- INHIBITOR OF APOPTOSIS (IAP) PROTEIN ANTAGONISTS
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Provided herein are compounds that modulate the activity of melanoma inhibitor of apoptosis (ML-IAP) protein, compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.
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Paragraph 00250
(2021/11/06)
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- Design and synthesis of tripeptidyl furylketones as selective inhibitors against the β5 subunit of human 20S proteasome
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A series of tripeptidic proteasome inhibitors with furylketone as C-terminus were designed and synthesized. Biochemical evaluations against β1, β2 and β5 subunits revealed that they acted selectively on β5 subunit with IC50s against chymotrypsin-like (CT-L) activity in micromolar range. LC-MS/MS analysis of the ligand-20S proteasome mixture showed that the most potent compound 11m (IC50 = 0.18 μM) made no covalent modification on 20S proteasome. However, it was identified acting in a slowly reversible manner in wash-out assay and the reversibility was much lower than that of MG132, suggesting the possibility of these tripeptidic furylketones forming reversible covalent bonds with 20S proteasome. Several compounds were selected for anti-proliferative assay towards multiple cancer cell lines, and compound 11m displayed comparable potency to positive control (MG132) in all cell lines tested. Furthermore, the pharmacokinetic (PK) data in rats indicated 11m behaved similarly (Cmax, 2007 μg/L; AUC0?t, 680 μg/L·h; Vss, 0.66 L/kg) to the clinical used agent carfilzomib. All these data suggest 11m is a good lead compound to be developed to novel anti-tumor agent.
- Lü, Zirui,Li, Xiaona,Niu, Yan,Sun, Qi,Wang, Chao,Xi, Dandan,Xu, Fengrong,Xu, Ping,Zhou, Tongliang
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- EPHA4 CYCLIC PEPTIDE ANTAGONISTS AND METHODS OF USE THEREOF
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Disclosed herein are compounds and methods of use thereof for the modulation of EphA4 receptor activity. In an aspect, is provided a method of treating or preventing a disease or disorder mediated by EphA4, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein, including certain embodiments, or the structural Formula (I), (l-A), (II), (III), (IV), (IV-1), (V), (Vl-A), (Vl-B), (VII-1), (VII-2), (VIII-1), or (VIII-2), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
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Paragraph 0645-0646; 0648
(2019/11/19)
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- Design, synthesis and preliminary bioactivity studies of indomethacin derivatives as Bcl-2/Mcl-1 dual inhibitors
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Bcl-2 family proteins, which divides into pro-apoptosis proteins and anti-apoptosis proteins, are involved in cell apoptosis progression. As numerous studies illustrated, targeting Bcl-2 family proteins is more and more attractive and practicable to cancer treatment. In this work, we designed and synthesized a series of indomethacin derivatives as new inhibitors for Bcl-2 family proteins. Our results of binding assay to Bcl-2 proteins, MTT assay and apoptotic assay indicated that some compounds had potent binding affinity to Bcl-2/Mcl-1 but not Bcl-XL. Furthermore, compound 8j showed improved anti-proliferative activity than known Bcl-2 inhibitor WL-276.
- Chen, Chen,Nie, Yiming,Xu, Guangsen,Yang, Xinying,Fang, Hao,Hou, Xuben
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p. 2771 - 2783
(2019/05/15)
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- Preparation method of O-methyl-threonine/tyrosine
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The invention relates to a preparation method of O-methyl-threonine/tyrosine. The preparation method mainly overcomes the disadvantages of the existing method that a toxic reagent is volatile, the reagent is dangerous, the steps are long, the yield is low, and the like. The preparation method of the O-methyl-threonine/tyrosine comprises the following steps: N-t-butyloxycarboryl-threonine/tyrosineis catalyzed by sodium hydroxide and reacts with dimethyl sulfate to generate N-t-butyloxycarboryl-O-methyl-threonine/tyrosine, and then t-butyloxycarboryl is removed from the N-t-butyloxycarboryl-O-methyl-threonine/tyrosine through acid substances to obtain the product O-methyl-threonine/tyrosine. The product has important application in the fields of antibiotics and polypeptide drugs.
