- Antineoplastic activity of linear leucine homodipeptides and their potential mechanisms of action
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Galaxamide is a rare cyclic homopentapeptide composed of three leucines and two N-methyl leucines isolated from marine algae Galaxaura filamentosa. The strong antitumor activity of this compound makes it a promising candidate for tumor therapy. The synthesis of galaxamide, however, is a complex process, and it has poor water solubility. On the basis of its special chemical composition, we designed a series of linear leucine homopeptides. Among seven dipeptide derivatives, five compounds with terminal protection groups and methyl substitution of the hydrogen in the amido group showed remarkable inhibitory effects against various cancer cells. N-Tertbutyl-d-leucine-N-methyl-d-leucinebenzyl (A7), the only stereomer condensed by two d-leucines, showed the highest antineoplastic activity. A7-Treated cells showed cell cycle arrest and morphological changes typical of cells undergoing apoptosis. The population of Annexin-V positive/propidium iodide-negative cells also increased, indicating the induction of early apoptosis. A7 promoted the cleavage of caspase-9 and caspase-3, as well as increased intracellular Ca 2+ levels and decreased the mitochondrial membrane potential. Collectively, certain linear leucine dipeptides derived from cyclic pentapeptide are able to inhibit tumor cell proliferation through cell cycle arrest and apoptosis induction. The N-methyl group in the side chain and the d/l conformation of the amino-Acid residue are critical for their activity.
- Lei, Yun,Yang, Xiao-Xia,Guo, Wei,Zhang, Fu-Yong,Liao, Xiao-Jian,Yang, Hui-Fu,Xu, Shi-Hai,Xiong, Sheng
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p. 503 - 512
(2018/06/04)
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- Design, synthesis, and evaluation of cystargolide-based β-lactones as potent proteasome inhibitors
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The peptidic β-lactone proteasome inhibitors (PIs) cystargolides A and B were used to conduct structure-activity relationship (SAR) studies in order to assess their anticancer potential. A total of 24 different analogs were designed, synthesized and evaluated for proteasome inhibition, for cytotoxicity towards several cancer cell lines, and for their ability to enter intact cells. X-ray crystallographic analysis and subunit selectivity was used to determine the specific subunit binding associated with the structural modification of the β-lactone (P1), peptidic core, (Px and Py), and end-cap (Pz) of our scaffold. The cystargolide derivative 5k, structurally unique at both Py and P1, exhibited the most promising inhibitory activity for the β5 subunit of human proteasomes (IC50 = 3.1 nM) and significant cytotoxicity towards MCF-7 (IC50 = 416 nM), MDA-MB-231 (IC50 = 74 nM) and RPMI 8226 (IC50 = 41 nM) cancer cell lines. Cellular infiltration assays revealed that minor structural modifications have significant effects on the ability of our PIs to inhibit intracellular proteasomes, and we identified 5k as a promising candidate for continued therapeutic studies. Our novel drug lead 5k is a more potent proteasome inhibitor than carfilzomib with mid-to-low nanomolar IC50 measurements and it is cytotoxic against multiple cancer cell lines at levels approaching those of carfilzomib.
- Niroula, Doleshwar,Hallada, Liam P.,Le Chapelain, Camille,Ganegamage, Susantha K.,Dotson, Devon,Rogelj, Snezna,Groll, Michael,Tello-Aburto, Rodolfo
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supporting information
p. 962 - 977
(2018/09/04)
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- One-step preparation of enantiopure l- or d-amino acid benzyl esters avoiding the use of banned solvents
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The enantiomers of amino acid benzyl esters are very important synthetic intermediates. Many of them are currently prepared by treatment with benzyl alcohol and p-toluenesulfonic acid in refluxing benzene or carbon tetrachloride, to azeotropically remove water, and then precipitated as tosylate salt by adding diethyl ether. Here, we report a very efficient preparation of eight l- or d-amino acid benzyl esters (Ala, Phe, Tyr, Phg, Val, Leu, Lys, Ser), in which these highly hazardous solvents are dismissed using cyclohexane as a water azeotroping solvent and ethyl acetate to precipitate the tosylate salt. With some work-up modifications and lower yield, the procedure can be applied also to methionine. Chiral HPLC analysis shows that all the benzyl esters, including the highly racemizable ones such as those of phenylglycine, tyrosine and methionine, are formed enantiomerically pure under these new reaction conditions thus validating the solvents replacement. Contrariwise, toluene cannot be used in place of benzene or carbon tetrachloride because leading to partially or totally racemized amino acid benzyl esters depending on the polar effect of the amino acid α-side chain as expressed by Taft’s substituent constant (σ*).
