103478-62-2Relevant articles and documents
Design and synthesis of analogues of marine natural product galaxamide, an N-methylated cyclic pentapeptide, as potential anti-tumor agent in vitro
Lunagariya, Jignesh,Zhong, Shenghui,Chen, Jianwei,Bai, Defa,Bhadja, Poonam,Long, Weili,Liao, Xiaojian,Tang, Xiaoli,Xu, Shihai
, (2016)
Herein, we report design and synthesis of novel 26 galaxamide analogues with N-methylated cyclo-pentapeptide, and their in vitro anti-tumor activity towards the panel of human tumor cell line, such as, A549, A549/DPP, HepG2 and SMMC-7721 using MTT assay. We have also investigated the effect of galaxamide and its representative analogues on growth, cell-cycle phases, and induction of apoptosis in SMMC-7721 cells in vitro. Reckon with the significance of conformational space and N-Me aminoacid (aa) comprising this compound template, we designed the analogues with modification in N-Me-aa position, change in aa configuration from L to D aa and substitute one Leu-aa to D/L Phe-aa residue with respective to the parent structure. The efficient solid phase parallel synthesis approach is employed for the linear pentapeptide residue containing N-Me aa, followed by solution phase macrocyclisation to afford target cyclo pentapeptide compounds. In the present study, all galaxamide analogues exhibited growth inhibition in A549, A549/DPP, SMMC-7721 and HepG2 cell lines. Compounds 6, 18, and 22 exhibited interesting activities towards all cell line tested, while Compounds 1, 4, 15, and 22 showed strong activity towards SMMC-7221 cell line in the range of 1-2 μg/mL IC50. Flow cytometry experiment revealed that galaxamide analogues namely Compounds 6, 18, and 22 induced concentration dependent SMMC-7721 cell apoptosis after 48 h. These compounds induced G0/G1 phase cell-cycle arrest and morphological changes indicating induction of apoptosis. Thus, findings of our study suggest that the galaxamide and its analogues 6, 18 and 22 exerted growth inhibitory effect on SMMC-7721 cells by arresting the cell cycle in the G0/G1 phase and inducing apoptosis. Compound 1 showed promising anti-tumor activity towards SMMC-7721 cancer cell line, which is 9 and 10 fold higher than galaxamide and reference DPP (cisplatin), respectively.
Multiple N-methylation by a designed approach enhances receptor selectivity
Chatterjee, Jayanta,Ovadia, Oded,Zahn, Grit,Marinelli, Luciana,Hoffman, Amnon,Gilon, Chaim,Kessler, Horst
, p. 5878 - 5881 (2007)
An unselective cyclic peptide integrin ligand was sequentially N-methylated by a designed approach, where only the externally oriented (solvent exposed) amide bonds were N-methylated. The N-methylation resulted in tremendous enhancement in selectivity amo
CycLS: Accurate, whole-library sequencing of cyclic peptides using tandem mass spectrometry
Townsend, Chad,Furukawa, Akihiro,Schwochert, Joshua,Pye, Cameron R.,Edmondson, Quinn,Lokey, R. Scott
, p. 1232 - 1238 (2018)
Cyclic peptides are of great interest as therapeutic compounds due to their potential for specificity and intracellular activity, but specific compounds can be difficult to identify from large libraries without resorting to molecular encoding techniques. Large libraries of cyclic peptides are often DNA-encoded or linearized before sequencing, but both of those deconvolution strategies constrain the chemistry, assays, and quantification methods which can be used. We developed an automated sequencing program, CycLS, to identify cyclic peptides contained within large synthetic libraries. CycLS facilitates quick and easy identification of all library-members via tandem mass spectrometry data without requiring any specific chemical moieties or modifications within the library. Validation of CycLS against a library of 400 cyclic hexapeptide peptoid hybrids (peptomers) of unique mass yielded a result of 95% accuracy when compared against a simulated library size of 234,256 compounds. CycLS was also evaluated by resynthesizing pure compounds from a separate 1800-member library of cyclic hexapeptides and hexapeptomers with high mass redundancy. Of 22 peptides resynthesized, 17 recapitulated the retention times and fragmentation patterns assigned to them from the whole-library bulk assay results. Implementing a database-matching approach, CycLS is fast and provides a robust method for sequencing cyclic peptides that is particularly applicable to the deconvolution of synthetic libraries.