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Paragraph 0016
(2018/06/21)
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- 4-oxo-alkylated tetramic acid compounds and preparation method thereof
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The invention relates to novel compounds and a preparation method thereof. The general structural formula is shown as formula I in the description. Animal experiments prove that the compounds have the effect of saving memories of animal models, are high in safety, have no mutagenicity, can remain in blood for hours after oral administration and intravenous injection, can enter brains and can be used for preparing drugs for treating diseases such as Alzihemer's disease, Parkinson's disease, Huntington's disease, vascular dementia, schizophrenia, autism and the like.
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- 4-oxo-alkylated tetramic acid compound as well as preparation method and application thereof
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The invention relates to a novel compound as well as preparation method and application thereof. The structural formula of the novel compound is as shown in a formula I. Animal tests show that the compound provided by the invention has a memory effect of rescuing animal models, is high in security and free of mutagenicity induction, can be retained for hours in blood after oral taking and intravenous injection, can be fed into brains and can be used for preparing medicines for treating senile dementia, Parkinsonism, Huntington diseases, vascular dementia, schizophrenia, autism and the like.
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- Synthesis, bioactivity, docking and molecular dynamics studies of furan-based peptides as 20s proteasome inhibitors
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Proteasome inhibitors are promising compounds for a number of therapies, including cardiovascular and eye diseases, diabetes, and cancers. We previously reported a series of furanbased peptidic inhibitors with moderate potencies against the proteasome b5 subunit, hypothesizing that the C-terminal furyl ketone motif could form a covalent bond with the catalytic residue, threonine 1. In this context, we describe further optimizations of the furan-based peptides, and a series of dipeptidic and tripeptidic inhibitors were designed and synthesized, aiming at improved potency and better solubility. Most of the tripeptidic inhibitors demonstrated improved potency and selectivity as b5 subunit inhibitors in both enzymatic and cellular assays, and good antineoplastic activities in various tumor cell lines were also observed. However, no inhibitory effects were observed for the dipeptidic compounds, which led us to presume that a noncovalent binding mode is adopted. Docking studies and molecular dynamics simulations were carried out to verify this presumption, with results showing that the distance between the furyl ketone motif and Thr1 is slightly too long to form covalent bond.
- Sun, Qi,Xu, Bo,Niu, Yan,Xu, Fengrong,Liang, Lei,Wang, Chao,Yu, Jiapei,Yan, Gang,Wang, Wei,Jin, Hongwei,Xu, Ping
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p. 498 - 510
(2015/03/18)
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- Synthesis and conformation studies of rubiyunnanin B analogs
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Five new analogs 4-8 of rubiyunnanin B (1), mainly modified on the tetrapeptide subunit, were synthesized. These agents 4-8 were substituted d-Ala-l-Ala-l-Tyr(OMe)-l-Ala, d-Ala-l-Ala-l-Phe-l-Ala, d-Ala-l-Ala-l-Try-l-Ala, d-Ala-l-Ala-l-Pro-l-Ala, and d-Ala-l-Ala-l-Ala for the d-Ala-l-Ala-l-N-Me-Tyr(OMe)-l-Ala tetrapeptide subunit. Unlike the natural product, the synthetic agents 4-8 adopt only a single solution conformation, and the central peptide bond in the cyclodityrosine subunit of compounds 4-8 adopt trans stereochemistry. Cytotoxic activities of analogs 4-8 against three human cancer cell lines including A549, BGC-823, and HeLa were evaluated and all the five synthesized peptides exhibited no effects against the test cell lines. These compounds were also evaluated for their antiinsulin resistance and insulin sensitizing activities and none of them showed activity in these assays.
