- LINKING AMINO ACID SEQUENCES, MANUFACTURING METHOD THEREOF, AND USE THEREOF
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This invention provides compositions comprising linked amino acid sequences, pharmaceutical compositions comprising linked amino acid sequences, and methods of making thereof. This invention also provides methods of delivering said compositions to subjects and methods of treating various disorders and diseases using the said compositions.
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Page/Page column 170-171
(2021/08/20)
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- THERAPEUTIC COMPOUNDS AND METHODS
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Disclosed herein are compounds of formula I: (I) or pharmaceutically acceptable salts thereof, wherein R1, R2, and R3 may any of the values defined herein, as well as compositions comprising such compounds. Also disclosed are methods for treating diseases including neurodegenerative disorders such as Parkinson's Disease and Alzheimer's Disease.
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- A short, rigid linker between pyrene and guanidiniocarbonyl-pyrrole induced a new set of spectroscopic responses to the ds-DNA secondary structure
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A novel pyrene-guanidiniocarbonyl-pyrrole dye, characterised by a short, rigid linker between the two chromophores, interacts strongly with ds-DNA but only negligibly with ds-RNA. Under neutral conditions the dye shows strong selectivity toward AT-DNA (with respect to GC-DNA). Binding is accompanied by a specific ICD band at 350 nm and fluorescence quenching for all DNAs/RNAs studied. At pH 5 the affinity of the dye is reversed, now favouring GC-DNA over AT-DNA. A strong emission increase for AT-DNA is observed but with quenching for GC-DNA.
- Radi Stojkovi, Marijana,Piotrowski, Patryciusz,Schmuck, Carsten,Piantanida, Ivo
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p. 1629 - 1633
(2015/02/19)
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- A diversity-oriented synthesis strategy enabling the combinatorial-type variation of macrocyclic peptidomimetic scaffolds
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Macrocyclic peptidomimetics are associated with a broad range of biological activities. However, despite such potentially valuable properties, the macrocyclic peptidomimetic structural class is generally considered as being poorly explored within drug discovery. This has been attributed to the lack of general methods for producing collections of macrocyclic peptidomimetics with high levels of structural, and thus shape, diversity. In particular, there is a lack of scaffold diversity in current macrocyclic peptidomimetic libraries; indeed, the efficient construction of diverse molecular scaffolds presents a formidable general challenge to the synthetic chemist. Herein we describe a new, advanced strategy for the diversity-oriented synthesis (DOS) of macrocyclic peptidomimetics that enables the combinatorial variation of molecular scaffolds (core macrocyclic ring architectures). The generality and robustness of this DOS strategy is demonstrated by the step-efficient synthesis of a structurally diverse library of over 200 macrocyclic peptidomimetic compounds, each based around a distinct molecular scaffold and isolated in milligram quantities, from readily available building-blocks. To the best of our knowledge this represents an unprecedented level of scaffold diversity in a synthetically derived library of macrocyclic peptidomimetics. Cheminformatic analysis indicated that the library compounds access regions of chemical space that are distinct from those addressed by top-selling brand-name drugs and macrocyclic natural products, illustrating the value of our DOS approach to sample regions of chemical space underexploited in current drug discovery efforts. An analysis of three-dimensional molecular shapes illustrated that the DOS library has a relatively high level of shape diversity.
- Isidro-Llobet, Albert,Hadje Georgiou, Kathy,Galloway, Warren R. J. D.,Giacomini, Elisa,Hansen, Mette R.,Méndez-Abt, Gabriela,Tan, Yaw Sing,Carro, Laura,Sore, Hannah F.,Spring, David R.
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p. 4570 - 4580
(2015/04/14)
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- 2-PYRIDYL CARBOXAMIDE-CONTAINING SPLEEN TYROSINE KINASE (SYK) INHIBITORS
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The invention provides certain 2-pyridyl carboxamide-containing compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein A and B are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds, and methods of using the compounds for treating diseases or conditions mediated by Spleen Tyrosine Kinase (Syk) kinase.
