Acetylenic Amino Research Articles

Chemo-, regio-, and stereoselective catalyst-free addition of diphenylphosphine oxide to acetylenic amino ketones. Synthesis of Z-diphenylphosphoryl(organylamino)alkenones

Chemo-, regio-, and stereoselective catalyst-free addition of diphenylphosphine oxide to acetylenic amino ketones. Synthesis of Z-diphenylphosphoryl(organylamino)alkenones

Biologically Active Acetylenic Amino Alcohol and N-Hydroxylated 1,2,3,4-Tetrahydro-β-carboline Constituents of the New Zealand Ascidian Pseudodistoma opacum.

The first occurrence of an acetylenic 1-amino-2-alcohol, distaminolyne A (1), isolated from the New Zealand ascidian Pseudodistoma opacum, is reported. The isolation and structure elucidation of 1 and assignment of absolute configuration using the exciton coupled circular dichroism technique are described. In addition, a new N-9 hydroxy analogue (2) of the known P. opacum metabolite 7-bromohomotrypargine is also reported. Antimicrobial screening identified modest activity of 1 toward Escherichia coli, Staphylococcus aureus, and Mycobacterim tuberculosis, while 2 exhibited a moderate antimalarial activity (IC50 3.82 μM) toward a chloroquine-resistant strain (FcB1) of Plasmodium falciparum.

α,β-Acetylenic Amino Thiolester Inhibitors of Aldehyde Dehydrogenases 1&3: Suppressors of Apoptogenic Aldehyde Oxidation and Activators of Apoptosis

The aim of this minireview is to recapitulate the evidence in the literature supporting a role for the aldehyde dehydrogenases (ALDH1, ALDH2 and ALDH3) in controlling the levels of 3 endogenous apoptogenic aldehydes: methional, malondialdehyde (MDA) and 4-hydroxynonenal (HNE). All 3 aldehydes are formed during the metabolism of cellular constituents. Methional is derived from the oxidative decarboxylation of 4-methylthio-2-oxobutanoate coming from the methionine salvage pathway. MDA arises from the peroxidation of lipids and also from methional subjected to attack by reactive oxygen species (ROS). HNE is formed primarily from lipid peroxidation by ROS attack. One major origin of ROS is the dysfunctional electron transport chain in the mitochondria of cancer cells. As bifunctional electrophilic compounds, HNE forms adducts with cellular nucleophiles e.g. GSH, whilst MDA acts as a potent DNA/protein cross-linking agent in vitro and in vivo. Cancer cells protect themselves from the apoptogenic effect of these aldehydes by the ALDHs that oxidize them to their non-apoptogenic carboxylic acids. Indeed, the over-expression of ALDH3 protects cells from HNE-induced apoptosis. The inhibition of ALDH1 allows methional to reach its apoptogenic threshold in BAF3bcl2 that were resistant to methional-inducible apoptosis. One member of the α,β-acetylenic N-substituted aminothiol ester family is an "active-enzyme-dependent", competitive, irreversible inhibitor of ALDH1 in vitro, an inhibitor of ALDH1 and ALDH3 in rat and human cancer cells in culture, an irreversible apoptogen on chemoresistant bcl2(+++) murine lymphoid and human epithelial cancer cells but a reversible cytostatic compound on human prostate epithelial normal cells in culture.

Synthesis of some Acetylenic Amino Derivatives from Salicylic Acid

New derivatives of acetylenic amines containing salicylate group have been synthesized through Mannich reaction which involved reaction of propargyl salicylate with paraformaldehyde and secondary amines.The structural formula of the synthesized compounds have been investigated by physical and spectroscopic methods.

ChemInform Abstract: Preparation of a Serine-Derived Organozinc Reagent in Tetrahydrofuran: Synthesis of Novel, Enantiomerically Pure Allenic, Acetylenic, and Heteroaryl Amino Acids.

ChemInform Abstract: Preparation of a Serine-Derived Organozinc Reagent in Tetrahydrofuran: Synthesis of Novel, Enantiomerically Pure Allenic, Acetylenic, and Heteroaryl Amino Acids.

Synthesis of Triazole-Linked Manno- and Glucopyranosyl Amino Acids

The synthesis of two types of triazole-linked glycosyl amino acids, at C-4 and at the anomeric position for mannopyranose and glucopyranose derivatives, respectively, via a copper-catalyzed [3+2] cycloaddition of acetylenic amino acid derivatives and azide-containing glycoside is described.

Expedient synthesis of triazole-linked glycosyl amino acids and peptides.

[structure: see text] An expedient, high-yielding synthesis of two types of triazole-linked glycopeptides is described. These novel and stable glycopeptide mimics were prepared via Cu(I)-catalyzed [3 + 2] cycloaddition of either azide-functionalized glycosides and acetylenic amino acids or acetylenic glycosides and azide-containing amino acids.

Ring-closing alkyne metathesis mediated synthesis of cyclic β-turn mimetics

The application of ring-closing alkyne metathesis to synthesise conformationally restricted peptidic β-turn mimics has been investigated. A range of oligopeptides containing either two acetylenic amino acids, or two cysteine residues have been synthesised and subjected to suitable cyclisation conditions. The structures of the cyclic compounds are investigated by 2D NMR analysis.