- Liu, Na-Na,Zhao, Si-Meng,Zhao, Jing-Feng,Zeng, Guang-Zhi,Tan, Ning-Hua,Liu, Jian-Ping
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p. 6630 - 6640
(2015/03/30)
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- Total synthesis of proposed structure of coibamide A, a highly N- and O-methylated cytotoxic marine cyclodepsipeptide
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Total synthesis of the originally proposed structure of coibamide A, a highly N- and O-methylated cytotoxic marine cyclodepsipeptide, has been accomplished by using a [(4+1)+3+3]-peptide fragment-coupling strategy and careful examination and optimization
- He, Wei,Qiu, Hai-Bo,Chen, Yi-Jie,Xi, Jie,Yao, Zhu-Jun
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supporting information
p. 6109 - 6112
(2015/01/09)
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- Enzymatic basis of ribosomal peptide prenylation in cyanobacteria
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The enzymatic basis of ribosomal peptide natural product prenylation has not been reported. Here, we characterize a prenyltransferase, LynF, from the TruF enzyme family. LynF is the first characterized representative of the TruF protein family, which is responsible for both reverse- and forward-O-prenylation of tyrosine, serine, and threonine in cyclic peptides known as cyanobactins. We show that LynF reverse O-prenylates tyrosine in macrocyclic peptides. Based upon these results, we propose that the TruF family prenylates mature cyclic peptides, from which the leader sequence and other enzyme recognition elements have been excised. This differs from the common model of ribosomal peptide biosynthesis, in which a leader sequence is required to direct post-translational modifications. In addition, we find that reverse O-prenylated tyrosine derivatives undergo a facile Claisen rearrangement at 'physiological' temperature in aqueous buffers, leading to forward C-prenylated products. Although the Claisen rearrangement route to natural products has been chemically anticipated for at least 40 years, it has not been demonstrated as a route to prenylated natural products. Here, we show that the Claisen rearrangement drives phenolic C-prenylation in at least one case, suggesting that this route should be reconsidered as a mechanism for the biosynthesis of prenylated phenolic compounds.
- McIntosh, John A.,Donia, Mohamed S.,Nair, Satish K.,Schmidt, Eric W.
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supporting information; experimental part
p. 13698 - 13705
(2011/10/12)
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- Endomorphin-1 analogs with enhanced metabolic stability and systemic analgesic activity: Design, synthesis, and pharmacological characterization
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We synthesized four new analogs of endomorphin-1 by systematic chemical modifications. To identify the best possible drug candidates for clinical pain management and to investigate the potential contribution of these alterations to the biological activity, their pharmacological properties were determined. All of the analogs showed significantly enhanced metabolic stability. The fact that centrally mediated analgesia following peripheral administration was observed with one of the analogs suggested the approach design undertaken here had validity in the development of endomorphin-1 as a successful opioid drug for the clinic.
- Liu, Hongmei,Zhang, Bangzhi,Liu, Xuefeng,Wang, Changlin,Ni, Jingman,Wang, Rui
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p. 1694 - 1702
(2008/02/03)
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- ORALLY ACTIVE RENIN INHIBITORS
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This invention relates to compounds of the formula STR1 wherein Q, Z, D, E, R 3, R 4, R 5 and R 6 are defined as below, and the pharmaceutically acceptable salts thereof are disclosed. The compounds are useful as antihypertensive agents.
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- N-Desmethyl derivatives of deoxybouvardin and RA-VII: Synthesis and evaluation
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The synthesis of the complete set of seven N-desmethyl derivatives of RA-VII (8) are described. Thus, the synthesis of the four 14-membered cycloisodityrosine derivatives 21-24 and their coupling with the two tetrapeptides 32 and 33 followed by formation of the 18-membered ring with macrocyclization provided the full set of seven desmethyl derivatives 14-20 of RA-VII (8). The solution phase conformational properties of 8 and 14-20 were examined by 1D and 2D 1H NMR to reveal the role of N-methylation on the key conformational aspects of the natural agents. In contrast to each of the simple cycloisodityrosine derivatives 21-24 which adopt a single, rigid solution conformation possessing a secondary or tertiary trans amide central to the 14-membered ring, the natural agents including 8 adopt a single predominant solution conformation (83-88%) that corresponds closely to the X-ray structure conformation which possesses an inherently disfavored cis C30-N29 tertiary amide central to the 14-membered cycloisodityrosine subunit. Moreover, this cis amide is the predominant conformation (85-95%) observed with N29-desmethyl