- Bolchi, Cristiano,Bavo, Francesco,Pallavicini, Marco
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p. 965 - 974
(2017/04/11)
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- A One-Pot Synthesis of Symmetrical and Unsymmetrical Dipeptide Ureas
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We describe a flexible and high yielding synthesis of 1,3-disubstituted ureas that allows for the construction of both symmetrical and unsymmetrical dipeptide ureas, including easy access to 13C-labelled ureas, from amino acids and carbon dioxide at atmospheric pressure. We describe a flexible and high yielding synthesis of 1,3-disubstituted ureas, that allows for the construction of both symmetrical and unsymmetrical dipeptide ureas, including easy access to 13C labelled ureas, from amino acids and carbon dioxide at atmospheric pressure.
- Fayad, Antoine Abou,Pubill-Ulldemolins, Cristina,Sharma, Sunil V.,Day, David,Goss, Rebecca J. M.
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p. 5603 - 5609
(2015/09/01)
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- Esterification of unprotected a-Amino acids in ionic liquids as the reaction media
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Ionic liquid 1,3-dimethylimidazolium methanesulfonate was used to prepare a-amino acids benzylic esters from unprotected amino acids and benzyl chloride. Esterification of several amino acids was achieved with satisfactory yields: by-products can be removed by a simple work-up procedure to afford the pure product. The described method is simple, mild, rapid and save.
- Biondini, Daniele,Brinchi, Lucia,Germani, Raimondo,Goracci, Laura,Savelli, Gianfranco
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experimental part
p. 39 - 44
(2010/08/22)
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- Microwave-assisted synthesis of pyridylpyrroles from N-acylated amino acids
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A small library of 3- and 4-pyridyl-substituted pyrroles was prepared from N-acylated amino acids. Nicotinoyl or isonicotinoyl chloride was used for the N-acylation of benzyl esters of amino acids. Debenzylation by palladium-catalyzed hydrogenation gave N-acylated amino acids. Dehydration of the acylated amino acids gave cyclic intermediates, münchnones or azlactones, which were treated in situ with alkynes in 1,3-dipolar cycloadditions. The starting materials were prepared in a parallel fashion, and microwave irradiation was used to facilitate the cycloaddition reactions. The regiochemistry of the cycloaddition was studied.
- Harju, Kirsi,Manevski, Nenad,Yli-Kauhaluoma, Jari
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supporting information; experimental part
p. 9702 - 9706
(2010/02/27)
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- Antiviral phosphoramidates
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The invention provides novel nucleoside compounds of formula I wherein R1, R2a, R2b, R3, R4, R5, R6, R8a, R9 and R10 are as defined herein which are useful for the treatment of Hepatitis C Virus (HCV) mediated diseases. The invention further provides methods for treatment or prophylaxis of HCV mediated diseases with compounds of formula I and pharmaceutical compositions comprising these compounds,
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Page/Page column 18
(2008/06/13)
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- Studies on Angiotensin Converting Enzyme Inhibitors. 4. Synthesis and Angiotensin Converting Enzyme Inhibitory Activities of 3-Acyl-1-alkyl-2-oxoimidazolidine-4-carboxylic Acid Derivatives
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(4S)-1-Alkyl-3-acyl>-2-oxoimidazolidine-4-carboxylic acid derivatives (3) were prepared by two methods.Their angiotensin converting enzyme (ACE) inhibitory activities and antihypertensive effects were evaluated, and the structure-activity relationships were discussed.The dicarboxylic acids 3a-n possessing S,S,S configuration showed potent in vitro ACE inhibitory activities with IC 50 values of 1.1x10-8-1.5x10-9 M.The most potent compound in this series, monoester 3p, had an ID 50 value of 0.24 mg/kg, po for inhibition of angiotensin I induced pressor response in normotensive rats and produced a dose-dependent decrease in systolic blood pressure of spontaneously hypertensive rats (SHRs) at doses of 1-10 mg/kg, po.
- Hayashi, Kimiaki,Nunami, Ken-ichi,Kato, Jyoji,Yoneda, Naoto,Kubo, Masami,et al.
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p. 289 - 297
(2007/10/02)
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- Application of 4-Polystyryltriphenylmethyl Chloride to the Syntheses of Peptides and Amino Acid Derivatives
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Use of polymer-bound trityl chloride as an α-amino protecting group of amino acids allows simple and high-yield syntheses of amino acid derivatives and peptides.
- Barlos, Kleomenis,Gatos, Dimitrios,Kallitsis, Ioannis,Papaioannou, Dionysios,Sotiriou, Petros
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p. 1079 - 1082
(2007/10/02)
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- Threonyl-valyline leucine containing peptides and pharmaceutical compositions
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Polypeptides, omega-N-acylated and/or hydrocarbon-containing esters or amides of polypeptides are useful in the treatment of schizophrenia. The polypeptide-containing materials have a characteristic T-V-L structure, i.e., STR1 The preferred compositions are N-acylated T-V-L containing polypeptides, especially amides.
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