- METHODS OF SYNTHESIZING AZTREONAM DERIVATIVES
-
Disclosed herein are aztreonam derivatives, therapeutic methods of using the aztreonam derivatives, and methods of synthesizing aztreonam derivatives. The aztreonam derivatives can be administered orally to provide orally bioavailable aztreonam.
- -
-
Paragraph 408
(2020/11/03)
-
- Toward Orally Absorbed Prodrugs of the Antibiotic Aztreonam. Design of Novel Prodrugs of Sulfate Containing Drugs. Part 2
-
Aztreonam, first discovered in 1980, is an FDA approved, intravenous, monocyclic beta-lactam antibiotic. Aztreonam is active against Gram-negative bacteria and is still used today. The oral bioavailability of aztreonam in humans is less than 1%. Herein we describe the design and synthesis of potential oral prodrugs of aztreonam.
- Ding, Pingyu,Duncton, Matthew A. J.,Fan, Dazhong,Gordon, Eric M.,Grygorash, Ruslan,Li, Xianfeng,Low, Eddy,Ni, Zhi-Jie,Qi, Longwu,Sun, Jiawei,Wang, Brian J.,Yu, Guijun
-
supporting information
p. 162 - 165
(2020/01/31)
-
- Silver-Promoted Direct Phosphorylation of Bulky C(sp2)-H Bond to Build Fully Substituted β-Phosphonodehydroamino Acids
-
A general and practical cross-dehydrogenative coupling protocol between readily available trisubstituted α,β-dehydro α-amino carboxylic esters and H-phosphites is described. This C(sp2)-H phosphorylation reaction proceeds with absolute Z-selectivity promoted by silver salt in a radical relay manner. The bulky tetrasubstituted β-phosphonodehydroamino acids were obtained in grams and added new modules to the toolkit for peptide modifications.
- Cao, Hao-Qiang,Liu, Hao-Nan,Liu, Zhe-Yuan,Qiao, Baokun,Zhang, Fa-Guang,Ma, Jun-An
-
supporting information
p. 6414 - 6419
(2020/09/02)
-
- Mild, Rapid, and Chemoselective Procedure for the Introduction of the 9-Phenyl-9-fluorenyl Protecting Group into Amines, Acids, Alcohols, Sulfonamides, Amides, and Thiols
-
The 9-phenyl-9-fluorenyl (PhF) group has been used as an Nα protecting group of amino acids and their derivatives mainly as a result of its ability to prevent racemization. However, installing this group using the standard protocol, which employs 9-bromo-9-phenylfluorene/K3PO4/Pb(NO3)2, often takes days and yields can be variable. Here, we demonstrate that the PhF group can be introduced into the amino group of Weinreb's amides and methyl esters of amino acids, as well as into alcohols and carboxylic acids, rapidly and in excellent yields, using 9-chloro-9-phenylfluorene (PhFCl)/N-methylmorpholine (NMM)/AgNO3. Nα-PhF-protected amino acids can be prepared from unprotected α-amino acids, rapidly and often in near quantitative yields, by treatment with N,O-bis(trimethylsilyl)acetamide (BSA) and then PhFCl/NMM/AgNO3. Primary alcohols can be protected with the PhF group in the presence of secondary alcohols in moderate yield. Using PhFCl/AgNO3, a primary alcohol can be protected in good yield in the presence of a primary ammonium salt or a carboxylic acid. Primary sulfonamides and amides can be protected in moderate to good yields using phenylfluorenyl alcohol (PhFOH)/BF3·OEt2/K3PO4, while thiols can be protected in good to excellent yield using PhFOH/BF3·OEt2 even in the presence of a carboxylic acid or primary ammonium group.
- Soley, Jacob,Taylor, Scott D.
