- On-Resin Preparation of Allenamidyl Peptides: A Versatile Chemoselective Conjugation and Intramolecular Cyclisation Tool
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The ability to modify peptides and proteins chemoselectively is of continued interest in medicinal chemistry, with peptide conjugation, lipidation, stapling, and disulfide engineering at the forefront of modern peptide chemistry. Herein we report a robust method for the on-resin preparation of allenamide-modified peptides, an unexplored functionality for peptides that provides a versatile chemical tool for chemoselective inter- or intramolecular bridging reactions with thiols. The bridging reaction is biocompatible, occurring spontaneously at pH 7.4 in catalyst-free aqueous media. By this “click” approach, a model peptide was successfully modified with a diverse range of alkyl and aryl thiols. Furthermore, this technique was demonstrated as a valuable tool to induce spontaneous intramolecular cyclisation by preparation of an oxytocin analogue, in which the native disulfide bridge was replaced with a vinyl sulfide moiety formed by thia-Michael addition of a cysteine thiol to the allenamide handle.
- Brimble, Margaret A.,Cameron, Alan J.,Harris, Paul W. R.
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supporting information
p. 18054 - 18061
(2020/09/07)
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- Method for synthesizing tetrahydroindazole compound
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The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing a tetrahydroindazole compound. The synthesis method comprises the steps of synthesis of 5,5-dimethyl-2-acetyl-1,3-cyclohexanedione, synthesis of 2 fluoro-4-hydrazinylbenzonitrile, synthesis of 2-fluoro-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-)benzonitrile, synthesis of 2-(4-hydroxycyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-)benzonitrile, and synthesis of 2-(4-hydroxycyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-)benzamide. The yield of the intermediate 2-fluoro-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-)benzonitrile is up to 93%, the purity is high, and the prepared tetrahydroindazolecompound is high in purity and suitable for mass production.
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Paragraph 0035; 0036; 0047; 0048; 0059; 0060; 0075
(2019/06/27)
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- ONE-BEAD-TWO-COMPOUND MACROCYCLIC LIBRARY AND METHODS OF PREPARATION AND USE
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A one-bead-two-compound combinatorial synthesis technique provides libraries of macrocyclic peptidomimetic compounds and compositions with use as ligands for the Ephrin type-A receptor 2 (EphA2). The one-bead-two-compound technique and libraries of macrocyclic compounds are useful as research tools in drug discovery and/or to treat or prevent a range of diseases or disorders.
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Paragraph 0158; 0159
(2018/11/02)
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- Acid Chlorides as Formal Carbon Dianion Linchpin Reagents in the Aluminum Chloride-Mediated Dieckmann Cyclization of Dicarboxylic Acids
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The development of acid chlorides as formal dianion linchpin reagents that enable access to cyclic 2-alkyl- and 2-acyl-1,3-alkanediones from dicarboxylic acids is described herein. Mechanistic experiments relying on 13C-labeling studies confirm the role of acid chlorides as carbon dianion linchpin reagents and have led to a revised reaction mechanism for the aluminum(III)-mediated Dieckmann cyclization of dicarboxylic acids with acid chlorides.
- Armaly, Ahlam M.,Bar, Sukanta,Schindler, Corinna S.
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supporting information
p. 3962 - 3965
(2017/08/15)
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- A 2 - (grantane - 3 - amino) - 4 - tetrahydroindazole substituted benzamide compound and use thereof
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The invention belongs to the field of medicines, and particularly relates to a 2-(granatane3-amino)-4-tetrahydronaphthalene indazole-substituted benzamide compound and an application thereof. The 2-(granatane3-amino)-4-tetrahydronaphthalene indazole-substituted benzamide compound has a structure shown in a formula I in the specification, wherein R1 is a hydrogen group or an alkyl group and the like; R2 is a hydrogen group, an alkyl group or a hetero-atom-substituted alkyl group and the like. The compound is obtained by substituting the second site of 4-tetrahydronaphthalene indazole-substituted benzamide with granatane-3-amino. Growth of a plurality of tumor cells can be inhibited; the tumor cells can be induced to move towards an apoptosis channel; and the 2-(granatane3-amino)-4-tetrahydronaphthalene indazole-substituted benzamide compound has potential application value in the fields such as tumor treatment and auxiliary treatment.
