- 97. Synthesis of Unnatural Lipophilic N-(9H-Fluoren-9-ylmethoxy)carbonyl-Substituted α-Amino Acids and Their Incorporation into Cyclic RGD-Peptides: A Structure-Activity Study
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The ανβ3 integrin is implicated in human tumor metastasis and angiogenesis. It has been shown that structures of the sequence cyclo(-Arg1-Gly2-Asp3-D-Phe 4-Xaa5-) (I) and cyclo(-Arg1-Gly2-Asp3-Phe 4-D-Xaa5-) (II) bind with high affinity and the latter with high selectivity to this receptor. The residues Xaa and D-Xaa accept a broad variety of amino acids. Here, we report on the synthesis, activities, and conformational analysis of cyclic Arg-Gly-Asp (RGD) peptides containing lipophilic amino acids Xaa or D-Xaa in position 5. For I, these were (2S)-2-aminohexadecanoic acid (Ahd) and N-hexadecylglycine (Hd-Gly) and in II, D-Ahd and Hd-Gly, and, for control purposes, Ahd were incorporated (Fig. 1). The enantiomerically pure α-amino acids were obtained by non-enantioselective synthesis and subsequent enzymatic separation of isomers using acylase I (Scheme). Hd-Gly was prepared in a modified procedure according to Stewart from ethyl bromoacetate and hexadecylamine (Scheme). The synthesis and physicochemical properties of the corresponding (9H-fluoren-9-ylmethoxy)carbonyl (Fmoc) derivatives, compatible with solid-phase peptide synthesis, are described. Structure elucidation by NMR reveals that the lipid modification has no significant impact on the template structures when incorporated into them. For peptides I with Xaa = Ahd or Hd-Gly (1 or 2), a βII′/γ-turn-like arrangement with D-Phe in i + 1 position of the β-turn is found. Peptides II with D-Xaa = D-Ahd or Hd-Gly (3 or 4) exhibit a βII′/γ-turn conformation with Gly in i + 1 position of the β-turn, whereas II with Ahd instead of D-Xaa, i.e., lacking a D-amino acid in position 4 or 5 (5), adopts no defined conformation. However, in assays of receptor specificity employing human ανβ3 integrin, the compounds exhibit IC50 values ranging from nanomolar to less than millimolar. These results indicate that although the arrangement of the pharmacophoric groups is preserved in the target compounds, the biological activity is highly dependent on spatial requirements of the lipid anchor in the receptor binding pocket. Obviously, only certain positions do not affect the binding.
- Koppitz, Marcus,Huenges, Martin,Gratias, Rainer,Kessler, Horst,Goodman, Simon L.,Jonczyk, Alfred
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- Unsymmetrical azo initiators increase efficiency of radical generation in aqueous dispersions, liposomal membranes, and lipoproteins
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Lipid peroxidation studies often employ the use of azo initiators to produce a slow, steady source of free radicals, but the lack of initiators capable of efficiently generating radicals in lipid aggregates such as micelles and membranes has created persistent problems in these investigations. We report here the synthesis and study of unsymmetrically substituted (hydrophilic/hydrophobic) azo initiators C-8, C-12, and C-16 that increase the efficiency of radical generation in lipophilic regions of aqueous emulsions such as micelles and liposomes. Radical generation from these initiators was monitored in micelles, liposomes, and lipoproteins by the use of two radical scavengers, one that scavengers lipophilic peroxyl radicals and one that scavenges hydrophilic peroxyls. The lipophilic radical scavenger used was the well-known antioxidant α-tocopherol and the hydrophilic radical scavenger used was uric acid. Two peroxyl radicals are trapped by each of these scavengers, tocopherol presumably being biased toward reacting with lipid soluble radicals, uric acid presumably reacting preferentially with water-soluble radicals. In Triton X-100 micelles the unsymmetrical initiators C-8 and C-16 display an increase in both α-TOH (α- tocopherol) trapping and in overall radical generation efficiency compared to the symmetrical initiators C-0 (hydrophilic) and MeOAMVN (lipophilic). The unsymmetrical azo initiators performance in liposomes was excellent (increased cage escape with lipid compartment access). In low-density lipoprotein oxidations, the initiators C-8, C-12, and C-16 also provided advantages over C-0 and MeOAMVN. The hydrophilic/hydrophobic character of the two radicals generated from the unsymmetrical initiators is an important factor for separating the geminate radical pair. These initiators, when compared to the widely used symmetrical azo initiators, provide an advantage of free radical production, lipophilic access, and constant radical generation in the investigation of lipid peroxidation in various media.
- Culbertson, Sean M.,Porter, Ned A.
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- One-pot, two-step synthesis of unnatural α-amino acids involving the exhaustive aerobic oxidation of 1,2-diols
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Herein, we report the nor-AZADO-catalyzed exhaustive aerobic oxidations of 1,2-diols to α-keto acids. Combining oxidation with transamination using dl-2-phenylglycine led to the synthesis of free α-amino acids (AAs) in one pot. This method enables the rapid and flexible preparation of a variety of valuable unnatural AAs, such as fluorescent AAs, photoactivatable AAs, and other functional AAs for bioorthogonal reactions.
