- Elastase Inhibitor Cyclotheonellazole A: Total Synthesis and in Vivo Biological Evaluation for Acute Lung Injury
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Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is one of the most common complications in COVID-19. Elastase has been recognized as an important target to prevent ALI/ARDS in the patient of COVID-19. Cyclotheonellazole A (CTL-A) is a nat
- Chen, Yue,Cui, Yingjun,Deng, Yangping,Fu, Qiang,Jiang, Peng,Li, Jing,Lin, Jianping,Liu, Yang,Meng, Qing,Sun, Yuanjun,Wang, Liang,Wang, Mukuo,Xu, Honglei,Ye, Baijun,Zhang, Mengyi,Zhang, Songming,Zhang, Tingrong,Zhao, Xiuhe
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- Design, Synthesis, and Pharmacokinetic Evaluation of Phosphate and Amino Acid Ester Prodrugs for Improving the Oral Bioavailability of the HIV-1 Protease Inhibitor Atazanavir
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Phosphate and amino acid prodrugs of the HIV-1 protease inhibitor (PI) atazanavir (1) were prepared and evaluated to address solubility and absorption limitations. While the phosphate prodrug failed to release 1 in rats, the introduction of a methylene spacer facilitated prodrug activation, but parent exposure was lower than that following direct administration of 1. Val amino acid and Val-Val dipeptides imparted low plasma exposure of the parent, although the exposure of the prodrugs was high, reflecting good absorption. Screening of additional amino acids resulted in the identification of an l-Phe ester that offered an improved exposure of 1 and reduced levels of the circulating prodrug. Further molecular editing focusing on the linker design culminated in the discovery of the self-immolative l-Phe-Sar dipeptide derivative 74 that gave four-fold improved AUC and eight-fold higher Ctrough values of 1 compared with oral administration of the drug itself, demonstrating a successful prodrug approach to the oral delivery of 1.
- Subbaiah, Murugaiah A.M.,Mandlekar, Sandhya,Desikan, Sridhar,Ramar, Thangeswaran,Subramani, Lakshumanan,Annadurai, Mathiazhagan,Desai, Salil D.,Sinha, Sarmistha,Jenkins, Susan M.,Krystal, Mark R.,Subramanian, Murali,Sridhar, Srikanth,Padmanabhan, Shweta,Bhutani, Priyadeep,Arla, Rambabu,Singh, Shashyendra,Sinha, Jaydeep,Thakur, Megha,Kadow, John F.,Meanwell, Nicholas A.
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p. 3553 - 3574
(2019/04/17)
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- Improved binding affinities of pyrrolidine derivatives as Mcl-1 inhibitors by modifying amino acid side chains
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As an important member of anti-apoptotic Bcl-2 protein, myeloid cell leukemia sequence 1 (Mcl-1) protein is an attractive target for cancer therapy. In this study, a new series of pyrrolidine derivatives as Mcl-1 inhibitors were developed by mainly modifying the amino acid side chain of compound 1. Among them, compound 18 (Ki= 0.077 μM) exhibited better potent inhibitory activities towards Mcl-1 protein compared to positive control Gossypol (Ki= 0.18 μM). In addition, compound 40 possessed good antiproliferative activities against PC-3 cells (Ki= 8.45 μM), which was the same as positive control Gossypol (Ki= 7.54 μM).
- Wan, Yichao,Liu, Tingting,Li, Xiaoxian,Chen, Chen,Fang, Hao
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p. 138 - 152
(2016/12/22)
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- Synthesis and Antibacterial Activity of Four Stereoisomers of the Spider-Pathogenic Fungus Metabolite Torrubiellone D
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Four stereoisomers of the spider-pathogenic fungus metabolite torrubiellone D were synthesized for the first time in 10% overall yield starting from l-tyrosine or d-tyrosine. The 3-decatrienoyl side chain was assembled and attached via (E)-selective HWE and Wittig olefinations. Their antibiotic activities against drug-susceptible Escherichia coli strains differed considerably.