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Paragraph 0061; 0062; 0063
(2017/08/25)
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- One-Bead-Two-Compound Thioether Bridged Macrocyclic γ-AApeptide Screening Library against EphA2
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Identification of molecular ligands that recognize peptides or proteins is significant but poses a fundamental challenge in chemical biology and biomedical sciences. Development of cyclic peptidomimetic library is scarce, and thus discovery of cyclic peptidomimetic ligands for protein targets is rare. Herein we report the unprecedented one-bead-two-compound (OBTC) combinatorial library based on a novel class of the macrocyclic peptidomimetics γ-AApeptides. In the library, we utilized the coding peptide tags synthesized with Dde-protected α-amino acids, which were orthogonal to solid phase synthesis of γ-AApeptides. Employing the thioether linkage, the desired macrocyclic γ-AApeptides were found to be effective for ligand identification. Screening the library against the receptor tyrosine kinase EphA2 led to the discovery of one lead compound that tightly bound to EphA2 (Kd = 81 nM) and potently antagonized EphA2-mediated signaling. This new approach of macrocyclic peptidomimetic library may lead to a novel platform for biomacromolecular surface recognition and function modulation.
- Shi, Yan,Challa, Sridevi,Sang, Peng,She, Fengyu,Li, Chunpu,Gray, Geoffrey M.,Nimmagadda, Alekhya,Teng, Peng,Odom, Timothy,Wang, Yan,Van Der Vaart, Arjan,Li, Qi,Cai, Jianfeng
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p. 9290 - 9298
(2017/11/30)
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- New Protocol for the Synthesis of 2-Alkanoyl- and 2-Aryloyl-5,5-dimethylcyclohexane-1,3-diones by the Reaction of Dimedone with Various Aldehydes and Cyanogen Bromide in the Presence of Triethylamine
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A new route for the synthesis of 2-alkanoyl(aryloyl)-5,5-dimethylcyclohexane-1,3-diones as cyclic β-triketones is described. This synthesis was conducted by the reaction of dimedone with cyanogen bromide and triethylamine to form first the intermediate salt, followed by the addition of various aliphatic and aromatic aldehydes. The structures of the products were characterized by IR, 1H, and 13C NMR spectroscopic techniques. A reaction mechanism is proposed.
- Kashani, Elmira,Pesyan, Nader Noroozi,Rashidnejad, Hamid
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p. 2079 - 2084
(2016/07/06)
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- INDAZOLYL- AND INDOLYL-BENZAMIDE DERIVATIVES
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The invention relates to indazolylbenzamide, indolylbenzamide, benzo[d]imidazolyl-benzamide, and benzo[d]triazolylbenzamide derivatives of formula useful in the treatment and/or prevention of diseases and/or conditions related to cell proliferation, such as cancer, infection, inflammation and inflammation-associated disorders, and conditions associated with angiogenesis.
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Paragraph 0272
(2016/04/09)
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- Active immunisation of mice with GnRH lipopeptide vaccine candidates: Importance of T helper or multi-dimer GnRH epitope
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Active immunisation against gonadotropin releasing hormone (GnRH) is a potential alternative to surgical castration. This study focused on the development of a GnRH subunit lipopeptide vaccine. A library of vaccine candidates that contained one or more (up to eight) copies of monomeric or dimeric GnRH peptide antigen, an adjuvanting lipidic moiety based on lipoamino acids, and an additional T helper epitope, was synthesised by solid phase peptide synthesis. The candidates were evaluated in vivo in order to determine the minimal components of this vaccine necessary to induce a systemic immune response. BALB/c mice were immunised with GnRH lipopeptide conjugates, co-administered with or without Complete Freund's Adjuvant, followed by two additional immunisations. Significant GnRH-specific IgG titres were detected in sera obtained from mice immunised with four of the seven lipopeptides tested, with an increase in titres observed after successive immunisations. This study highlights the importance of for epitope optimisation and delivery system design when producing anti-hapten antibodies in vivo. The results of this study also contribute to the development of future clinical and veterinary immunocontraceptives.
- Goodwin, Daryn,Simerska, Pavla,Chang, Cheng-Hung,Mansfeld, Friederike M.,Varamini, Pegah,D'Occhio, Michael J.,Toth, Istvan
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p. 4848 - 4854
(2014/11/07)
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- COMPOUNDS AND METHODS FOR TARGETING HSP90
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Described herein are compounds that may selectively bind to Hsp90, methods of using the compounds, and kits including the compounds. The compounds may include detection moieties such as fluorophores that may allow for selective detection of Hsp90 in a sample.
