cas 3392-12-9, tert-Butoxycarbonyl-L-valine N-hydroxysuccinimide ester

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2-AMINO-N-(AMINO-OXO-ARYL-LAMBDA6-SULFANYLIDENE)ACETAMIDE COMPOUNDS AND THEIR THERAPEUTIC USE
The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain 2-amino-N-(amino-oxo-aryl-λ6- sulfanylidene)acetamide compounds (referred to herein as ANASIA compounds) that, inter alia, inhibit (e.g., selectively inhibit) bacterial aminoacyl-tRNA synthetase (aaRS) (e.g., bacterial leucyl-tRNA synthetase, LeuRS). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit (e.g., selectively inhibit) bacterial aminoacyl-tRNA synthetase; to treat disorders that are ameliorated by the inhibition (e.g., selective inhibition) of bacterial aminoacyl-tRNA synthetase; to treat bacterial infections; etc.
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Page/Page column 97; 98

(2021/06/26)

The antibody-drug conjugate hemiasterlin derivatives and their pharmaceutically (by machine translation)
[Problem] to give one specific target cell cytotoxic, normal cells to the cytotoxic is suppressed, the antibody-drug conjugate medicine hemiasterlin derivatives. (2) Formula [a]:[In the formula, mAb antibody expressed, q is 1 - 8 represents an integer of, h are 1 - 5 represents an integer of, g is an alanine residue (Ala) to represent, g is 1 - 4 represents an integer of, Y is a single bond or a formula (Y-a 1) is represented by the group, Z is formula (Z-a 1), equation (Z-a 2), equation (Z-a 3), formula (Z-a 4), formula (Z-a 5), type (Z-a 6), formula (Za-a 1), equation (Za-in 2), equation (Za-a 3), formula (Za-a 4), formula (Za-a 5), type (Za d 6), formula (Za-a 7), type (Za-in 8), or a group represented by formula (Za-a 10) (Za-a 9) formula a] is expressed by, antibody-drug conjugate or its pharmaceutically acceptable salt containing a drug. [Drawing] no (by machine translation)
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Paragraph 0384; 0388; 0428-0429

(2020/12/01)

An optimal “Click” formulation strategy for antibody-drug conjugate synthesis
As a versatile reaction for bioconjugation, Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC) has enormous potential in the synthesis of antibody-drug conjugates (ADCs). In order to optimize CuAAC-based ADC synthesis, we characterized kinetically different formulation processes by mimicking ADC synthesis using small molecules and subsequently revealed unique kinetic behaviors of different combinations of alkyne and azide conditions. Our results indicate that under ADC synthesis conditions, for an alkyne-containing drug, its concentration has minimal impact on the reaction rate when an antibody has a non-metal-chelating azide but is proportional to concentration when an antibody contains a metal-chelating azide; however, for an alkyne-containing antibody, the ADC synthesis rate is proportional to the concentration of a drug with a non-metal-chelating azide but displays almost no dependence on drug concentration with a metal-chelating azide. Based on our results, we designed and tested an optimal “click” formulation strategy that allowed rapid and cost-effective synthesis of a new ADC.
Vatansever, Erol C.,Kang, Jeffrey,Tuley, Alfred,Ward, E. Sally,Liu, Wenshe Ray
supporting information

(2020/10/20)

