- Optimization of globomycin analogs as novel gram-negative antibiotics
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Discovery of novel classes of Gram-negative antibiotics with activity against multi-drug resistant infections is a critical unmet need. As an essential member of the lipoprotein biosynthetic pathway, lipoprotein signal peptidase II (LspA) is an attractive target for antibacterial drug discovery, with the natural product inhibitor globomycin offering a modestly-active starting point. Informed by structure-based design, the globomycin depsipeptide was optimized to improve activity against E. coli. Backbone modifications, together with adjustment of physicochemical properties, afforded potent compounds with good in vivo pharmacokinetic profiles. Optimized compounds such as 51 (E. coli MIC 3.1 μM) and 61 (E. coli MIC 0.78 μM) demonstrate broad spectrum activity against gram-negative pathogens and may provide opportunities for future antibiotic discovery.
- Braun, Marie-Gabrielle,Burdick, Daniel J.,Castanedo, Georgette M.,Chen, Yi-Chen,Cheng, Yun-Xing,Cheong, Jonathan,Daniels, Blake,Deshmukh, Gauri,Fu, Yuhong,Garland, Keira,Gibbons, Paul,Gloor, Susan L.,Hanan, Emily J.,Hua, Rongbao,Kapadia, Sharookh B.,Labadie, Sharada,Liu, Xiongcai,Pantua, Homer,Pastor, Richard,Stivala, Craig,Xu, Min,Xu, Yiming,Zheng, Hao
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supporting information
(2020/08/13)
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- CYCLIC PEPTIDE ANTIBIOTICS
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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.
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Paragraph 00136
(2020/09/27)
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- CYCLIC PEPTIDE ANTIBIOTICS
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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.
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Paragraph 00257
(2019/04/11)
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- Stereoselective synthesis of the C3-C12 subunit of laulimalide
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A stereoselective synthesis of the C3-C12 subunit of the tumor growth inhibitors laulimalide is disclosed. The key steps of the synthesis include asymmetric alkylation using Oppolzer's protocol and an asymmetric hetero-Diels-Alder reaction using Jacobsen'
- Raghavan, Sadagopan,Samanta, Pradip Kumar
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p. 913 - 915
(2015/03/03)
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- Stereoselective synthesis of stable isotope-labeled L-α-amino acids: Electrophilic amination of oppolzer's acyl sultams in the synthesis of L-[15N]alanine, L-[15N]valine, L-[15N]leucine, L-[15N]phenylalanine and
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Using 1-chloro-1-[15N]nitrosocyclohexane, we have prepared five L-[α-15N]amino acids. The stereoselective electophillic hydroxyamination of (S)-acylbornane-10,2-sultams, followed by Zn(o)/H+ reduction, and alkaline cleavag
- Lodwig,Unkefer
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p. 239 - 248
(2007/10/03)
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- CONTROLLING STEREOCHEMISTRY IN RADICAL ADDITION AND CYCLIZATION REACTIONS WITH OPPOLZER'S CAMPHOR SULTAM
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Acrylate derivatives of Oppolzer's camphor sultam exhibit good to excellent levels of stereoselectivity in typical radical allylations and alkene and alkyne cyclizations.
- Curran, Dennis P.,Shen, Wang,Zhang, Jiancun,Gieb, Steven J.,Lin, Chien-Hsing
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p. 1773 - 1788
(2007/10/02)
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- Asymmetric Synthesis of α-Amino Acids and α-N-Hydroxyamino Acids from N-Acylbornane-10,2-sultams: 1-Chloro-1-nitrosocyclohexane as a Practical +> Equivalent
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Successive treatment of N-acylsultams 3 with sodium hexamethyldisilazide, 1-chloro-1-nitrosocyclohexane (1), and aq.HCl gave diastereoisomerically pure, crystalline N-hydroxyamino-acid derivatives 5.These were converted into various amino acids 7, N-hydroxyamino acids 8, and an N-Boc-amino acid 9. (S,S)-Isoleucine (17) and (S,S)-2-acetamido-3-phenylbutyric acid (23) were obtained from N-crotonoylsultam 15 via 1,4-addition of an organomagnesium or organocopper reagent followed by enolate 'amination' with 1.
- Oppolzer, Wolfgang,Tamura, Osamu,Deerberg, Joerg
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p. 1965 - 1978
(2007/10/02)
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