-
-
- General Fmoc-Based Solid-Phase Synthesis of Complex Depsipeptides Circumventing Problematic Fmoc Removal
-
Development of an Fmoc-based solid-phase depsipeptide methodology has been hampered by base-promoted fragmentation and diketoperazine formation upon Fmoc group elimination. Such a strategy would be a useful tool given the number of commercially available Fmoc-protected residues. Herein we report that the addition of small percentages of organic acids to the Fmoc-removal cocktail proves effective to circumvent these drawbacks and most importantly, allowed the development of an exclusively solid-phase stepwise methodology to prepare a highly complex depsipeptide with multiple and consecutive esters bonds. Alongside, the optimal protecting group scheme for residue incorporation, which is not as straightforward as it is for traditional peptide synthesis, was explored. The developed stepwise strategy proved effective for the synthesis of a highly complex cyclodepsipeptide, being comparable to the yields obtained when using traditional combined chemistry approaches.
- Lobo-Ruiz, Ariadna,Tulla-Puche, Judit
-
supporting information
p. 183 - 192
(2020/01/24)
-
- AZTREONAM DERIVATIVES AND USES THEREOF
-
Disclosed herein are aztreonam derivatives, therapeutic methods of using the aztreonam derivatives, particularly in combination with β-lactamase inhibitors, and pharmaceutical compositions thereof. The aztreonam derivatives can be administered orally to provide orally bioavailable aztreonam.
- -
-
Paragraph 1078; 1079
(2019/04/18)
-
- CYCLIC PEPTIDE ANTIBIOTICS
-
Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of lipoprotein signal peptidase II (LspA), a key protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.
- -
-
Paragraph 00293
(2019/04/11)
-
- SPIRO-LACTAM NMDA MODULATORS AND METHODS OF USING SAME
-
Disclosed are compounds having potency in the modulation of NMDA receptor activity. Such compounds can be used in the treatment of conditions such as depression and related disorders. Orally delivered formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
- -
-
-
- Straightforward synthesis of fluorinated amino acids by Michael addition of ethyl bromodifluoroacetate to α,β-unsaturated α-amino acid derivatives
-
Copper-mediated Michael addition of ethyl bromodifluoroacetate to N-protected α,β-unsaturated α-amino acid esters was applied for straightforward synthesis of γ,γ-difluorinated analogues of glutamic acid (compound 1) and glutamine (compound 10). Moreover, a proline-based, sterically constrained analog of γ,γ-difluoroglutamic acid (compound 24) was prepared.
- Kondratov, Ivan S.,Bugera, Maxym Ya.,Tolmachova, Nataliya A.,Daniliuc, Constantin G.,Haufe, Günter
-
p. 100 - 108
(2018/05/09)
-
- Pharmaceutical combination of an atypical antipsychotic and an NMDA modulator for the treatment of schizophrenia,bipolar disorder, cognitive impairment and major depressive disorder
-
This disclosure features combinations of NMDA modulators and atypical antipsychotics. The disclosure provides for example, methods of treating schizophrenia, bipolar disorder, and/or cognitive impairment disorder in a patient in need thereof, comprising administering e.g., rapastinel and an atypical antipsychotic.
- -
-
Paragraph 0179; 0208; 0209
(2018/10/11)
-
- SPIRO-LACTAM NMDA RECEPTOR MODULATORS AND USES THEREOF
-
Disclosed are compounds having enhanced potency in the modulation of NMDA receptor activity. Such compounds can be used in the treatment of conditions such as depression and related disorders. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
- -
-
-
- Total Synthesis and Functional Evaluation of Fourteen Derivatives of Lysocin E: Importance of Cationic, Hydrophobic, and Aromatic Moieties for Antibacterial Activity
-
Lysocin E (1) is a structurally complex 37-membered depsipeptide comprising 12 amino-acid residues with an N-methylated amide and an ester linkage. Compound 1 binds to menaquinone (MK) in the bacterial membrane to exert its potent bactericidal activity. To decipher the biologically important functionalities within this unique antibiotic, we performed a comprehensive structure-activity relationship (SAR) study by systematically changing the side-chain structures of l-Thr-1, d-Arg-2, N-Me-d-Phe-5, d-Arg-7, l-Glu-8, and d-Trp-10. First, we achieved total synthesis of the 14 new side-chain analogues of 1 by employing a solid-phase strategy. We then evaluated the MK-dependent liposomal disruption and antimicrobial activity against Staphylococcus aureus by 1 and its analogues. Correlating data between the liposome and bacteria experiments revealed that membrane lysis was mainly responsible for the antibacterial functions. Altering the cationic guanidine moiety of d-Arg-2/7 to a neutral amide, and the C7-acyl group of l-Thr-1 to the C2 or C11 counterpart decreased the antimicrobial activities four- or eight-fold. More drastically, chemical mutation of d-Trp-10 to d-Ala-10 totally abolished the bioactivities. These important findings led us to propose the biological roles of the side-chain functionalities.