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Paragraph 00292
(2013/04/24)
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- Aminomethylene peptide nucleic acid (am -PNA): Synthesis, regio-/stereospecific DNA binding, and differential cell uptake of (α/γ, R / S) am- PNA analogues
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Inherently chiral, cationic am-PNAs having pendant aminomethylene groups at α(R/S) or γ(S) sites on PNA backbone have been synthesized. The modified PNAs are shown to stabilize duplexes with complementary cDNA in a regio- and stereo-preferred manner with γ(S)-am PNA superior to α(R/S)-am PNAs and α(R)-am PNA better than the α(S) isomer. The enhanced stabilization of am-PNA:DNA duplexes is accompanied by a greater discrimination of mismatched bases. This seems to be a combined result of both electrostatic interactions and conformational preorganization of backbone favoring the cDNA binding. The am-PNAs are demonstrated to effectively traverse the cell membrane, localize in the nucleus of HeLa cells, and exhibit low toxicity to cells.
- Mitra, Roopa,Ganesh, Krishna N.
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p. 5696 - 5704
(2012/08/07)
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- PNAs grafted with (α/γ, R/S)-aminomethylene pendants: Regio and stereo specific effects on DNA binding and improved cell uptake
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PNAs grafted with cationic aminomethylene (am) pendants on the backbone at the glycyl (α) or ethylenediamine (γ) segments show regio (α/γ) and stereochemistry (R/S) dependent binding with complementary DNA. These are efficiently taken up by cells, with γ(S-am) aeg-PNA being the best in all properties.
- Mitra, Roopa,Ganesh
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p. 1198 - 1200
(2011/03/20)
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- Inhibition of glyoxalase I: The first low-nanomolar tight-binding inhibitors
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A series of rational modifications to the structure of known S-(N-aryl-N-hydroxycarbamoyl)glutathione-based glyoxalase I inhibitors culminated in the discovery of the first single-digit nanomolar inhibitor. This study makes available key information about possible means to address the issues of metabolic instability, low potency, and synthetic complexicity that have plagued the area of glyoxalase I inhibition. Knowledge garnered from this study has implications in the design of inhibitors with higher conformational definition and lower peptidic character.
- More, Swati S.,Vince, Robert
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scheme or table
p. 4650 - 4656
(2010/03/01)
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- Design, synthesis and biological evaluation of glutathione peptidomimetics as components of anti-Parkinson prodrugs
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Plethoras of CNS-active drugs fail to effect their pharmacologic response due to their in vivo inability to cross the blood-brain barrier (BBB). The classical prodrug approach to overcome this frailty involves lipophilic derivatives of the polar drug, but we herein report a novel approach by which endogenous transporters at BBB are exploited for brain drug delivery. The crucial role played by glutathione in pathogenesis of Parkinson's and the presence of its influx transporters at the basolateral membrane of BBB served as the basis for our anti-Parkinson prodrug design strategy. A metabolically stable analogue of glutathione is used as a carrier for delivery of dopamine and adamantamine. An account of successful syntheses of these prodrugs along with their transport characteristics and stability determination is discussed.
- More, Swati S.,Vince, Robert
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supporting information; experimental part
p. 4581 - 4588
(2009/06/06)
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- Mapping the landscape of potentially primordial informational oligomers: Oligodipeptides and oligodipeptoids tagged with triazines as recognition elements
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(Chemical Equation Presented) Pairing up: Oligodipeptide, oligodeoxy-dipeptide, or oligodipeptoid backbones tagged with the 2,4-diaminotriazine nucleus pair strongly with complementary DNA and RNA. This is in sharp contrast with the behavior of the 2,4-dioxotriazine nucleus, which does not act as a nucleo-base in these systems.
- Mittapalli, Gopi Kumar,Reddy, Kondreddi Ravinder,Xiong, Hui,Munoz, Omar,Han, Bo,De Riccardis, Francesco,Krishnamurthy, Ramanarayanan,Eschenmoser, Albert
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p. 2470 - 2477
(2008/03/11)
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- Proteasome inhibitors and methods of using the same
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The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly or indirectly with proteasome activity.
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Page/Page column 44
(2008/06/13)
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- Facile way to synthesize Nα-Boc-Nβ-Cbz-2, 3-diaminopropionic acid derivatives via 5-oxazolidinone
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An economical and facile synthesis of Nα-Boc-N β-Cbz-2,3-diaminopropionic acid derivatives is reported. The key aspect of this method is employment of N-Boc-5-oxazolidinone moiety to simultaneously provide proper protection of α-amid
- Teng, Hanbing,Jiang, Zhengguo,Wu, Lamei,Su, Jiangtao,Feng, Xichun,Qiu, Guofu,Liang, Shucai,Hu, Xianming
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p. 3803 - 3807
(2007/10/03)
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- A metabolically stable tight-binding transition-state inhibitor of glyoxalase-I
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The design, synthesis, and enzyme kinetics evaluation of a transition-state inhibitor of glyoxalase-I is described. The union of the hydroxamic acid zinc-chelator with a urea isostere for the glu-cys amide bond led to a glutathione analog which retained inhibitory potency toward glyoxalase-I while possessing resistance toward γ-glutamyltranspeptidase mediated breakdown. This compound is viewed as a potential lead for the development of second-generation glyoxalase-I inhibitors wherein, the problems pertaining to metabolism and selectivity are overcome.
