- 6-Halo-2-pyridone as an efficient organocatalyst for ester aminolysis
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It was found that 6-halo-2-pyridones catalysed ester aminolysis in which not only reactive aryl esters but also relatively less reactive methyl and benzyl esters could be used as a substrate. The reaction could be performed without strictly dry and anaerobic conditions and the 6-chloro-2-pyridone catalyst could be recovered quantitatively after reaction. The method could be applied to dipeptide synthesis from methyl or benzyl esters of amino acids, where a high enantiomeric purity of the products was maintained. The mechanism involving dual activation of ester and amine substrates through hydrogen bonding between catalyst and substrates is proposed where 6-halo-2-pyridones act as a bifunctional Br?nsted acid/base catalyst.
- Okamoto, Sentaro,Watanabe, Yusuke,Yamada, Takeshi
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- Dual-protected amino acid derivatives as new antitubercular agents
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Tuberculosis is an infectious disease with high incidence and growing drug-resistant rates. In an attempt to develop new antitubercular agents, 35 compounds were synthesized, most of them bearing a carbamate and enantiopure amino acid moiety. These compounds had their activity evaluated toward a Mycobacterium tuberculosis strain (ATCC 27294) and cytotoxicity against fibroblast MRC-5 cells (ATCC CCL-171). Three of the prepared derivatives presented a good antimicrobial inhibition and two of them a moderate cytotoxicity. The lipophilicity seems to play a vital role in the cell growth activity, with best results for the derivatives with a higher logP.
- de Castro, Pedro P.,Campos, Débora L.,Pavan, Fernando R.,Amarante, Giovanni W.
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- Asymmetric enolate alkylation via templation with chiral synthetic receptors
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C3-Symmetric chiral receptors have been developed for enantioselective alkylation of sodium enolates of active methylene compounds. It has been demonstrated that a 1:1 binding complex forms between these receptors and sodium enolates in THF-d8/CD3CN by 1H NMR titration experiments. Moderate enantiomeric enrichment of the benzylation product of 2-acetylcyclohexanone has been demonstrated using this strategy. Templation of enolate alkylation by synthetic receptors represents a new approach to asymmetric induction.
- Postnikova, Brenda J.,Anslyn, Eric V.
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- Direct amidation of non-activated carboxylic acid and amine derivatives catalyzed by TiCp2Cl2
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This paper described a mild and efficient direct amidation of non-activated carboxylic acid and amine derivatives catalyzed by TiCp2Cl2. Arylacetic acid derivatives reacted with different amines to afford the corresponding amides in good to excellent yield except of aniline. Aryl formic acids failed to react with aniline but smoothly reacted with aliphatic amines and benzylamine in moderate to good yield, fatty acids reacting with benzyl and aliphatic amines give amides in good to excellent yield. Chiral amino acids derivatives were transformed into amides without racemization in moderate yield. The possible mechanism of direct amidation catalyzed by TiCp2Cl2 was discussed. This catalytic method is very suitable for the amidation of low sterically hindered arylacetic acid, fatty acids with different low sterically hindered amines except aniline, as well as the amidation of aryl formic acid with benzyl and aliphatic amines.
- Wang, Hui,Dong, Wei,Hou, Zhipeng,Cheng, Lidan,Li, Xiufen,Huang, Longjiang
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- Cytotoxic activity of synthetic chiral amino acid derivatives
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Cancer is a chronic degenerative disease considered one of the most important causes of death worldwide. In this context, a series of dual-protected amino acid derivatives was synthesized and evaluated as potential novel anticancer agents. The 40 derivatives were prepared in up to three reaction steps. The cytotoxic activities were screened in vitro against a panel of tumor and non-tumor cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Among the synthesized derivatives, three of them showed promising activity against cancer cells with half-maximal inhibitory concentration (IC50) ranging between 1.7-6.1 μM. The most promising derivative, bearing both a lipophilic N-alkyl diamine moiety and a protected amino acid scaffold showed a selectivity index of 3.4 towards tumor cells. The N-alkyl diamine moiety seems to play a crucial role in the enhancement of the anticancer activity. On the other hand, the incorporation of an amino acid scaffold resulted in increase in the selectivity towards cancer cell lines.
