7769-79-1Relevant academic research and scientific papers
Structure-activity relationship of lipid core peptide-based Group A Streptococcus vaccine candidates
Chan, Amy,Hussein, Waleed M.,Ghaffar, Khairunnisa Abdul,Marasini, Nirmal,Mostafa, Ahmed,Eskandari, Sharareh,Batzloff, Michael R.,Good, Michael F.,Skwarczynski, Mariusz,Toth, Istvan
, p. 3095 - 3101 (2016)
Infection with Group A Streptococcus (GAS) can result in a range of different illnesses, some of which are fatal. Currently, our efforts to develop a vaccine against GAS focuses on the lipid core peptide (LCP) system, a subunit vaccine containing a lipoamino acid (LAA) moiety which allows the stimulation of systemic antibody activity. In the present study, a peptide (J14) representing the B-cell epitope from the GAS M protein was incorporated alongside a universal T-helper epitope (P25) in four LCP constructs of different spatial orientation or LAA lengths. Through structure-activity studies, it was discovered that while the alteration of the LCP orientation had a weaker effect on immunostimulation, increasing the LAA side chain length within the construct increased antibody responses in murine models. Furthermore, the mice immunised with the lead LCP construct were also able to maintain antibody activity throughout the course of five months. These findings highlight the importance of LAA moieties in the development of intranasal peptide vaccines and confirmed that its side chain length has an effect on the immunogenicity of the structure.
2-Aminohydroxamic acid derivatives as inhibitors of Bacillus cereus phosphatidylcholine preferred phospholipase C PC-PLCBc
González-Bulnes, Patricia,González-Roura, Albert,Canals, Daniel,Delgado, Antonio,Casas, Josefina,Llebaria, Amadeu
supporting information; experimental part, p. 8549 - 8555 (2011/02/25)
Phosphatidylcholine preferring phospholipase C (PC-PLC) is an important enzyme that plays a key role in a variety of cellular events and lipid homoeostases. Bacillus cereus phospholipase C (PC-PLCBc) has antigenic similarity with the elusive mammalian PC-PLC, which has not thus far been isolated and purified. Therefore the discovery of inhibitors of PC-PLC Bc is of current interest. Here, we describe the synthesis and biological evaluation of a new type of compounds inhibiting PC-PLCBc. These compounds have been designed by evolution of previously described 2-aminohydroxamic acid PC-PLCBc inhibitors that block the enzyme by coordination of the zinc active site atoms present in PC-PLCBc [Gonzalez-Roura, A.; Navarro, I.; Delgado, A.; Llebaria, A.; Casas, J. Angew. Chem. Int. Ed. 2004, 43, 862]. The new compounds maintain the zinc coordinating groups and possess an extra trimethylammonium function, linked to the hydroxyamide nitrogen by an alkyl chain, which is expected to mimic the trimethylammonium group of the phosphatidylcholine PC-PLCBc substrates. Some of the compounds described inhibit the enzyme with IC 50's in the low micromolar range. Unexpectedly, the most potent inhibitors found are those that possess a trimethylammonium group but have chemically blocked the zinc coordinating functionalities. The results obtained suggest that PC-PLCBc inhibition is not due to the interaction of compounds with the phospholipase catalytic zinc atoms, but rather results from the inhibitor cationic group recognition by the PC-PLCBc amino acids involved in choline lipid binding.
Synthesis and evaluation of some lipidic aminoalcohols and diamines as immunomodulators
Olmo, Esther del,Plaza, Alvaro,Muro, Antonio,Martinez-Fernandez, Antonio R.,Nogal-Ruiz, Juan J.,Lopez-Perez, Jose L.,Feliciano, Arturo San
, p. 6091 - 6095 (2007/10/03)
Lymphoproliferation inhibition and cytotoxicity of a number of lipidic aminoacids, aminoalcohols and diamines were evaluated as a preliminary screening to select potential immunomodulators. The four most potent/less toxic compounds were submitted to delayed hypersensibility (DTH) assays to define the best to be evaluated further Graft-vs-Host, NO production and other immunoevaluation (CD4+, CD45, CD8, CD11b, I-Ek, and NK cells) assays, to establish their immunomodulation potential for being further considered as auxiliary agents for vaccination against some parasitic infections. Compounds 5d, 6d, 6f, 7a, and 9a, fairly inhibited the lymphoproliferation (71.6-79.5%, at 3.2-2.4 nM), while the aminoalcohol derivative 6f and the diamine 7a gave the most promising results in the DTH assays. Diamine derivative 8b induced nitrite production on normal macrophages, whereas compounds 6f and 7a induced nitrite production on LPS pre-stimulated macrophages. These two last compounds have been selected to follow in vivo vaccination assays.
