- MONOBACTAM COMPOUNDS AND USE THEREFOR
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Monobactam compounds and a use therefor. Specifically provided are chemical compounds represented by formula (I) or isomers, pharmaceutically acceptable salts, solvates, crystals, or prodrugs thereof, preparation methods therefor, pharmaceutical compositions containing said compounds, and a use of said compounds or compositions in treating bacterial infection. The present compounds feature excellent antibacterial activity, and have great hopes of becoming a therapeutic agent for bacterial infection.
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- Gold-Catalyzed Amide/Carbamate-Linked N, O-Acetal Formation with Bulky Amides and Alcohols
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A gold-catalyzed N,O-acetal formation was established to construct an amide/carbamate-linked N,O-acetal substructure with bulky alcohols. The acyliminium cation species generated from o-alkynylbenzoic acid ester in the presence of a gold catalyst is highly reactive and underwent nucleophilic attack of various bulky alcohols and phenols at room temperature under neutral conditions, leading to the corresponding N,O-acetals in yields of 34-89% with good functional group tolerance.
- Ohsawa, Kosuke,Ochiai, Shota,Kubota, Junya,Doi, Takayuki
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p. 1281 - 1291
(2021/01/14)
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- APPLICATION OF MONOCYCLIC BETA-LACTAM COMPOUND IN PHARMACY
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An application of a compound represented by formula (I) and pharmaceutically acceptable salts thereof in preparation of a drug for treating pneumonia.
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Paragraph 0039; 0043; 0044
(2021/11/04)
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- Preparation method of (2S) -substituted -3 - deuterium - L - valdi
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The preparation method of the (2S) IV-substituted - deuterium -3 - valine ester compound represented - L - is simple in process. The yield is high, benzene is not needed to be dissolved, the environment is friendly, and the method is suitable for industrialized mass production.
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- MONOCYCLIC B-LACTAM COMPOUND FOR TREATING BACTERIAL INFECTION
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Disclosed are a class of new monocyclic β-lactam compounds, an isomer thereof or pharmaceutically acceptable salts thereof, and a pharmaceutical composition comprising the compounds, and the use of same in preparing drugs for treating diseases associated
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Paragraph 0072
(2020/12/16)
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- Organic total synthesis method of D-penicillamine
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The invention discloses an organic total synthesis method of D-penicillamine, which comprises the following steps: carrying out Grignard reaction on a derivative of Lserine ester and a methyl Grignardreagent to obtain a first intermediate; carrying out oxidation reaction on the first intermediate and an oxidizing agent to obtain a second intermediate; carrying out sulfonylation reaction on the second intermediate and a sulfonylation reagent to obtain a third intermediate; carrying out thiolation reaction on the third intermediate and a vulcanization reagent to obtain a fourth intermediate; and carrying out hydrolysis reaction on the fourth intermediate to obtain the D-penicillamine. The initial raw materials are cheap and easy to obtain, particularly, cheap, easy-to-obtain and high-optical-purity Lserine ester derivatives can be used as the raw materials, the whole synthetic route for preparing the Dapenem is a new organic total synthesis process route, the process is simple, the reaction condition requirement is low, no toxin is left, and the safety performance is good; the product yield and the optical purity are high; and large-scale production is easy to realize.
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Paragraph 0023-0025; 0028-0029
(2020/11/23)
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- Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety
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UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a Zn2+ deacetylase that is essential for the survival of most pathogenic Gram-negative bacteria. ACHN-975 (N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose-limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN-975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on its overall profile, compound 26 (LPXC-516, (S)-N-(2-(hydroxyamino)-1-(3-methoxy-1,1-dioxidothietan-3-yl)-2-oxoethyl)-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided a solubility of >30 mg mL?1 for parenteral administration and conversion into the active drug with a t1/2 of approximately two minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.