- de Castro, Pedro P.,Siqueira, Raoni P.,Conforte, Luiza,Franco, Chris H.J.,Bressan, Gustavo C.,Amarante, Giovanni W.
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p. 193 - 200
(2019/12/28)
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- Study on anti-proliferative activity in cancer cells and preliminary structure–activity relationship of pseudo-peptide chiral thioureas
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In our previous studies, we have shown that thiourea compounds containing phosphate esters have potent antitumor activity and can be used as a novel strategy for the development of antitumor agents. Herein, a series of novel phosphonate thioureas 5–38 have been synthesized, which were fully characterized by 1H NMR,13C NMR spectrum, elemental analysis. Three human cancer cell lines (Bcap-37, BGC-823, and PC-3) have been used to investigate these compounds’ antitumor activities. After the summarization of the structure–activity relationships, we found that the variation of R, R1, and R2 in these novel phosphonate thioureas contribute to the antitumor activities. All these SAR-guided efforts may lead to novel antitumor drugs in the market in the near future.
- Liao, Peng,Hu, Shi-Qin,Zhang, Hong,Xu, Liang-Bi,Liu, Jing-Zi,He, Bin,Liao, Shang-Gao,Li, Yong-Jun
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p. 300 - 304
(2018/02/15)
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- [...] - Orn (ClCH2NH) - AA - benzylamine, its synthesis, activity and application (by machine translation)
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The invention discloses the following formula of 13 for β - Carboline -3 - formyl - Orn (ClCH2 NH) - AA - NHCH2 C6 H5 (In the formula AA is selected from L - Arg, L - Asn, L - Asp, L - Glu, L - Gly, L - Ile, L - Leu, L - Met, L - Phe, L - Pro, L - Thr, L - Trp, L - Val residue), discloses a process for their preparation, discloses their inhibition of tumor cell growth, therefore this invention discloses their use as anti-tumor medicament. (by machine translation)
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Paragraph 0041; 0100; 0101
(2017/08/27)
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- Hafnium-catalyzed direct amide formation at room temperature
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Herein, the first example of a metal-catalyzed protocol for direct amidation of nonactivated carboxylic acids at ambient temperature (26 °C) is presented. The mild reaction conditions give rise to high yields of a range of amides in reaction times as short as 90 min, employing a commercial hafnium complex, [Hf(Cp)2Cl2], as catalyst. Amino acids are transformed into their corresponding amides without racemization, and the catalyst displays full selectivity for the amidation of carboxylic acids over esters. Electronic properties of the carboxylic acids were found to have a strong influence on the rate of the amidation reaction, and the need for a balanced amount of molecular sieves was observed to be highly important for optimal reaction outcome.
- Lundberg, Helena,Adolfsson, Hans
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p. 3271 - 3277
(2015/06/16)
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- Sodium methoxide: A simple but highly efficient catalyst for the direct amidation of esters
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A simple NaOMe catalyst provides superior accessibility to a wide variety of functionalized amides including peptides through direct amination of esters in an atom-economical and environmentally benign way.
- Ohshima, Takashi,Hayashi, Yukiko,Agura, Kazushi,Fujii, Yuka,Yoshiyama, Asako,Mashima, Kazushi
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supporting information; experimental part
p. 5434 - 5436
(2012/07/03)
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- Catalyst and solvent-free amidation of inactive esters of N-protected amino acids
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A catalyst free procedure for the preparation of amides from inactive esters of N-protected amino acids and various amines is demonstrated under mild reaction conditions. Our effort to recover excess amine and generated alcohol is an approach towards environment friendly and cost effective synthesis under easy operational conditions.