- Kaji, Takuya,Murai, Motoki,Itoh, Hiroaki,Yasukawa, Jyunichiro,Hamamoto, Hiroshi,Sekimizu, Kazuhisa,Inoue, Masayuki
-
supporting information
p. 16912 - 16919
(2016/11/16)
-
- 2-OXO-2,3,4,5-TETRAHYDRO-1 H-BENZO[B]DIAZEPINES AND THEIR USE IN THE TREATMENT OF CANCER
-
Disclosed are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein W, Y, Z, R1, R2, R3, R4 and R5 are described herein, and methods of using said compounds in the treatment of cancer.
- -
-
Paragraph 0338
(2015/09/22)
-
- Stellatolides, a new cyclodepsipeptide family from the sponge ecionemia acervus: Isolation, solid-phase total synthesis, and full structural assignment of stellatolide a
-
The marine environment is a rich source of metabolites with potential therapeutic properties and applications for humans. Here we describe the first isolation, solid-phase total synthesis, and full structural assignment of a new class of cyclodepsipeptides from the Madagascan sponge Ecionemia acervus that shows in vitro cytotoxic activities at submicromolar concentrations. Seven structures belonging to a new family of compounds, given the general name stellatolides, were characterized. The sequence and stereochemistry of all the amino acids in these molecules were established by a combination of spectroscopic analysis, chemical degradation, and derivatization studies. Furthermore, the complete structure of stellatolide A was confirmed by an efficient solid-phase method for the first total synthesis and the full structural assignment of this molecule, including the asymmetric synthesis of the unique B-hydroxy acid moiety (Z)-3-hydroxy-6,8-dimethylnon-4-enoic acid.
- Martin, Maria Jesus,Rodriguez-Acebes, Raquel,Garcia-Ramos, Yésica,Martinez, Valentin,Murcia, Carmen,Digon, Isabel,Marco, Isabel,Pelay-Gimeno, Marta,Fernández, Rogelio,Reyes, Fernando,Francesch, Andrés M.,Munt, Simon,Tulla-Puche, Judit,Albericio, Fernando,Cuevas, Carmen
-
supporting information
p. 6754 - 6762
(2014/05/20)
-
- Synthesis and antimycobacterial activity of 2,1′-dihydropyridomycins
-
Dihydropyridomycins 2 and 3, which lack the characteristic enol ester moiety of the potent antimycobacterial natural product pyridomycin (1), have been prepared from L-Thr, R- and S-hydroxy isovaleric acid, and 3-pyridinecarboxaldehyde. The 2R isomer 2 shows only 4-fold lower anti-Mtb activity than 1, indicating that the enol ester moiety in the natural product is not critical for its biological activity. This finding establishes 2 as a potent and more practical lead for anti-TB drug discovery.