- Inada, Haruki,Furukawa, Keisuke,Shibuya, Masatoshi,Yamamoto, Yoshihiko
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p. 15105 - 15108
(2019/12/26)
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- Sequential reactions from catalytic hydroformylation toward the synthesis of amino compounds
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Different families of new amino compounds were efficiently synthesized, through optimized sequential processes, involving rhodium catalyzed hydroformylation as the key step. The selection of appropriate hydroformylation catalytic systems and reaction conditions allowed obtaining aldehydes derived from several n-alkyl olefins, cholest-4-ene and 3-vinyl-1H-indole, which were subsequently transformed, in one-pot, in to α-amino acids via hydroformylation/Strecker reaction, and in to tertiary amines via hydroaminomethylation, with excellent yields.
- Almeida, Ana R.,Carrilho, Rui M.B.,Peixoto, Andreia F.,Abreu, Artur R.,Silva, Artur,Pereira, Mariette M.
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supporting information
p. 2389 - 2395
(2017/04/03)
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- Solid-phase synthesis of chlorofusin analogues
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(Chemical Equation Presented) We report an efficient and versatile solid-phase synthesis through which two series of chlorofusin analogues, one bearing varying chromophores and the other with various amino acid substitutions in the cyclic peptide, were synthesized. These peptides were prepared using a strategy involving side-chain immobilization, on-resin cyclization, and postcyclization modification. The success of these syntheses demonstrates the broad utility of the method. Both series of analogues were evaluated for their inhibitory activity against the p53/MDM2 interaction but were shown to be inactive in the concentration range tested. This suggests that the full chromophore structure may be required for activity.
- Woon, Esther C. Y.,Arcieri, Mariangela,Wilderspin, Andrew F.,Malkinson, John P.,Searcey, Mark
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p. 5146 - 5151
(2008/02/07)
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- IMPROVED INHIBITORS FOR THE SOLUBLE EPOXIDE HYDROLASE
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Inhibitors of the soluble epoxide hydrolase (sEH) are provided that incorporate multiple pharmacophores and are useful in the treatment of diseases
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Page/Page column 61-62
(2010/11/08)
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- Synthesis of a library of polycationic lipid core dendrimers and their evaluation in the delivery of an oligonucleotide with hVEGF inhibition
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This article follows on from our previous work in the area of non-viral gene delivery using polycationic dendrimers (PCDs). Herein we report on the synthesis and efficacy of a new library of lipid core PCDs in the delivery of the anti-angiogenic oligonucleotide (ODN-1) to retinal pigment epithelial cells. ELISA was used to monitor hVEGF levels in cells transfected with dendriplexes, Cytofectin GSV and control (non-transfected). At 48 h, hVEGF titres had returned to that of the untransfected control for Cytofectin GSV however, a number of dendriplexes continued to exhibit a marked reduction in hVEGF titres.
- Parekh, Harendra S.,Marano, Robert J.,Rakoczy, Elizabeth P.,Blanchfield, Joanne,Toth, Istvan
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p. 4775 - 4780
(2007/10/03)
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- Lipidic Peptides, I Synthesis, Resolution and Structural Elucidation of Lipidic Amino Acids and Their Homo- and Hetero-Oligomers
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The α-amino acids with long alkyl side chains, the so-called lipidic amino acids 1a-e, and their homo-oligomers, the lipidic peptides 1p-aj, represent a class of compounds which combine the structural properties of peptides and proteins with the characteristics of lipids and membranes.The amino acids were synthesised from the appropriate alkyl bromide and diethyl acetamidomalonate.Resolution was made chemically, by forming diastereomers of the amino acid esters with an optically pure α-pinene derivative.The protected homo-oligomers were synthesised in solution with the assistance of a water-soluble carbodiimide coupling agent.In order to modify the physical and chemical properties of the peptides, a series of protected hetero-oligomers were prepared, by similar methods, incorporating either other amino acids (3a-d, 7a-i) or side-chain-substituted lipidic amino acids (6a-d).
- Gibbons, William A.,Hughes, Richard A.,Charalambous, Mario,Christodoulou, Marika,Szeto, Alice,et al.
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p. 1175 - 1183
(2007/10/02)
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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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- The Synthesis of Amino Acids via Organoboranes
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The reaction of the acetate (1) with organoboranes provides a convenient, new route to amino acids.
- O'Donnell, Martin J.,Falmagne, Jean-Bernard
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p. 1168 - 1169
(2007/10/02)
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- SYNTHESIS OF AMINO ACIDS. ALKYLATION OF ALDIMINE AND KETIMINE DERIVATIVES OF GLYCINE ETHYL ESTER UNDER VARIOUS PHASE-TRANSFER CONDITIONS
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The Schiff base derived from glycine ethyl ester and p-chlorobenzaldehyde can be alkylated by the ion-pair extraction method as well as under catalytic liquid-liquid or solid-liquid phase-transfer conditions.This imine is compared with the corresponding benzophenone Schiff base.
- Ghosez, Leon,Antoine, Jean-Pierre,Deffense, Etienne,Navarro, Mirtha,Libert, Valery,et al.
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p. 4255 - 4258
(2007/10/02)
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