ABSTRACT
A series of fluorescent unnatural amino acids (UAAs) bearing stilbene and meta-phenylenevinylene (m-PPV) backbone have been synthesized and their optical properties were studied. These novel UAAs were derived from protected diiodo-l-tyrosine using palladium-catalyzed Heck couplings with a series of styrene analogs. Unlike the other fluorescent UAAs, whose emissions are restricted to a narrow range of wavelengths, these new amino acids display the emission peaks at broad range wavelengths (from 400-800 nm); including NIR with QY of 4% in HEPES buffer. The incorporation of both pyridine and phenol functional groups leads to distinct red, green, and blue (RGB) emission, in its basic, acidic and neutral states, respectively. More importantly, these amino acids showed reversible pH and redox response showing their promise as stimuli responsive fluorescent probes. To further demonstrate the utility of these UAAs in peptide synthesis, one of the amino acids was incorporated into a cell penetrating peptide (CPP) sequence through standard solid phase peptide synthesis. Resultant CPP was treated with two different cell lines and the internalization was monitored by confocal fluorescence microscopy.
ABSTRACT
The discovery, structure elucidation, and solid-phase synthesis of namalide, a marine natural product, are described. Namalide is a cyclic tetrapeptide; its macrocycle is formed by only three amino acids, with an exocyclic ureido phenylalanine moiety at its C-terminus. The absolute configuration of namalide was established, and analogs were generated through Fmoc-based solid phase peptide synthesis. We found that only natural namalide and not its analogs containing l-Lys or l-allo-Ile inhibited carboxypeptidase A at submicromolar concentrations. In parallel, an inverse virtual screening approach aimed at identifying protein targets of namalide selected carboxypeptidase A as the third highest scoring hit. Namalide represents a new anabaenopeptin-type scaffold, and its protease inhibitory activity demonstrates that the 13-membered macrolactam can exhibit similar activity as the more common hexapeptides.
Subject(s)
Oligopeptides/chemical synthesis , Peptides, Cyclic/chemical synthesis , Porifera/chemistry , Protease Inhibitors/chemical synthesis , Animals , Carboxypeptidases A/antagonists & inhibitors , Chymotrypsin/antagonists & inhibitors , Models, Molecular , Molecular Conformation , Oligopeptides/chemistry , Oligopeptides/isolation & purification , Peptides, Cyclic/chemistry , Peptides, Cyclic/isolation & purification , Protease Inhibitors/chemistry , Protease Inhibitors/isolation & purification , Solid-Phase Synthesis Techniques , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Synthesis of the marine natural products motualevic acids A, E, and analogs in which modifications have been made to the omega-brominated lipid (E)-14,14-dibromotetra-deca-2,13-dienoic acid or amino acid unit are reported, together with antimicrobial activities against Staphylococcus aureus, methicillin-resistant S. aureus, Enterococcus faecium, and vancomycin-resistant Enterococcus.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Fatty Acids, Unsaturated/chemical synthesis , Fatty Acids, Unsaturated/pharmacology , Glycine/analogs & derivatives , Anti-Bacterial Agents/chemistry , Enterococcus/drug effects , Enterococcus faecium/drug effects , Fatty Acids, Unsaturated/chemistry , Glycine/chemical synthesis , Glycine/chemistry , Glycine/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
The first Ir-catalyzed asymmetric hydrogenations of vinyl boronates have been performed using low catalyst loadings (0.5 mol%) and pressure (as low as 1 bar). Good selectivities (76-98% ee) were obtained for a range of substrates.
Subject(s)
Iridium/chemistry , Vinyl Compounds/chemistry , Catalysis , Hydrogenation , Models, Molecular , Organophosphorus Compounds , StereoisomerismABSTRACT
Diphenylvinylphosphine oxides and di- and trisubstituted vinylphosphonates have been employed as substrates in iridium-catalyzed asymmetric hydrogenations. Complete conversions and excellent enantioselectivities (up to and above 99% ee) were observed for a range of substrates with both aromatic and aliphatic groups at the prochiral carbon. We have also hydrogenated electron-deficient carboxyethylvinylphosphonates with excellent stereoselectivity (up to and above 99% ee). The hydrogenated products of both classes of substrates are synthetically useful intermediates.
Subject(s)
Iridium/chemistry , Organophosphonates/chemistry , Organophosphorus Compounds/chemistry , Oxides/chemistry , Vinyl Compounds/chemistry , Catalysis , Hydrogenation , Ligands , Nitrogen/chemistry , Phosphorus/chemistry , StereoisomerismABSTRACT
We previously reported the phosphine-free Cp*Ru(diamine)-catalyzed hydrogenation of aryl methyl ketones. Herein we present the first report of ruthenium-diamine-catalyzed imine hydrogenation to form amines. The most effective catalyst, I/KOtBu, completely converted several imines to amines at room temperature. The effect of electron-donating and -withdrawing groups on the reaction was investigated using a suitable series of substrates. The asymmetric version of the reaction was studied for two substrates, and the chiral amine products could be obtained in moderate enantiomeric excess.