- Cohen, Frederick,Aggen, James B.,Andrews, Logan D.,Assar, Zahra,Boggs, Jen,Choi, Taylor,Dozzo, Paola,Easterday, Ashton N.,Haglund, Cat M.,Hildebrandt, Darin J.,Holt, Melissa C.,Joly, Kristin,Jubb, Adrian,Kamal, Zeeshan,Kane, Timothy R.,Konradi, Andrei W.,Krause, Kevin M.,Linsell, Martin S.,Machajewski, Timothy D.,Miroshnikova, Olga,Moser, Heinz E.,Nieto, Vincent,Phan, Thu,Plato, Craig,Serio, Alisa W.,Seroogy, Julie,Shakhmin, Anton,Stein, Adam J.,Sun, Alex D.,Sviridov, Serguei,Wang, Zhan,Wlasichuk, Kenneth,Yang, Wen,Zhou, Xiaoming,Zhu, Hai,Cirz, Ryan T.
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supporting information
p. 1560 - 1572
(2019/08/16)
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- The journey of total synthesis toward nannocystin Ax
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Herein we describe the detail on our full investigations that led to the achievement of the total synthesis of nannocystin Ax, a 21-membered macrocyclic natural product composing of a tripeptide fragment and a polyketide fragment, which featured in 8 longest linear steps in with 13.9% total overall yield. The key synthetic strategy relied on the late-stage stille coupling for the macrolactonization to construct the 21-membered ring, while direct connection between the tripeptide fragment and the polyketide fragment failed. 1H NMR experiments reveal that nannocystin Ax should exist as conformational mixtures in deuterated solvents.
- Liu, Rong,Xia, Mengwei,Zhang, Yanhui,Fu, Shaomin,Liu, Bo
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p. 1781 - 1794
(2019/01/04)
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- A motif-Oriented Total Synthesis of Nannocystin Ax. Preparation and Biological Assessment of Analogues
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The highly cytotoxic cyclodepsipeptides of the nannocystin family are known to bind to the eukaryotic translation elongation factor 1α (EF-1α). Analysis of the docking pose, as proposed by a previous in silico study, suggested that the trisubstituted alkene moiety and the neighboring methyl ether form a domain that might be closely correlated with biological activity. This hypothesis sponsored a synthetic campaign which was designed to be motif-oriented : specifically, a sequence of ring closing alkyne metathesis (RCAM) followed by hydroxy-directed trans-hydrostannation of the resulting cycloalkyne was conceived, which allowed this potentially anchoring substructure to be systematically addressed at a late stage. This inherently flexible approach opened access to nannocystin Ax (1) itself as well as to 10 non-natural analogues. While the biological data confirmed the remarkable potency of this class of compounds and showed that the domain in question is indeed an innate part of the pharmacophore, the specific structure/activity relationships can only partly be reconciled with the original in silico docking study; therefore, we conclude that this model needs to be carefully revisited.
- Meng, Zhanchao,Souillart, Laetitia,Monks, Brendan,Huwyler, Nikolas,Herrmann, Jennifer,Müller, Rolf,Fürstner, Alois
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p. 6977 - 6994
(2018/07/15)
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- Total synthesis of nannocystin Ax
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A concise total synthesis of nannocystin Ax, a natural depsipeptide recently isolated from myxobacteria, has been accomplished. By following a convergent strategy, the target molecule was assembled from three fragments. Each fragment can be synthesized expeditiously from readily achievable compounds. The key elements in this total synthesis feature Kobayashi's remote asymmetric induction with vinylketene silyl N,O-acetal, Roush's asymmetric crotylboration of aldehyde, Mitsunobu's esterification and macrocyclization via Stille cross-coupling.
- Zhang, Yan-Hui,Liu, Rong,Liu, Bo
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supporting information
p. 5549 - 5552
(2017/07/11)
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- NIPECOTIC ACID DERIVATIVE AND USE THEREOF FOR MEDICAL PURPOSES
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The present invention aims to provide a compound having an sEH-inhibiting activity and to provide a pharmaceutical having a therapeutic effect and a prophylactic effect on chronic renal disease and pulmonary hypertension based on the sEH-inhibiting action. The present invention provides nipecotic acid derivatives represented by the chemical formula below and pharmaceutically acceptable salts thereof.