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Paragraph 00220-00221
(2014/03/21)
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- A highly selective Hsp90 affinity chromatography resin with a cleavable linker
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Over 200 proteins have been identified that interact with the protein chaperone Hsp90, a recognized therapeutic target thought to participate in non-oncogene addiction in a variety of human cancers. However, defining Hsp90 clients is challenging because interactions between Hsp90 and its physiologically relevant targets involve low affinity binding and are thought to be transient. Using a chemo-proteomic strategy, we have developed a novel orthogonally cleavable Hsp90 affinity resin that allows purification of the native protein and is quite selective for Hsp90 over its immediate family members, GRP94 and TRAP 1. We show that the resin can be used under low stringency conditions for the rapid, unambiguous capture of native Hsp90 in complex with a native client. We also show that the choice of linker used to tether the ligand to the insoluble support can have a dramatic effect on the selectivity of the affinity media.
- Hughes, Philip F.,Barrott, Jared J.,Carlson, David A.,Loiselle, David R.,Speer, Brittany L.,Bodoor, Khaldon,Rund, Lauretta A.,Haystead, Timothy A.J.
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supporting information; experimental part
p. 3298 - 3305
(2012/07/14)
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- Trimethyl-4-oxo-4,5,6,7-tetrahydroindazole-1-acetic acid: A new lead compound with selective COX-2 inhibitory activity
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A novel series of 3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazole-1-acetic acid derivatives was designed and synthesized by a new one-step pathway. Structure elucidation of the synthesized compounds was confirmed by various spectral and elemental analyses. The prepared compounds were evaluated for their ability to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) enzymes in vitro. Among the synthesized compounds, the 2-(3,6,6-trimethyl-4-oxo- 4,5,6,7-tetrahydroindazol-1-yl)acetic acid 4 emerged as the most potent COX-2 inhibitor (IC50 value: 150 nM) with the highest selectivity index (COX-1/COX-2 inhibition ratio: 570.6). Docking studies of compound 4 in the active site of COX-2 recognized its potential binding mode to the enzyme. Based on the preliminary results, compound 4 was considered as a lead compound for further optimization. Copyright
- Abdel-Rahman, Hamdy M.,Ozadali, Keriman
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p. 878 - 883
(2013/01/15)
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- Synthesis and in vitro anti-HSV-1 activity of a novel Hsp90 inhibitor BJ-B11
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In this study, a novel Hsp90 inhibitor BJ-B11, was synthesized and evaluated for in vitro antiviral activity against several viruses. Possible anti-HSV-1 mechanisms were also investigated. BJ-B11 displayed no antiviral activity against coxsackievirus B3 (CVB3), human respiratory syncytial virus (RSV) and influenza virus (H1N1), but exhibited potent anti-HSV-1 and HSV-2 activity with EC50 values of 0.42 ± 0.18 μM and 0.60 ± 0.21 μM, respectively. Additionally, the inhibitory effects of BJ-B11 against HSV-1 were likely to be introduced at early stage of infection. Our results indicate that BJ-B11 with alternative mechanisms of action is potent as an anti-HSV clinical trial candidate.
- Ju, Huai-Qiang,Xiang, Yang-Fei,Xin, Bao-Juan,Pei, Ying,Lu, Jia-Xin,Wang, Qiao-Li,Xia, Min,Qian, Chui-Wen,Ren, Zhe,Wang, Sha-Yan,Wang, Yi-Fei,Xing, Guo-Wen
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scheme or table
p. 1675 - 1677
(2011/05/11)
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- Orthogonal regioselective synthesis of N-alkyl-3-substituted tetrahydroindazolones
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A divergent strategy for the regioselective and orthogonal synthesis of complementary regioisomers of N-alkyl-3-substituted-tetrahydroindazolones 3 and 4 was achieved from. Boc-protected alkylhydrazmes 1. The robustness and sub-strate generality of this method were validated by synthesizing 3 and. 4 through the intra- and intermolecular condensation of 1 with various 2-acylcyclohexane-l,3-diones 2 and aldehydes, respectively.
- Kim, Jonghoon,Song, Heebum,Park, Seung Bum
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supporting information; experimental part
p. 3815 - 3822
(2010/09/10)
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- O-COORDINATED METAL CHELATES AND THEIR USE IN OPTICAL RECORDING MEDIA HAVING HIGH STORAGE CAPACITY
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The invention relates to novel o ptical recording materials that comprise specific and in some cases novel diketone enamines or metal chelates thereof and that have excellent recording and playback quality especially ata wavelength of 350-500 nm. The invention accordingly relates to an optical recording medium comprising a substrate, a recording layer and optionally a reflecting layer, wherein the recording layer comprises a compound of formula (I), wherein M is hydrogen, aluminium or, preferably, a transition metal, which may in addition be coordinated with one or more further ligands and/or, for balancing out an excess charge, where applicable, may have an electrostatic interaction with one or more further ions inside or outside the coordination sphere, but M in formulae (Ib) and (Ic) is not hydrogen, Q is C-H, N or C-R6, it being possible for the stereochernistry of the C=Q double bond to be either E or Z. For the exact definitions of R1 to R6 reference should be made to the description. Also claimed are the novel compounds, especially tetracoordinated chelates, and a process for the preparation thereof.