Novel aliphatic compounds, process for their preparation and their usage
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Page/Page column 12, (2010/02/05)
The present invention provides an aliphatic compound represented by the following formula (I) or pharmacologically acceptable salts thereof: where n denotes an integer of 1 to 11, and 1 denotes an integer of 1 to 16, the aliphatic compound being an optical isomer of the (2R,3S,2′S) configuration when the 8-position thereof is a double bond, or an optical isomer of the (2S,3R,2′RS) configuration when the 8-position is a single bond; methods for producing the compound or pharmacologically acceptable salts thereof; and uses of the compound in the treatment of cardiovascular diseases (e.g. arteriosclerosis, cardiac diseases), cancer, rheumatism, diabetic retinopathy, and respiratory diseases.
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
Koppitz, Marcus,Huenges, Martin,Gratias, Rainer,Kessler, Horst,Goodman, Simon L.,Jonczyk, Alfred
, p. 1280 - 1300 (2007/10/03)
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.
Lipidic Peptides, I Synthesis, Resolution and Structural Elucidation of Lipidic Amino Acids and Their Homo- and Hetero-Oligomers
Gibbons, William A.,Hughes, Richard A.,Charalambous, Mario,Christodoulou, Marika,Szeto, Alice,et al.
, p. 1175 - 1183 (2007/10/02)
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).
Synthesis and anticandidal properties of polyoxin L analogues containing α-amino fatty acids
Khare,Becker,Naider
, p. 650 - 656 (2007/10/02)
Analogues of polyoxin L containing amino acids with saturated fatty acid like side chains were synthesized from the benzyloxycarbonyl-protected α-amino fatty acid p-nitrophenyl ester and uracil polyoxin C. Transfer hydrogenolysis using palladium black and formic acid gave diastereomeric, dipeptidyl polyoxin L analogues containing α-aminooctanoic acid (3), α-aminododecanoic acid (4), or α-aminohexadecanoic acid (5) as the amine terminal residue in 40-60% yield. Diastereomers of 3 and 5 were resolved by using high-performance liquid chromatography on a reversed-phase column and designated as 3a, 3b and 5a, 5b. Analogues 3-5 were excellent inhibitors of chitin synthetase from Candida albicans; 4, the best inhibitor, had an ID50 of 0.5 μM. The L,L diastereomers of 3 and 5 were 1-2 orders of magnitude more potent chitin synthetase inhibitors than their D,L homologues. None of the synthetic polyoxin L analogues inhibited transport of trimethionine, but 3a, 4, and 5b caused decreases of 71%, 87%, and 83%, respectively, in the initial rate of uptake of dileucine. Compounds 3-5 were significantly more stable to peptidase degradation than polyoxin L analogues containing naturally occurring α-amino acids. Compound 4 inhibited growth of C. albicans in culture at 40-80 μg/mL. All other analogues were less potent antifungals. The results suggest that synthetic polyoxins can be designed to have increased affinity for a peptide transport system and to have increased stability against intracellular degradation in C. albicans.
SYNTHESIS OF (4E,8E,2S,3R,2'R)-N-2'-HYDROXYHEXADECANOYL-9-METHYL-4,8-SPHINGADIENINE, THE CERAMIDE PORTION OF THE FRUITING-INDUCING CEREBROSIDE IN A BASIDIOMYCETE SCHIZOPHYLLUM COMMUNE, AND ITS (2R,3S)-ISOMER
Mori, Kenji,Funaki, Yuji
, p. 2369 - 2378 (2007/10/02)
A synthesis of the natural enantiomer as well as its diastereomer of the title compound was accomplished, confirming the structure proposed for the fruiting-inducing cerebroside of Schizophyllum commune.