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- Stereocontrolled synthesis of syn-β-hydroxy-α-amino acids by direct aldolization of pseudoephenamine glycinamide
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β-Hydroxy-α-amino acids figure prominently as chiral building blocks in chemical synthesis and serve as precursors to numerous important medicines. Reported herein is a method for the synthesis of β-hydroxy- α-amino acid derivatives by aldolization of pseudoephenamine glycinamide, which can be prepared from pseudoephenamine in a one-flask protocol. Enolization of (R,R)- or (S,S)-pseudoephenamine glycinamide with lithium hexamethyldisilazide in the presence of LiCl followed by addition of an aldehyde or ketone substrate affords aldol addition products that are stereochemically homologous with L- or D-threonine, respectively. These products, which are typically solids, can be obtained in stereoisomerically pure form in yields of 55-98 %, and are readily transformed into β-hydroxy-α-amino acids by mild hydrolysis or into 2-amino-1,3-diols by reduction with sodium borohydride. This new chemistry greatly facilitates the construction of novel antibiotics of several different classes. On aldol: Enolization of (R,R)- or (S,S)-pseudoephenamine glycinamide with lithium hexamethyldisilazide (LiHMDS) in the presence of LiCl followed by addition of either an aldehyde or ketone substrate affords aldol addition products which are stereochemically homologous with L- or D-threonine, respectively. These products can be obtained in stereoisomerically pure form in yields of 55-98 %, and are readily transformed into β-hydroxy-α-amino acids by mild hydrolysis or into 2-amino-1,3-diols by reduction.
- Seiple, Ian B.,Mercer, Jaron A. M.,Sussman, Robin J.,Zhang, Ziyang,Myers, Andrew G.
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supporting information
p. 4642 - 4647
(2014/05/20)
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- AMIDINE SUBSTITUTED BETA - LACTAM COMPOUNDS, THEIR PREPARATION AND USE AS ANTIBACTERIAL AGENTS
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The present invention relates to novel β-lactam compounds of formula (I), their preparation and use. In particular, this invention relates to novel β-lactam compounds which are amidine substituted monobactam derivatives useful as antimicrobial agents and their preparation.
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Paragraph 00108; 00109
(2013/08/15)
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- Effects on polo-like kinase 1 polo-box domain binding affinities of peptides incurred by structural variation at the phosphoamino acid position
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Protein-protein interactions (PPIs) mediated by the polo-box domain (PBD) of polo-like kinase 1 (Plk1) serve important roles in cell proliferation. Critical elements in the high affinity recognition of peptides and proteins by PBD are derived from pThr/pS
- Qian, Wenjian,Park, Jung-Eun,Liu, Fa,Lee, Kyung S.,Burke Jr., Terrence R.
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p. 3996 - 4003
(2013/07/27)
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- Proof of the existence of an unstable amino acid: Pleurocybellaziridine in pleurocybella porrigens
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Angel's wing mushroom, Pleurocybella porrigens, caused fatal acute encephalopathy in Japan in 2004. The structures of cytotoxic amino acids previously isolated from the mushroom motivated a study to prove the existence of an aziridine amino acid, pleurocy
- Wakimoto, Toshiyuki,Asakawa, Tomohiro,Akahoshi, Saeko,Suzuki, Tomohiro,Nagai, Kaoru,Kawagishi, Hirokazu,Kan, Toshiyuki
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supporting information; experimental part
p. 1168 - 1170
(2011/04/18)
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- Total synthesis of the large non-ribosomal peptide polytheonamide B
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Polytheonamide B is by far the largest non-ribosomal peptide known at present, and displays extraordinary cytotoxicity (EC50 =68 pg ml -1 , mouse leukaemia P388 cells). Its 48 amino-acid residues include a variety of non-proteinogenic d- and l-amino acids, and the absolute stereochemistry of these amino acids alternate in sequence. These structural features induce the formation of a stable β-strand-type structure, giving rise to an overall tubular structure over 30A? in length. In a biological setting, this fold is believed to transport cations across the lipid bilayer through a pore, thereby acting as an ion channel. Here, we report the first chemical construction of polytheonamide B. Our synthesis relies on the combination of four key stages: syntheses of non-proteinogenic amino acids, a solid-phase assembly of four fragments of polytheonamide B, silver-mediated connection of the fragments and, finally, global deprotection. The synthetic material now available will allow studies of the relationships between its conformational properties, channel functions and cytotoxicity.