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Page/Page column 37
(2010/02/10)
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- 4,5,6,7-tetrahydroindazole derivatives as antitumor agents
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Compounds which are 4,5,6,7-tetrahydroindazole derivative formula (1), wherein the dotted line (x) represents a single or double bond; n is 0 or 1; R1, R2 and R3 have the meanings reported in the description; Ra, R′a, Rb, R′b, Rc, R′c have the meanings reported in the description, also comprising that Ra and Rb together and/or Ra and Rc together form a N-alkylpiperydinyl ring with 1 to 6 carbon atoms in the alkyl chain or a phenyl ring; or pharmaceutically acceptable salts thereof, are useful for treating cell proliferative disorders and Alzheimer's disease.
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Page column 40
(2010/02/06)
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- Parallel solid-phase synthesis of vitronectin receptor (αvβ3) inhibitors
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A combinatorial approach for rapid optimization of a vitronectin receptor (αvβ3) inhibitor lead was accomplished by solid-phase synthesis. Orthogonally bis protected 2,3-diaminopropionic acid was used to immobilize the C-terminus of the molecule. Selective deprotection and functionalization of the α-amino group followed by acyl resorcinol scaffold attachment and N-terminus diversification was used to explore structure-activity relationship (SAR). (C) 2000 Elsevier Science Ltd. All rights reserved.
- Gopalsamy, Ariamala,Yang, Hui,Ellingboe, John W.,Kees, Kenneth L.,Yoon, Jeanne,Murrills, Richard
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p. 1715 - 1718
(2007/10/03)
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- Photobleaching Activity of 2-(Phenylamino)methylidenecyclohexane-1,3-diones in Tobacco (Nicotiana tabacum) Cultured Cells
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A series of phenylalkylidenecyclohexane-1,3-dione derivatives were designed and synthesized as vinylogous analogs of phthalimides, which are known photobleaching herbicides. The bleaching activity of synthesized compounds was assayed with photomixotrophic tobacco cultured cells under either light or dark conditions. Both the chlorophyll and the carotenoid contents of the cells treated with the cyclic diones decreased to almost zero within 24 h under the light condition but not under the dark condition. This rapid emergence of bleaching activity with light is one of the most distinctive actions of Protox-inhibiting herbicides; however, the cyclic dione did not inhibit protoporphyrinogen oxidase in vitro. Thus, we concluded that the cyclic diones possessed a different herbicidal mode of action from Protox-inhibiting herbicide.
- Wang, Jing-Ming,Asami, Tadao,Che, Fan-Sik,Murofushi, Noboru,Yoshida, Shigeo
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p. 2728 - 2734
(2007/10/03)
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- -Photocycloaddition of Cyclohexene to 2-Acetyl-5,5-dimethyl-1,3-cyclohexanedione and 3-Acetyl-1,5,5-trimethyl-2,4-pyrrolidinedione
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Irradiation of solutions of excess cyclohexene and 2-acetyl-5,5-dimethyl-1,3-cyclohexanedione (1) and 3-acetyl-1,5,5-trimethyl-2,4-pyrrolidinedione (4) results mainly in the formation of 1,5-diones 2 and 5.These originate from intermediate cycloadducts of cyclohexene and the exo-enols of the cyclic 1,3-diketones.The yields decrease with increasing polarity of the solvent.In solution 2 and 5 are in equilibrium with the cyclic hemiacetals 3 and 6.Keywords: -Photocycloaddition; 2-Acetyl-5,5-dimethyl-1,3-cyclohexanedione; 3-Acetyl-1,5,5-trimethyl-2,4-pyrrolidinedione; 2-(2'-Acetyl-cyclohexyl)-5,5-dimethyl-1,3-cyclohexanedione; 3-(2'-Acetyl-cyclohexyl)-1,5,5-trimethyl-2,4-pyrrolidinedione.
- Henning, Hans-Georg,Mazunaitis, Giedrius
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