Binding and Action of Amino Acid Analogs of Chloramphenicol upon the Bacterial Ribosome
Antibiotic chloramphenicol (CHL) binds with a moderate affinity at the peptidyl transferase center of the bacterial ribosome and inhibits peptide bond formation. As an approach for modifying and potentially improving properties of this inhibitor, we explored ribosome binding and inhibitory activity of a number of amino acid analogs of CHL. The L-histidyl analog binds to the ribosome with the affinity exceeding that of CHL by 10 fold. Several of the newly synthesized analogs were able to inhibit protein synthesis and exhibited the mode of action that was distinct from the action of CHL. However, the inhibitory properties of the semi-synthetic CHL analogs did not correlate with their affinity and in general, the amino acid analogs of CHL were less active inhibitors of translation in comparison with the original antibiotic. The X-ray crystal structures of the Thermus thermophilus 70S ribosome in complex with three semi-synthetic analogs showed that CHL derivatives bind at the peptidyl transferase center, where the aminoacyl moiety of the tested compounds established idiosyncratic interactions with rRNA. Although still fairly inefficient inhibitors of translation, the synthesized compounds represent promising chemical scaffolds that target the peptidyl transferase center of the ribosome and potentially are suitable for further exploration.
Tereshchenkov, Andrey G.,Dobosz-Bartoszek, Malgorzata,Osterman, Ilya A.,Marks, James,Sergeeva, Vasilina A.,Kasatsky, Pavel,Komarova, Ekaterina S.,Stavrianidi, Andrey N.,Rodin, Igor A.,Konevega, Andrey L.,Sergiev, Petr V.,Sumbatyan, Natalia V.,Mankin, Alexander S.,Bogdanov, Alexey A.,Polikanov, Yury S.
p. 842 - 852
(2018/02/26)

MAYTANSINOID DERIVATIVES, CONJUGATES THEREOF, AND METHODS OF USE
Provided herein are maytansinoid derivatives, conjugates thereof, and methods of treating or preventing proliferative diseases with the same.
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Paragraph 0444; 0445

(2016/10/27)

SITE-SPECIFIC CONJUGATION THROUGH GLYCOPROTEINS LINKAGE AND METHOD THEREOF
A method for specific linkage to a glycoprotein includes obtaining a glycoprotein having a monoglycan or diglycan attached thereto; producing a reactive functional group on a sugar unit on the glycoprotein; and coupling a linker or a payload to the reactive functional group on the glycoprotein.
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Paragraph 00068; 00069; 00070

(2016/07/27)

An efficient and cost-effective approach to kahalalide F N-terminal modifications using a nuisance algal bloom of Bryopsis pennata
Background: Kahalalide F (KF) and its isomer iso-kahalalide F (isoKF), both of which can be isolated from the mollusk Elysia rufescens and its diet alga Bryopsis pennata, are potent cytotoxic agents that have advanced through five clinical trials. Due to a short half-life, narrow spectrum of activity, and a modest response in patients, further efforts to modify the molecule are required to address its limitations. In addition, due to the high cost in producing KF analogues using solid phase peptide synthesis (SPPS), a degradation and reconstruction approach was employed using natural KF from a seasonal algal bloom to generate KF analogues. Methods: N-protected KF was carefully hydrolyzed at the amide linkage between L-Thr12 and D-Val13 using dilute HCl. The synthesis of the C-terminal fragment began with the formation of hexanoic succinimide ester, followed by a reaction with dipeptides. The final coupling reaction was performed between the semisynthesized Fmoc-KF hydrolysis product and the C-terminal fragment, followed by the deprotection of the Fmoc group. Results: Six KF analogues with an addition of an amino acid residue on the N-terminal chain, D-Val14-isoKF (2), Val13-Val14-isoKF (3), D-Leu14-isoKF (4), D-Pro14-isoKF (5), D-Phe14-isoKF (6), and 3,4-2F-D-Phe14-isoKF (7) were prepared using semisynthesis at the exposed N-terminal chain. Conclusions: The overall yield of the medication was 45%. This approach is economical, efficient and amendable to large-scale production while eliminated a nuisance algal bloom. General significance: B. pennata blooms are capable of producing KF in good yields. The semisynthesis from the natural product produced N-terminal modifications for the construction of inexpensive semisynthetic KF libraries.
Wang, Bin,Waters, Amanda L.,Valeriote, Frederick A.,Hamann, Mark T.
p. 1849 - 1854
(2015/06/08)

ANTI-FOLATE RECEPTOR APLHA (FRA) ANTIBODY-DRUG CONJUGATES AND METHODS OF USING THEREOF
The present disclosure provides anti-folate receptor alpha (FRA) antibody-drug conjugates comprising a hydrophilic self-immolative linker. The present disclosures further provide compositions and methods for treating cancers.
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Paragraph 0269; 0273