Subject(s)
Diamines/chemistry , Imines/chemistry , Ruthenium Compounds/chemistry , Water/chemistry , Catalysis , Ligands , Molecular Structure , Phosphines/chemistry , StereoisomerismABSTRACT
The iridium-catalyzed asymmetric hydrogenation of various di- and trisubstituted enol phosphinates has been studied. Excellent enantioselectivities (up to >99% ee) and full conversion were observed for a range of substrates with both aromatic and aliphatic side chains. Enol phosphinates are structural analogues of enol acetates, and the hydrogenated alkyl phosphinate products can easily be transformed into the corresponding alcohols with conservation of stereochemistry. We have also hydrogenated, in excellent ee, several purely alkyl-substituted enol phosphinates, producing chiral alcohols that are difficult to obtain highly enantioselectively from ketone hydrogenations.
Subject(s)
Iridium/chemistry , Nitrogen/chemistry , Organophosphorus Compounds/chemistry , Phosphinic Acids/chemistry , Phosphorus/chemistry , Catalysis , Hydrogenation , Ketones/chemistry , Ligands , Models, Chemical , StereoisomerismABSTRACT
New thiazole-based chiral N,P-ligands that are open-chain analogues of known cyclic thiazole ligands have been synthesized and evaluated in the iridium-catalyzed asymmetric hydrogenation of trisubstituted olefins. Chirality was introduced into the ligands through a highly diastereoselective alkylation using Oppolzer's camphorsultam as chiral auxiliary. In general, the new catalysts are as reactive and selective as their cyclic counterparts for the asymmetric hydrogenation of various trisubstituted olefins.
Subject(s)
Alkenes/chemical synthesis , Iridium/chemistry , Organometallic Compounds/chemistry , Organometallic Compounds/chemical synthesis , Thiazoles/chemistry , Alkenes/chemistry , Alkylation , Catalysis , Crystallography, X-Ray , Hydrogenation , Ligands , Models, Molecular , Molecular Structure , StereoisomerismABSTRACT
[reaction: see text] Enol phosphinates, which are structural analogues of enol acetates, have for the first time been employed as substrates for Ir-catalyzed asymmetric hydrogenation. A number of enol phosphinates have been synthesized and reduced successfully with up to and above 99% ee.
Subject(s)
Iridium/chemistry , Nitrogen/chemistry , Phosphinic Acids/chemistry , Phosphorus/chemistry , Catalysis , Hydrogenation , Ligands , Molecular Structure , Phosphinic Acids/chemical synthesis , StereoisomerismABSTRACT
We have earlier reported the synthesis and antisense properties of the conformationally constrained oxetane-C and -T containing oligonucleotides, which have shown effective down-regulation of the proto-oncogene c-myb mRNA in the K562 human leukemia cells. Here we report on the straightforward syntheses of the oxetane-A and oxetane-G nucleosides as well as their incorporations into antisense oligonucleotides (AONs), and compare their structural and antisense properties with those of the T and C modified AONs (including the thermostability and RNase H recruitment capability of the AON/RNA hybrid duplex by Michaelis-Menten kinetic analyses, their resistance in the human serum, as well as in the presence of exo and endonucleases).
Subject(s)
Adenosine/analogs & derivatives , Cytidine/analogs & derivatives , Ethers, Cyclic/chemistry , Guanosine/analogs & derivatives , Oligonucleotides/chemistry , Thymidine/analogs & derivatives , Adenosine/chemistry , Base Sequence , Circular Dichroism , Cytidine/chemistry , Deoxyribonuclease I/chemistry , Deoxyribonuclease I/metabolism , Ethers, Cyclic/metabolism , Guanosine/chemistry , Humans , Kinetics , Models, Molecular , Molecular Sequence Data , Nucleic Acid Conformation , Nucleic Acid Heteroduplexes/chemistry , Nucleic Acid Heteroduplexes/metabolism , Oligonucleotides/blood , Oligonucleotides/chemical synthesis , Oligonucleotides/metabolism , Proto-Oncogene Mas , RNA/chemistry , RNA/metabolism , Ribonuclease H/chemistry , Ribonuclease H/metabolism , Thermodynamics , Thymidine/chemistryABSTRACT
The pH titration and NMR studies (pH 6.6-12.5) in the heptameric isosequential ssDNA and ssRNA molecules, [d/r(5'-CAQ1GQ2AC-3', with variable Q1/Q2)], show that the pKa of the central G residue within the heptameric ssDNAs (DeltapKa = 0.67 +/- 0.03) and ssRNAs (DeltapKa = 0.49 +/- 0.02) is sequence-dependent. This variable pKa of the G clearly shows that its pseudoaromatic character, hence, its chemical reactivity, is strongly modulated and tuned by its sequence context. In contradistinction to the ssDNAs, the electrostatic transmission of the pKa of the G moiety to the neighboring A or C residues in the heptameric ssRNAs (as observed by the response of the aromatic marker protons of As or Cs) is found to be uniquely dependent upon the sequence composition. This demonstrates that the neighboring As or Cs in ssRNAs have variable electrostatic efficiency to interact with the central G/G-, which is owing to the variable pseudoaromatic characters (giving variable chemical reactivities) of the flanking As or Cs compared to those of the isosequential ssDNAs. The sequence-dependent variation of pKa of the central G and the modulation of its pKa transmission through the nearest-neighbors by variable electrostatic interaction is owing to the electronically coupled nature of the constituent nucleobases across the single strand, which demonstrates the unique chemical basis of the sequence context specificity of DNA or RNA in dictating the biological interaction, recognition, and function with any specific ligand.