Probing the Physicochemical Boundaries of Cell Permeability and Oral Bioavailability in Lipophilic Macrocycles Inspired by Natural Products
Bockus, Andrew T.,Lexa, Katrina W.,Pye, Cameron R.,Kalgutkar, Amit S.,Gardner, Jarret W.,Hund, Kathryn C.R.,Hewitt, William M.,Schwochert, Joshua A.,Glassey, Emerson,Price, David A.,Mathiowetz, Alan M.,Liras, Spiros,Jacobson, Matthew P.,Lokey, R. Scott
, p. 4581 - 4589 (2015)
Cyclic peptide natural products contain a variety of conserved, nonproteinogenic structural elements such as d-amino acids and amide N-methylation. In addition, many cyclic peptides incorporate γ-amino acids and other elements derived from polyketide synt
Interplay among Conformation, Intramolecular Hydrogen Bonds, and Chameleonicity in the Membrane Permeability and Cyclophilin A Binding of Macrocyclic Peptide Cyclosporin O Derivatives
Lee, Dongjae,Lee, Sungjin,Choi, Jieun,Song, Yoo-Kyung,Kim, Min Ju,Shin, Dae-Seop,Bae, Myung Ae,Kim, Yong-Chul,Park, Chin-Ju,Lee, Kyeong-Ryoon,Choi, Jun-Ho,Seo, Jiwon
, p. 8272 - 8286 (2021)
A macrocyclic peptide scaffold with well-established structure-property relationship is desirable for tackling undruggable targets. Here, we adopted a natural macrocycle, cyclosporin O (CsO) and its derivatives (CP1-3), and evaluated the impact of conformation on membrane permeability, cyclophilin A (CypA) binding, and the pharmacokinetic (PK) profile. In nonpolar media,CsOshowed a similar conformation to cyclosporin A (CsA), a well-known chameleonic macrocycle, but less chameleonic behavior in a polar environment. The weak chameleonicity ofCsOresulted in decreased membrane permeability; however, the more rigid conformation ofCsOwas not detrimental to its PK profile.CsOexhibited a higher plasma concentration thanCsA, which resulted from minimal CypA binding and lower accumulation in red blood cells and moderate oral bioavailability (F= 12%). Our study aids understanding ofCsO, a macrocyclic peptide that is less explored thanCsAbut with greater potential for diversity generation and rational design.
Synthesis of Marine Cyclopeptide Galaxamide Analogues as Potential Anticancer Agents
Li, Daichun,Liao, Xiaojian,Xu, Shihai,Zhao, Bingxin,Zhong, Shenghui
, (2022/03/02)
In this paper, eight new galaxamide analogues (Z-1~Z-8) were synthesized and evaluated for their cytotoxic activities against five cancer cell lines, MCF-7, MD-MBA-231, HepG2, Hela, and A549, using MTT assays. The modified analogue Z-6 displayed broad spectrum cytotoxic activity toward each tested cell line with IC50 values of 1.65 ± 0.30 (MCF-7), 2.91 ± 0.17 (HepG2), 4.59 ± 0.27 (MD-MBA-231), 5.69 ± 0.37 (Hela), and 5.96 ± 0.41 (A549) μg/mL, respectively. The galaxamides Z-3 and Z-6 induced concentration-dependent apoptosis of the MCF-7 cells after 72 h as evaluated by the flow cytometry experiment. The results showed that these compounds could induce MCF-7 cell apoptosis by arresting the G0/G1 phase of the cell cycle and finally achieving the effect of inhibiting the proliferation of MCF-7 cells.
Investigation for the cyclization efficiency of linear tetrapeptides: Synthesis of tentoxin B and dihydrotentoxin
Sato, Ryota,Oyama, Kie,Konno, Hiroyuki
supporting information, p. 6173 - 6181 (2018/09/17)
Investigation of the cyclization efficiency of N-methyl linear tetrapeptides using a molecular modeling study and chemical synthesis is described. The linear peptide with two N-methyl groups, MeAla-Leu-MePhe-Gly, forms γ-turn like conformation with the am
Anthelmintic PF1022A: Stepwise solid-phase synthesis of a cyclodepsipeptide containing N-methyl amino acids
Lüttenberg, Sebastian,Sondermann, Frank,Scherkenbeck, Jürgen
experimental part, p. 2068 - 2073 (2012/03/27)
Cyclodepsipeptides of the enniation-, PF1022-, and verticilide-family represent a diverse class of highly interesting natural products with respect to their manifold biological activities. However, until now no stepwise solid-phase synthesis has been accomplished due to the difficult combination of N-methyl amino acids and hydroxycarboxylic acids. We report here the first stepwise solid-phase synthesis of the anthelmintic cyclooctadepsipeptide PF1022A based on an Fmoc/THP-ether protecting group strategy on Wang-resin. The standard conditions of our synthesis allow an unproblematic adaption to an automated peptide synthesizer.
A preparation of N-Fmoc-N-methyl-α-amino acids and N-nosyl-N-methyl-α-amino acids
Di Gioia, Maria Luisa,Leggio, Antonella,Liguori, Angelo,Perri, Francesca,Siciliano, Carlo,Viscomi, Maria Caterina
scheme or table, p. 133 - 143 (2010/08/19)
A convenient route for the synthesis of lipophilic N-Fmoc-N-methyl-α- amino acids and N-nosyl-N-methyl-α-amino acids, interesting building blocks to be used for the preparation of N-methylated peptides, is presented. Both nosyl- and Fmoc-protected monomer
An efficient preparation of N-Methyl-α-amino acids from N-Nosyl-α-amino acid phenacyl esters
Leggio, Antonella,Belsito, Emilia Lucia,De Marco, Rosaria,Liguori, Angelo,Perri, Francesca,Viscomi, Maria Caterina
supporting information; experimental part, p. 1386 - 1392 (2010/06/11)
Chemical Equation Presented In this paper we describe a simple and efficient solution-phase synthesis of N-methyl-TV-nosyl-α-amino acids and N-Fmoc-N-methyl-α-amino acids. This represents a very important application in peptide synthesis to obtain N-methylated peptides in both solution and solid phase. The developed methodology involves the use of N-nosyl-α-amino acids with the carboxyl function protected as a phenacyl ester and the methylating reagent diazomethane. An important aspect of this synthetic strategy is the possibility to selectively deprotect the carboxyl function or alternatively both amino and carboxyl moieties by using the same reagent with a different molar excess and under mild conditions. Furthermore, the adopted procedure keeps unchanged the acid-sensitive side chain protecting groups used in Fmoc-based synthetic strategies.