- Nadimpally, Krishna Chaitanya,Thalluri, Kishore,Palakurthy, Nani Babu,Saha, Abhijit,Mandal, Bhubaneswar
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p. 2579 - 2582
(2011/06/21)
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- NEW COMPOUNDS
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The invention provides compounds of the formula I wherein Q is aryl or heterocyclyl any of which is optionally substituted; Z is O, S, NRa or S(=O)p; Y is NH, NHNH, CH2NH, O, S or S(=O)p; n is 0, 1, 2 or 3; m is 0, 1 or 2; p is 1 or 2; Ra is H or C1-C4alkyl; R1 is hydrogen, C1-C6alkyl, C0-C3alkanediylC3-C7cycloalkyl, C0-C3alkanediylaryl or C0- C3alkanediylheterocyclyl; R2 is hydrogen or C1-C6alkyl; X' is hydrogen, fluoro, hydroxy, amino or C1-C6alkoxy; X" is hydrogen, or when X' is fluoro, then X" may also be fluoro; R3is C1-C6alkyl; R4' is C1-C6alkyl; R4" is H or C1-C6alkyl; or R4' and R4" together with the carbon atom to which they are attached define a C3-C6cycloalkyl; W is C1-C6alkyl, C3-C7cycloalkyl, aryl or heterocyclyl any of which is optionally substituted; or a pharmaceutically acceptable salt, hydrate or N-oxide thereof. The compounds of the invention are inhibitors of aspartyl proteases such as renin and are among other things useful for the treatment of conditions associated with activities of the RAS, such as hypertension, heart failure and renal insufficiency.
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Page/Page column 63
(2008/12/07)
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- A chiral primary amine thiourea catalyst for the highly enantioselective direct conjugate addition of α,α-disubstituted aldehydes to nitroalkenes
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(Chemical Equation Presented) Dual activation: The bifunctional primary amine thiourea catalyst 1 promotes the highly enantioselective direct conjugate addition of α-branched aldehydes to nitroalkenes (see scheme). Cooperative activation of both the nucleophile and electrophile allows the use of mild reaction conditions and provides access to a wide variety of adducts with vicinal quaternary and tertiary stereogenic centers (>90% ee).
- Lalonde, Mathieu P.,Chen, Yonggang,Jacobsen, Eric N.
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p. 6366 - 6370
(2007/10/03)
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- PEPTIDIC COMPOUNDS
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The present invention provides a compound of formula (I), (II), (III) and (IV) as defined herein and pharmaceutically acceptable derivatives thereof. The present invention further provides use of the compounds of the present invention in the treatment of bacterial infection and in the treatment of HIV infection. Also provided are pharmaceutical compositions comprising the compounds of the present invention.
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Page/Page column 67
(2008/06/13)
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- Tripodal peptides with chiral conformations stabilized by interstrand hydrogen bonds
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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
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p. 6653 - 6661
(2007/10/02)
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- N-Haloacetyl-amino-acid amides as active-site-directed inhibitors of papain and cathepsin B
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A series of N-haloacetyl-amino-acid amides were synthesized and tested as models of cysteine-protease inhibitors. They irreversibly inactivated papain and cathepsin B via a reversible enzyme-inhibitor intermediate. Apparent second-order rate constants of inactivation ranging from 65 to 16,700 M-1 s-1 were observed. Reactivity against papain, as compared to glutathione, was increased 16,400-fold for N-bromoacetyl-leucine isopentylamide and 25,700-fold for the corresponding iodoacetyl derivative; these increases are probably due to proximity effects. No inhibition of trypsin, chymotrypsin and porcine pancreatic elastase was observed. Haloacetamides represent an interesting class of easily synthesized, efficient, irreversible inhibitors of cysteine proteases, which have low non-specific alkylating properties.
- Girodano,Gallina,Ottaviano,Consalvi,Scandurra
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p. 865 - 873
(2007/10/02)
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- Design and synthesis of HIV protease inhibitors. Variations of the carboxy terminus of the HIV protease inhibitor L-682,679
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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
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p. 2852 - 2857
(2007/10/02)
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- A Stereocontrolled Synthesis of Hydroxyethylene Dipeptide Isosteres Using Novel, Chiral Aminoalkyl Epoxides and γ-(Aminoalkyl) γ-Lactones
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A stereocontrolled synthesis of the hydroxyethylene dipeptide isosteric unit 1 is described.This synthesis is capable of providing all eight stereoisomers of 1 and is amenable to variation of substituents R1 and R2.Also described are the novel chiral epoxides 2 and substituted γ-lactones 3, key intermediates in this synthesis having potentially broad application.
- Evans, Ben E.,Rittle, Kenneth E.,Homnick, Carl F.,Springer, James P.,Hirshfield, Jordan,Veber, Daniel F.
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p. 4615 - 4625
(2007/10/02)
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