(2016/06/28)

HYDROPHILIC SELF-IMMOLATIVE LINKERS AND CONJUGATES THEREOF
The present disclosure provides compounds with a hydrophilic self-immolative linker, which is cleavable under appropriate conditions and incorporates a hydrophilic group to provide better solubility of the compound. The compounds of the present disclosure comprise a drug moiety, a targeting moiety capable of targeting a selected cell population, and a linker which contains an acyl unit, an optional spacer unit for providing distance between the drug moiety and the targeting moiety, a peptide linker which can be cleavable under appropriate conditions, a hydrophilic self-immolative linker, and an optional second self-immolative spacer or cyclization self-elimination linker.
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Paragraph 240; 244

(2014/07/08)

PRODRUGS OF GUANFACINE
Prodrugs of guanfacine with amino acids or short peptides, pharmaceutical compositions containing such prodrugs and a method for providing therapeutic benefit in the treatment of ADHD/ODD (attention deficient hyperactivity disorder and oppositional defiance disorder) with guanfacine prodrugs are provided herein. Additionally, methods for minimizing or avoiding the adverse gastrointestinal side effects associated with guanfacine administration, as well as improving the pharmacokinetics of guanfacine are provided herein.
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Page/Page column 23-24

(2011/04/18)

A facile synthesis and crystallographic analysis of N-protected β-amino alcohols and short peptaibols
A facile, efficient and racemization-free method for the synthesis of N-protected β-amino alcohols and peptaibols using N-hydroxysuccinimide active esters is described. Using this method, dipeptide, tripeptide and pentapeptide alcohols were isolated in high yields. The conformations in crystals of β-amino alcohol, dipeptide and tripeptide alcohols were analysed, with a well-defined type III β-turn being observed in the tripeptide alcohol crystals. This method is found to be compatible with Fmoc-, Boc- and other side-chain protecting groups.
Jadhav, Sandip V.,Bandyopadhyay, Anupam,Benke, Sushil N.,Mali, Sachitanand M.,Gopi, Hosahudya N.
supporting information; experimental part
p. 4182 - 4187
(2011/06/28)

Procedure for the oxidation of β-amino alcohols to α-amino aldehydes
A novel procedure for the mild oxidation of β-amino alcohols to α-amino aldehydes using commercially available manganese(IV) oxide is reported. There are several important advantages of the new method, such as high enantiopurity of the reaction and the absence of either over-oxidation or any reaction by-products during the process. A number of N-protected L-α-amino aldehydes was obtained. All new compounds were characterized by their NMR spectra and optical rotation data. Georg Thieme Verlag Stuttgart.
Sergeev, Maxim E.,Pronin, Victor B.,Voyushina, Tatiana L.
p. 2802 - 2804
(2007/10/03)

CYCLIC HEMIACETAL DERIVATIVE AND USE THEREOF
A compound represented by the following formula (I) wherein R1 is a lower alkyl group, R2 is a hydrogen, a halogen, a cyano group, a lower alkyl group or a lower alkoxy group, and n is 0 or 1, which has a calpain inhibitory activity, is provided.
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Page 8

(2010/02/09)

O-succinimidyl-1,3-dimethyl-1,3-trimethyleneuronium salts as efficient reagents in active ester synthesis
The new uronium salts O-succinimidyl-1,3-dimethyl-1,3-trimethyleneuronium hexafluorophosphate (HSDU) and tetrafluoroborate (TSDU) have been prepared from 1,3-dimethylpropyleneurea (DMPU) and employed in the synthesis of N-hydroxysuccinimide-derived active esters. High yields were obtained at room temperature in short reaction times and no racemization was observed.
Bailén, Miguel A,Chinchilla, Rafael,Dodsworth, David J,Nájera, Carmen
p. 1661 - 1664
(2007/10/03)