- More, Swati S.,Vince, Robert
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p. 6039 - 6042
(2007/10/03)
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- PEPTIDOMIMETICS SELECTIVE FOR THE SOMATOSTATIN RECEPTOR SUBTYPES 1 AND/OR 4
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The invention relates to (hetero)arylsulfonylamino based peptidomimetics of formula (I), wherein A, D, E, J, Q1 R1 , R2, R3, p and j are defined as disclosed, or a pharmaceutically acceptable salt or ester thereof. Compounds of formula (I) possess high affinity and selectivity for the somatostatin receptor subtypes sst1 and/or sst4 and can be used for the treatment or diagnosis of diseases or conditions wherein sst1 and/or sst4 agonists or antagonists are indicated to be useful.
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Page/Page column 37
(2010/11/24)
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- Studies on the mechanism of 1,2-dihydropyrazin-2-one ring formation from dipeptidyl chloromethyl ketone and its chemical properties: Immediate deamination during catalytic hydrogenation
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1,2-Dihydropyrazin-2-one derivatives, which have two aminoalkyl groups at the positions 3 and 6, were found to be efficient tools for the construction of potent, selective and long-acting opioid mimetics. During the course of preparation, we found that the catalytic hydrogenation of 3,6- bis(benzyloxycarbonylaminomethyl)-5-methyl-1,2-dihydropyrazin-2-one to remove the benzyloxycarbonyl groups resulted in a side reaction. By MS and NMR studies and by preparation of additional 1,2-dihydropyrazin-2-one derivatives, the structure of the by-product was identified as 3-aminomethyl-5,6-dimethyl-1,2- dihydropyrazin-2-one. Preparation of additional compounds substituted with deuterium provided us with sufficient information to confirm the structure of the product and to support a cyclization mechanism in its formation.
- Miyazaki, Anna,Fujisawa, Yutaka,Shiotani, Kimitaka,Fujita, Yoshio,Li, Tingyou,Tsuda, Yuko,Yokoi, Toshio,Bryant, Sharon D.,Lazarus, Lawrence H.,Okada, Yoshio
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p. 1152 - 1158
(2007/10/03)
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- PROTEASOME INHIBITORS AND METHODS OF USING THE SAME
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The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly of indirectly with proteasome activity.
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Page/Page column 224
(2008/06/13)
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- An Efficient Synthesis of a Probe for Protein Function: 2,3-Diaminopropionic Acid with Orthogonal Protecting Groups
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(Matrix presented) An efficient and cost-effective synthesis of N(α)-Boc2-N(β)-Cbz-2,3-diaminopropionic acid is reported. The synthesis starts from commercially available N(α)-Boc-Asp(OBn)-OH and employs a Curtius rearrangement to establish the β-nitrogen. Proper protection of the α-nitrogen is essential for the success of the Curtius rearrangement.
- Englund, Ethan A.,Gopi, Hosahudya N.,Appella, Daniel H.
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p. 213 - 215
(2007/10/03)
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- An approach toward the total synthesis of cyclotheonamides; preparation of a C(1) to N(14) segment
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The C(1) to N(14) segment of the potent thrombin inhibitor cyclotheonamide A was prepared from L-arginine, L-proline, and L-asparagine. The arginine backbone was extended via a cyanohydrin, and the usual diaminopropanoic acid residue was obtained from hypervalent iodine oxidation of the asparagine side chain.
- Wipf, Peter,Kim, Hong-Yong
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p. 4275 - 4278
(2007/10/02)
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- Synthesis and Antiviral Activity of Poly(β-L-α,β-diaminopropionic acid)
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Synthesis of a new polycation, poly(β-L-Dap), by polymerisation of Nα-Boc-Dap-OPcp and subsequent treatment of poly(Nα-Boc-β-L-Dap) with HBr/TFA/AcOH is described.The ability of this basic polypeptide to inhibit replication of Ranikh
- Gangopadhyay, A. K.,Mathur, K. B.
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p. 483 - 484
(2007/10/02)
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