- Horlacher, Oliver P.,Hartkoorn, Ruben C.,Cole, Stewart T.,Altmann, Karl-Heinz
-
p. 264 - 268
(2013/03/29)
-
- Influence of steric parameters on the synthesis of tetramates from α-amino-β-alkoxy-esters and Ph3PCCO
-
α-Aminoesters react with Ph3PCCO in a domino addition-Wittig cyclization sequence affording enantiomerically pure tetramates. In the case of β-oxo functionalized α-aminoesters, e.g., esters of serine, threonine or β-hydroxyornithine the yields of this reaction depend heavily on the bulkiness of the β-OR group and on the configuration of β-carbon atom C-3. Smaller residues and 2R/3R-configured aminoesters give better yields. The alkoxycarbonyl group of the ester moiety and the residue on the N-atom are less important. These findings can be accounted for by assuming an early puckered transition state for the intramolecular ring-closing Wittig reaction. The addition of sub-stoichiometric amounts of benzoic acid or N-hydroxysuccinimide (for acid-sensitive compounds) is advantageous in some cases as it accelerates the formation of the intermediate amide ylides.
- Loke, Inga,Park, Natja,Kempf, Karl,Jagusch, Carsten,Schobert, Rainer,Laschat, Sabine
-
supporting information; experimental part
p. 697 - 704
(2012/01/05)
-
- Total synthesis of Lys3 tamandarin M: A potential affinity ligand
-
The synthesis of Lys3 tamandarin M is described. This analogue can be used as a protein affinity ligand to probe the mechanism of action of this unique class of molecules.
- Lassen, Kenneth M.,Joullie, Madeleine M.
-
supporting information; experimental part
p. 5306 - 5309
(2011/02/26)
-
- Depsipeptide methodology for solid-phase peptide synthesis: Circumventing side reactions and development of an automated technique via depsidipeptide units
-
The depsipeptide technique is a recently developed method for peptide synthesis which is applicable to difficult sequences when the synthetic difficulty arises because of aggregation phenomena. In the present work, application of the depsipeptide method t
- Coin, Irene,Doelling, Rudolf,Krause, Eberhard,Bienert, Michael,Beyermann, Michael,Sferdean, Calin Dan,Carpino, Louis A.
-
p. 6171 - 6177
(2007/10/03)
-
- Biomimetic stereoselective formation of methyllanthionine.
-
Fmoc-(2R,3S)-3-methyl-Se-phenylselenocysteine was used for the synthesis of dehydrobutyrine (Dhb)-containing peptides. Biomimetic cyclization via Michael addition of Cys to a Dhb yielded the B-ring of the lantibiotic subtilin as a single diastereomer. The methyllanthionine product was shown to have the natural configuration by preparation of the authentic stereoisomer. The formation of a single isomer suggests that the prepeptide has a strong intrinsic preference for the stereochemistry observed in lantibiotics. [reaction: see text]
- Zhou, Hao,van der Donk, Wilfred A
-
p. 1335 - 1338
(2007/10/03)
-
- Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
-
Compounds of Formula (1.0.0): are described wherein A is for example aryl, heteroaryl or heterocyclyl, Y is preferably —C(═O)—; B is independently selected from a group of moieties, the most preferred of which are those of partial Formulas (1.1.2) and (1.1.6): and E is a single bond; oxygen; 1,1-cyclopropyl; C(CH3)2; CF2; or a bridging moiety of partial Formula (1.9.0): where R1ais hydrogen when R1has the meaning of a mono-valent substituent; and R1ais a single bond when R1has the meaning of a di-valent substituent. Said compounds are useful in methods of treating or preventing an inflammatory, autoimmune or respiratory diseases by inhibiting cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4.
- -
-
-
- Analogs of the β-turn of the cyclodepsipeptide didemnin B
-
Three side chain analogs of didemnin B were synthesized. All three analogs of the only conventional type II β-turn present in didemnin B differed in the functionality incorporated in the threonine residue. The cytotoxic activities of these analogs were evaluated, and one of them exhibited weak activity.
- Ramanjulu, Joshi M.,Joullie, Madeleine M.
-
p. 311 - 314
(2007/10/02)
-