Combinatorial synthesis through disulfide exchange: Discovery of potent psammaplin A type antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA)
Psammaplin A is a symmetrical bromotyrosine-derived disulfide natural product isolated from the Psammaplysilla sponge, which exhibits in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Inspired by the structure of this marine natural product, a combinatorial scrambling strategy for the construction of heterodimeric disulfide analogues was developed and applied to the construction of a 3828-membered library starting from 88 homodimeric disulfides. These psammaplin A analogues were screened directly against various gram positive bacterial strains leading to the discovery of a series of potent antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA). Among the most active leads derived from these studies are compounds 104, 105, 113, 115, 123, and 128. The present, catalytically-induced, disulfide exchange strategy may be extendable to other types of building blocks bearing thiol groups facilitating the construction of diverse discovery-oriented combinatorial libraries.
Nicolaou,Hughes, Robert,Pfefferkorn, Jeffrey A.,Barluenga, Sofia,Roecker
p. 4280 - 4295
(2007/10/03)

Inhibition of human neutrophil elastase. 4. Design, synthesis, X-ray crystallographic analysis, and structure-activity relationships for a series of P2-modified, orally active peptidyl pentafluoroethyl ketones
A series of P2-modified, orally active peptidic inhibitors of human neutrophil elastase (HNE) are reported. These pentafluoroethyl ketone-based inhibitors were designed using pentafluoroethyl ketone 1 as a model. Rational structural modifications were made at the P3, P2, and activating group (A(G)) portions of 1 based on structure-activity relationships (SAR) developed from in vitro (measured K(i)) data and information provided by modeling studies that docked inhibitor 1 into the active site of HNE. The modeling-based design was corroborated with X-ray crystallographic analysis of the complex between 1 and porcine pancreatic elastase (PPE) and subsequently the complex between 1 and HNE.
Cregge, Robert J.,Durham, Sherrie L.,Farr, Robert A.,Gallion, Steven L.,Hare, C. Michelle,Hoffman, Robert V.,Janusz, Michael J.,Kim, Hwa-Ok,Koehl, Jack R.,Mehdi, Shujaath,Metz, William A.,Peet, Norton P.,Pelton, John T.,Schreuder, Herman A.,Sunder, Shyam,Tardif, Chantal
p. 2461 - 2480
(2007/10/03)

New peptidyl-anthraquinones: Synthesis and DNA binding
Aminoacyl-hydroxy-anthraquinones bearing glicyl, valyl, lysyl and tryptophanyl residues in the side-chain were synthesized as new potential DNA-directed drugs. These compounds bind very tightly to double-stranded DNA by intercalating their planar portion into the nucleic acid and further stabilizing the complex through electrostatic contacts with the backbone phosphates. All protonated groups in the side-chains participate in the latter process. The free energy of DNA-binding corrected for the electrostatic contribution is similar for the lysyl and glicyl derivatives, which points to a common geometry of intercalation.
Zagotto, Giuseppe,Mitaritonna, Giovanni,Sissi, Claudia,Palumbo, Manlio
p. 2135 - 2141
(2007/10/03)

Tripodal peptides with chiral conformations stabilized by interstrand hydrogen bonds
C3 symmetric trispeptides are described that form chiral conformations and are therefore eminently suited to provide a new family of chiral receptor molecules when extended by appropriate binding sites. These trispeptides are composed of C3 symmetric trisamines as anchors and three symmetrically extending chiral amino acid residues. Their conformations in apolar solvents fall into two main classes. One is comprised of propeller-like conformations of preferred chiral sense that are stabilized by a belt of intramolecular H-bonds (hydrogen bonds) between adjacent strands. The other class has two of its strands connected by two H-bonds to form a 10-membered ring, while the third strand may hydrogen-bond to one of the other two. The effect of the anchors and amino acids on the relative stability of the H-bonded, chiral conformations has been established by a combination of spectroscopic and theoretical means. Trispeptides derived from more lipophilic α-amino acids show a higher population of the chiral conformations. Moreover, trispeptides that are based on tris(2-aminoethyl)amine (TREN) as anchor form stronger H-bonds than those relying on 1,3,5-tris(aminomethyl)benzene (TRAM).
Tor, Yitzhak,Libman, Jacqueline,Shanzer, Abraham,Felder, Clifford E.,Lifson, Shneior
p. 6653 - 6661
(2007/10/02)