RA-VII (14) indicating that even a secondary C30-N29 amide adopts this inherently disfavored cis amide stereochemistry. The minor conformation of 8 observed in solution (12-17%) is shown to be derived from a minor cis C8-N9 tertiary amide which was not observed with its conversion to a secondary amide. Both N9-desmethyl RA-VII (15) and N9,N29-desmethyl RA-VII (18) adopt exclusively a single solution conformation that corresponds to the major solution conformations of 8 and 14. This conformation contains a characteristic cis C30-N29 amide central to a type VI β-turn and the cycloisodityrosine subunit, a trans C8-N9 amide central to a typical type II β-turn capped with a tight Ala4-NH-O=C-Ala1 hydrogen bond, and a trans C14-N15 N-methyl amide. In sharp contrast, removal of the N15 methyl group within 16, 17, 19, and 20 results in the adoption of solution conformations possessing the inherently favored trans C30-N29 amide central to the cycloisodityrosine 14-membered subunit. Thus, the N15-methyl group within 8 is responsible for the agents adoption of the disfavored cis C30-N29 amide central to the cycloisodityrosine subunit. Importantly, preceding studies have defined the cycloisodityrosine subunit of 8 as the pharmacophore and, in a reversal of the initially assigned roles, revealed that it is the tetrapeptide housed in the 18-membered ring that induces and maintains the rigid, normally inaccessible cis C30-N29 amide conformation within the 14-membered cycloisodityrosine subunit. The studies detailed herein reveal that it is the N15-methyl group that induces this conformational preference for the disfavored cis C30-N29 amide and that its removal results in a major conformational change with adoption of the trans C30-N29 amide and a loss of biological activity. Thus, the N15-methyl group is essential for maintenance of the conformational and biological properties of 8; the N9-methyl group is not essential, and its removal leads to exclusive population of a single biologically active conformation; and the N29-methyl group once thought essential to the adoption of the C30-N29 cis amide is not essential, and its removal does not alter the conformational or biological properties of 8.
- Boger, Dale L.,Zhou, Jiacheng
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p. 7364 - 7378
(2007/10/02)
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- CYCLOPROPANES AS CONFORMATIONALLY RESTRICTED PEPTIDE ISOSTERES. DESIGN AND SYNTHESIS OF NOVEL COLLAGENASE INHIBITORS
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The 1,2,3-trisubstituted cyclopropane derivatives 9 and 10 were prepared as conformationally constrained analogues of the known collagenase inhibitor 8.The syntheses of 9 and 10 featured the highly enantioselective Rh24 catalyzed cyclization of th
- Martin, Stephen F.,Oalmann, Christopher J.,Liras, Spiros
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p. 3521 - 3532
(2007/10/02)
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- Orally active renin inhibitors
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This invention relates to compounds of the formula wherein Q, Z, D, E, R3, R?, R? and R? are defined as below, and the pharmaceutically acceptable salts thereof are disclosed. The compounds are useful as antihypertensive agents.
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- Novel amino acid derivatives possessing renin-inhibitory activities
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An amino acid derivative of the general formula: wherein, R1? is a lower alkyl group and R11 is (wherein R111 is a lower alkyl group and n is an integer of 1 to 5) or a lower alkyl group which may be substituted by hydroxy group or methoxyethoxymethoxy group, or R1? and R11 are combinedly together with the adjacent nitrogen atom; R12 is a hydrogen atom, CnH2n+ 1-O-CO-(n is as defined above) or R13 is a lower alkyl group which may be substituted by substituent(s) selected from HOOC-(H?C)n-O-, R12-NH-(n and R12 are as defined above) and pyridyl group; X is-CH?-,-O-or-NH-and Y is-O-or-NH-; wherein (wherein Z is-O-,-S-,-S(O)-,-S(O)?-,-CH?-,-CH(OH)-,---,-NH-or and a and b are independently an integer of 1 to 4 and the total of a and b is not more than 5) ; R2 is an aralkyl group which may be substituted by lower alkyl group(s); R3 is a hydrogen atom or a lower alkyl group; R? is a lower alkyl group; and A is hydroxy group and B is a hydrogen atom, or A and B are carbonyl group combinedly together with the adjacent carbon atom, a pharmaceutically acceptable acid addition salt or an ester thereof is described. The compounds of the invention possess inhibitory activities against renin and are useful as an antihypertensive agent.
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- A-Acetyl-arginine-vasopressin, an Interesting Antagonist of the Vasopressor Response to Vasopressin
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The synthesis of N-acetyl-arginine-vasopressin was undertaken utilizing a combination of the stepwise active ester and fragment condensation methods.Ac-Tyr(Me)AVP is an antagonist of the vasopressor response to vasopr
- Jones, David A.,Sawyer, Wilbur H.
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p. 696 - 698
(2007/10/02)
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