- Inoue, Masayuki,Shinohara, Naoki,Tanabe, Shintaro,Takahashi, Tomoaki,Okura, Ken,Itoh, Hiroaki,Mizoguchi, Yuki,Iida, Maiko,Lee, Nayoung,Matsuoka, Shigeru
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supporting information; scheme or table
p. 280 - 285
(2010/09/03)
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- CCR5 ANTAGONISTS AS THERAPEUTIC AGENTS
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The present invention relates to compounds of formula (I) or pharmaceutically acceptable derivatives thereof, useful in the treatment or prophylaxis of CCR5-related diseases and disorders, for example, in the inhibition of HIV replication, the prevention or treatment of an HIV infection, and in the treatment of the resulting acquired immune deficiency syndrome (AIDS).
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- Tubulin inhibitors. Synthesis and biological activity of HTI-286 analogs with B-segment heterosubstituents
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Modifications of the B-segment of HTI-286 (2) produced a class of analogs incorporating heteroatom-substituents. The structure-activity relationship was studied. Analogs bearing methylsulfide and fluoride groups exhibited potency comparable to that of the parent compound HTI-286 and to paclitaxel in cytotoxicity assays against KB-3-1 cell lines. These analogs were more potent than paclitaxel against P-glycoprotein expressing KB-8-5 and KB-V1 cell lines. Several analogs showed strong inhibition of tubulin polymerization.
- Niu, Chuan,Smith, Daniel,Zask, Arie,Loganzo, Frank,Discafani, Carolyn,Beyer, Carl,Greenberger, Lee,Ayral-Kaloustian, Semiramis
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p. 4329 - 4332
(2007/10/03)
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- Serine as chiral educt for the practical synthesis of enantiopure N-protected β-hydroxyvaline
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N-tert-Butyloxycarbonyl- and N-benzenesulfonyl-β-hydroxyvalines 1a and 1b were, respectively, synthesized in enantiomerically pure form by a two-step protocol from their enantiomeric N-protected serine methyl esters 2a and 2b. The addition of CH3MgBr to 2a and 2b provided diols 3a and 3b, respectively as major products in 83% and 81% yields. Selective oxidation of diols 3a and 3b was performed using a TEMPO, NaClO2, NaOCl cocktail in 96% and 93% respective yields. This two-step process effectively furnished multigram amounts of enantiopure N-Boc-β-hydroxyvaline 1a.
- Dettwiler, James E.,Lubell, William D.
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p. 177 - 179
(2007/10/03)
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- Facile synthesis of L-3,4-didehydrovaline constituting an antibiotic, phomopsin A
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A convenient synthesis of δ,γ-unsaturated valine (L-3,4- didehydrovaline), an important constituent of an antibiotic phomopsin A, was achieved from H-D-Ser-OH through a seven-step conversion in 31percent overall yield.
- Yonezawa, Yasuchika,Shimizu, Kanetaka,Yoon, Kwan-Sik,Shin, Chung-Gi
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p. 634 - 636
(2007/10/03)
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- [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[2,2-dimethyl-4-oxo-1-(sulfooxy)-3-azetidinyl]amino]-2-oxoethylidene]-amino]oxy] acetic acid and intermediate
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Pharmaceutically acceptable salts of [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[2,2-dimethyl-4-oxo-1-(sulfooxy)-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy] acetic acid and a process useful in the preparation of such salts are disclosed herein.
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- Monosulfactams
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Antibacterial activity is exhibited by monocyclic β-lactam antibiotics having in the 1-position an --O--SO3 H activating group and in the 3-position an acylamino group of the formula STR1 wherein R3 and R4 are each indepen
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