- Bruckner, Sebastian,Bilitewski, Ursula,Schobert, Rainer
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supporting information
p. 1136 - 1139
(2016/03/15)
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- Design, synthesis and preliminary biological studies of pyrrolidine derivatives as Mcl-1 inhibitors
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Anti-apoptotic proteins, such as B-cell lymphoma (Bcl-2) protein, myeloid cell leukemia sequence 1 (Mcl-1) protein, are potential targets for cancer treatment. In the studies, a series of pyrrolidine derivatives were developed as potent Mcl-1 inhibitors. The preliminary biological studies suggested that most of target compounds exhibit good abilities for targeting Mcl-1 protein. Among them, compound 21 (Ki = 0.53 μM) exhibited equal inhibitory activities towards Mcl-1 protein compared to positive control gossypol (Ki = 0.39 μM). This compound also possessed good antiproliferative activities against MDA-MB-231 and PC-3 cancer cells.
- Wan, Yichao,Wang, Junhua,Sun, Feng'E,Chen, Minglu,Hou, Xuben,Fang, Hao
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p. 7685 - 7693
(2015/12/20)
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- Asymmetric syntheses and Wnt signal inhibitory activity of melleumin A and four analogues of melleumins A and B
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The first total synthesis of melleumin A and four analogues of melleumins A and B is described. The N-acyl L-Thr-Gly/β-hydroxy-γ-amino acid coupling/macrolactamization strategy allowed the efficient assembly of the three segments being free of epimerization. While the Jouin-Castro method with minor modification allows a rapid entrance to the key syn-β-hy-droxy-y-amino acid segment, required for the synthesis of melleumin A, an extension of our malimide-based methodology using a changed N-protecting group affords a flexible access to several anti-β-hydroxy-γ-amino acids, and hence analogues of melleumins A and B. Among them, unnatural 4-epi-melleumin B (2a) exhibits a modest inhibitory activity on Wnt signaling. The total synthesis of melleumin A allowed confirmation of its full structure.
- Luo, Jie-Min,Dai, Chao-Feng,Lin, Shu-Yong,Huang, Pei-Qiang
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supporting information; experimental part
p. 328 - 335
(2010/04/23)
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- PROTEIN TYROSINE PHOSPHATASE 1B INHIBITOR, PREPARATION METHODS AND USES THEREOF
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PTP1B inhibitors with the following structure (formula I). Experiments indicate that these inhibitors can effectively inhibit the activity of protein tyrosine phosphatase 1B (PTP1B). They can be used as insulin sensitisers. They can be used to prevent, delay or treat diseases which are related to insulin antagonism mediated by PTP1B, especially diabetes type II and obesity. The invention also provides methods for preparing these inhibitors.
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Page/Page column 15
(2009/12/27)
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- Synthetic studies of the cyclic depsipeptides bearing the 3-amino-6-hydroxy-2-piperidone (Ahp) unit. Total synthesis of the proposed structure of micropeptin T-20
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The first total synthesis of a cyclic depsipeptide possessing the 3-amino-6-hydroxy-2-piperidone (Ahp) unit was successfully achieved in a convergent manner by the oxidative construction of the Ahp unit at the later stage of the synthesis. This synthetic work provides data indicating that the structure of the target Ahp-depsipeptide, micropeptin T-20, should be re-examined.
- Yokokawa, Fumiaki,Inaizumi, Akiko,Shioiri, Takayuki
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p. 1459 - 1480
(2007/10/03)
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- An efficient synthesis of the piperazinone fragment of pseudotheonamide A1 via a stereoselective intramolecular Michael ring closure
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The stereoselective intramolecular Michael ring closure of the dipeptide efficiently gives the piperazinone fragment of pseudotheonamide A1, a serine protease inhibitor from the marine sponge Theonella swinhoei.
- Shioiri, Takayuki,Irako, Naoko
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p. 130 - 131
(2007/10/03)
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- Conformationally constrained nonpeptide β-turn mimetics of enkephalin
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The design, synthesis and in vitro biological analysis of a family of conformationally constrained nonpeptide mimetics incorporating a 4→1 β-turn prosthetic unit to examine the proposed biological significance of this conformer is described.
- Gardner, Benjamin,Nakanishi, Hiroshi,Kahn, Michael
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p. 3433 - 3448
(2007/10/02)
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- Chemoselective N-Ethylation of Boc Amino Acids without Racemization
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The Boc derivatives of amino acids such as phenylalanine, methionine, and tyrosine benzyl ethers have been selectively ethylated to give, respectively, the enantiomerically pure Boc-N-ethyl amino acids 12, 20, and 23.The benzyl, trimethylsilyl, and tert-b
- Hansen, Donald W.,Pilipauskas, Daniel
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p. 945 - 950
(2007/10/02)
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