An improved method for the synthesis of active esters of N-protected amino acids and subsequent synthesis of dipeptides
4-Dimethylaminopyridine-catalyzed reaction of mixed carbonates 3 with N-protected amino acids 4 gave the corresponding active esters 5-9, from which dipeptides 11-18 were synthesized by aminolysis with amino acids 10.
Takeda,Ayabe,Suzuki,Konda,Harigaya
p. 689 - 691
(2007/10/02)

Design and synthesis of HIV protease inhibitors. Variations of the carboxy terminus of the HIV protease inhibitor L-682,679
A series of tetrapeptide analogues of 1 (L-682,679), in which the carboxy terminus has been shortened and modified, was prepared and their inhibitory activity measured against the HIV protease in a peptide cleavage assay. Selected examples were tested as inhibitors of virus spread in cell culture. Compound 12 was a 10-fold more potent enzyme inhibitor than 1 in vitro and 30-fold more potent in inhibiting the viral spread in cells.
DeSolms,Giuliani,Guare,Vacca,Sanders,Graham,Wiggins,Darke,Sigal,Zugay,Emini,Schleif,Quintero,Anderson,Huff
p. 2852 - 2857
(2007/10/02)

Novel Preparation of N-Protected Amino Acid Active Esters Using 1,2,2,2-Tetrachloroethyl Carbonates
1,2,2,2-Tetrachloroethyl chloroformate reacts with substituted phenols or N-hydroxy imides to yield crystalline and stable mixed aryl or oximido tetrachloroethyl carbonates.When allowed to react with an N-protected amino acid derivative, these compounds proved to be efficient for the syntheses of the corresponding active esters.A series of active esters including p-nitrophenol, trichlorophenol, pentafluorophenol, and N-hydroxysuccinimide derivatives were prepared by this new procedure.
Jaoudai, Mahmoud,Martinez, Jean,Castro, Bertrand
p. 2364 - 2367
(2007/10/02)

Synthesis of the dolastatin 3 isomer cyclo-[L-Pro-L-Leu-L-Val-(R,S)-(gln)Thz-(gly)Thz]
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Pettit,Holzapfel
p. 4580 - 4585
(2007/10/02)

LE CHLOROFORMIATE D'ISOPROPENYLE (IPCF) EN CHIMIE DES AMINO-ACIDES ET DES PEPTIDES - III SYNTHESE D'ESTERS ACTIFS D'AMINO ACIDES N-PROTEGES
Isopropenyl chloroformate (IPCF) was used for preparation of mixed carbonates (Aryl and isopropenyl) which are very suitable reagents for active ester synthesis of amino acid derivatives (Boc derivatives in particular).
Jaouadi, M.,Selve, C.,Dormoy, J. R.,Castro, B.,Martinez, J.
p. 1721 - 1722
(2007/10/02)

FORMATION CONSTANTS OF SILVER(I) COMPLEXES OF SOME SULPHUR-CONTAINING DIPEPTIDES AND VALYLVALINE
Formation constants at 25 deg C and l = 0.10 mol dm-3 (KNO3) have been determined for the complexes of AgI with a range of nine dipeptides which incorporate side-chains containing one (glycylmethionine and methionylglycine) or two sulphur donor atoms.In the latter case dipeptides formed from amino acids of the same and of different chiralities were studied (e.g.L-methionyl-L-methionine and L-methionyl-D-methionine).The results are compared with those for valylvaline.Values for the formation constants are interpreted in terms of the preferred conformations of the dipeptides, and the tendency for AgI to bond to S-donor atoms or to adopt linear co-ordination through the formation of dimeric complexes.
Lyons, Anthony Q.,Pettit, Leslie D.
p. 2305 - 2308
(2007/10/02)