(2007/10/02)
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- Stereochemistry of Piperazine-2,5-dione Formation by Self-condensation of DL-Amino Acid Esters
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'Racemic' piperazine-2,5-diones (diketopiperazines, dkps) have been synthesized by the self-condensation of DL-amino acid esters without solvent.It was found that 'racemic' dkps consisted of cis- and trans-isomers, and that cis-dkp was preferentially formed in the early stage of the self-condensation, the cis:trans ratios gradually decreasing with increasing reaction time.These results may be attributed to the difference in the rates of cyclization of two kinds of diastereoisomeric dipeptide esters, intermediates in the formation of dkps from DL-amino acid esters.It was further confirmed that the pre-cis-dipeptide ester, which formed cis-dkp, cyclized faster than the pre-trans-dipeptide ester in methanol.Differences in steric hindrance in the cyclization reaction of pre-cis- and pre-trans-isomers may be an important factor in the stereochemistry of self-condensation.
- Naraoka, Hiroshi,Harada, Kaoru
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p. 1557 - 1560
(2007/10/02)
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- Stereochemistry of Cyclic Dipeptides. Assignment of the Prochiral Methylenes of 1-Aminocyclopropane-1-carboxylic Acid
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The two enantiomeric methylene carbons of 1-aminocyclopropane-1-carboxylic acid (ACC) were differentiated by an NMR study.Several amino acids such as L-alanine, D-alanine, and 2-aminoisobutyric acid as well as ACC were condensed with L- and/or D-phenylala
- Woodard, Ronald W.
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p. 4796 - 4799
(2007/10/02)
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- DOUBLE INDUCTION ASYMETRIQUE : HYDROXYALKYLATION DIASTEREOSELECTIVE DE LA L-ALANINE PAR LE L-GLYCERALDEHYDE
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Synthesis of branched chain sugar derivative : Use of double asymmetric induction to enhance diastereoselection in hydroxyalkylation of L-alanine by glyceraldehyde.
- Depezay, Jean-Claude,Dureault, Annie,Prange, Thierry
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p. 1459 - 1462
(2007/10/02)
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- ENANTIOSELECTIVE SYNTHESIS OF NON-PROTEINOGENIC AMINO ACIDS VIA METALLATED BIS-LACTIM ETHERS OF 2,5-DIKETOPIPERAZINES
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Bis-lactim ethers 1 of 2,5-diketopiperazines contain a chiral inducing center, an acidic CH-bond and two sites susceptible to hydrolysis.They react with BuLi to give Li compounds of type 4, 15, 29 or 32, which possess a prochiral C atom.They readily add electrophiles (such as alkylating agents or carbonyl compounds) with unusually high diastereoface differentiation.In many cases the d.e-value (d.e. = diastereomeric excess = asymmetric induction) of the adduct exceeds 95percent.On hydrolysis the adducts are cleaved liberating the chiral auxiliary (used to build up the bis-lactim ether 1) and the target molecules, the optically active amino acid methyl esters of type 8, 19, 25 or 36.The two amino acid esters are separable either by fractional distillation or (eventually after further hydrolysis to amino acids) by chromatography.Transition state models are discussed that could explain the exceptionally high asymmetric induction and the predictability of the induced configuration.
- Schoellkopf, Ulrich
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p. 2085 - 2092
(2007/10/02)
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- Facile Synthesis of Cyclic Dipeptides and Detection of Racemization
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Several cyclic dipeptides were synthesized by refluxing methanolic solution of dipeptide methyl esters in high yield and purity.Cyclic dipeptides prepared by the Fischer method, the Nitecki method, and the present methanol-reflux method were compared with
- Ueda, Toshihisa,Saito, Morinobu,Kato, Tetsuo,Izumiya, Nobuo
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p. 568 - 572
(2007/10/02)
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- Asymmetric Syntheses via Heterocyclic Intermediates, V. - Asymmetric Synthesis of α-Methyl Amino Acids by Alkylation of the Lithiated Lactim Ether of cyclo-(L-Ala-L-Ala)
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The (3S,6S)-2,5-dimethoxy-3,6-dimethyl-3,6-dihydropyrazine (7) is obtained from cyclo-(L-Ala-L-Ala) 5 (93-95percent optically pure) and trimethyloxonium tetrafluoroborate.With butyllithium the lithio derivative 8 is formed which reacts with alkyl halides in good chemical yields and with more than 90percent diastereoselectivity, whereby R-configuration is induced at C-3.A model concept is discussed, which explains the remarkably high asymmetric induction. - Hydrolysis (0.25 N HCl, room temp.) gives L-alanine methyl ester (4) and the (R)-α-methyl amino acid methyl esters 13.The two amino acid esters are separable by distillation or chromatography.
- Schoellkopf, Ulrich,Hartwig, Wolfgang,Groth, Ulrich,Westphalen, Karl-Otto
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p. 696 - 708
(2007/10/02)
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- RhCl3-catalyzed Amide Bond Formation under Mild Conditions
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The reaction of carboxylic acid esters with amines is accelerated in the presence of catalytic amounts of RhCl3*3H2O at a reasonably low temperature; optically active 2,5-dioxopiperazines can be synthesized in high yield from the corresponding amino-acid esters using this procedure.
- Yamamoto, Yoshinori,Yatagai, Hidetaka,Maruyama, Kazuhiro
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p. 835 - 836
(2007/10/02)
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- 15N NMR Spectroscopy. 19 - Spectroscopic Characterization of Cyclodipeptides (2,5-Dioxopiperazines)
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Various cyclodipeptides containing glycine, alanine, leucine, valine, phenylalanine, phenylglycine and sarcosine units were synthesized by cyclization of dipeptide pentachlorophenyl esters.The 13C and natural abundance 15N NMR spectra of these heterocycles were measured in trifluoroacetic acid and compared with the spectra of the corresponding amino acids and polypeptides.The 13C NMR carbonyl signals of all cyclodipeptides show a 1.5-4.0 ppm upfield shift relative to the corresponding polypeptides.The 15N NMR signals show no such consistent relationship.The substituent effects and the neighbouring residue effects observed in the 15NMR spectra of the cyclodipeptides are different from those of polypeptides, while the one bond N-H coupling constant of cis and trans amide groups was almost identical.The nitrogen and the carbonyl signal of the Gly units in cyclo-Gly-Phe show an extraordinary downfield shift, reflecting the interaction of the phenyl group with the 2,5-dioxopiperazine ring.
- Kricheldorf, Hans R.
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