Palladium‐Catalyzed Synthesis of Novel Optically Active Tryptophan Analogues.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Palladium-catalyzed synthesis of novel optically active tryptophan analogues.

[reaction: see text] Both unsaturated proline derivatives and optically active tryptophan analogues have been obtained via Pd-catalyzed cyclization of aniline-containing acetylenic amino acids. The side chain length of the cyclization precursor determines which one of the two possible products will be formed.

Synthesis of Amino Acid Derived Cyclic Phosphorus Ylides

We recently reported the thermal elimination of Ph3PO from suitably protected aminoacyl ylides 1 as a route to acetylenic amino acid analogues 2. Pyrolysis of ylides such as 3 with a free amino group takes a different course. Ethanol is eliminated to give the c h i d cyclic ylides 4 which can be viewed as 3-triphenylphosphoranylidene tetramic acids. Specific examples prepared include 4 (R = Me, Pri), the parent compound 5 (from glycine) and the six-membered ring compound 6 (from p-alanine). Using a similar approach, bicyclic ylides such as 7 (from proline) can be prepared. In the case of the glutamate derived ylide 8, thermolysis initially gives a mixturc of 9 and 10 but these both cyclise to the bicyclic product 11 with time. The structure and reactivity of these interesting cyclic ylides are now being examined.

Pyrolysis of Cyclic Polyoxo Phosphorus Ylides

In an extension of our recent work on generating acetylenic amino acid derivatives by flash vacuum pyrolysis (FVP) of appropriate stabilised phosphorus ylides,1 we examined the ylides 1 with a free amino group. Rather than the expected acetylenic product these gave the novel cyclic ylides 2 with loss of ethanol. Preliminary attempts to bring about extrusion of Ph3PO from these gave rather confusing results so we have examined simpler cyclic ylides in an attempt to understand the processes involved.

Pyrolysis of Cyclic Polyoxo Phosphorus Ylides

In an extension of our recent work on generating acetylenic amino acid derivatives by flash vacuum pyrolysis (FVP) of appropriate stabilised phosphorus ylides,1 we examined the ylides 1 with a free amino group. Rather than the expected acetylenic product these gave the novel cyclic ylides 2 with loss of ethanol. Preliminary attempts to bring about extrusion of Ph3PO from these gave rather confusing results so we have examined simpler cyclic ylides in an attempt to understand the processes involved.

Pyrolysis of Amino Acid Derived Stabilised Ylides as a Route to Chiral Acetylenic Amines and Amino Acids and Gaba Analogues

Abstract We recently reported the pyrolysis of stabilised ylides as a method for overall conversion of carboxylic acids to homologous acetylenic esters and terminal alkynes.1,2 This has now been applied successfully to amino acids. A wide range of alkoxycarbonyl protected amino acids have been converted to the stable crystalline ylides 1. These have been fully characterised, and upon FVP, eliminate Ph3PO to afford the protected acetylenic amino acids 2 in good yield and without significant racemisation. Subsequent reactions of these extremely versatile intermediates have been used to gain access to a wide variety of chiral amine and amino acids of great interest as potential selective enzyme inhibitors and components for modified peptide structures.

Convenient synthesis of chiral α,β-acetylenic γ-amino acid derivatives and γ-aminobutyric acid analogues via stabilized ylides

Twelve examples of protected acetylenic amino acids are readily prepared in a two-step procedure involving formation and flash vacuum pyrolysis of chiral aminoacyl phosphorus ylieds.

Mechanisms of interaction of Escherichia coli threonine synthase with substrates and inhibitors.

Threonine synthase (TS), the last enzyme of the threonine biosynthetic pathway, catalyzes L-threonine formation from L-homoserine phosphate (HSerP; Km = 0.5 mM, V = 440 min-1) and DL-vinylglycine. Furthermore, TS catalyzes beta-elimination reactions with L-serine (Km = 150 mM, V = 4.7 min-1), DL-3-chloroalanine, L-threonine, and L-allo-threonine as substrates to yield pyruvate or alpha-ketobutyrate, while L-alanine, L-2-aminobutanoic acid, and L-2-amino-5-phosphonopentanoic acid are substrates for half-transamination reactions to form the pyridoxamine form of the enzyme and the corresponding alpha-keto acid. Spectral analyses of all these reactions revealed the transient formation of strongly absorbing long-wavelength chromophores (lambda max = 440-445 nm), implying the accumulation of the corresponding pyridoxaldimine p-quinonoidal intermediates. HSerP turnover was competitively inhibited by L-3-hydroxyhomoserine phosphate 1 (Ki = 0.050 mM), L-2,3-methanohomoserine phosphate 2 (Ki = 0.010 mM), L-2-amino-3-[(phosphonomethyl)thio)]propanoic acid 5 (Ki = 0.011 mM) and DL-E-2-amino-5-phosphono-4-pentenoic acid 10 (Ki = 0.54 mM). 5 and 10 induced the formation of long-wavelength quinonoidal chromophores (lambda max = 458 and 460 mm, epsilon 47,000 and 30,000 M-1 cm-1), while incubation with either 1 or 2 induced only minor spectral changes. DL-2-Amino-3-[(phosphonomethyl)amino)]propanoic acid inactivated TS (Ki = 0.057 mM, kinact = 1.44 min-1) with 1:1 stoichiometry, transient formation of a 450-nm chromophore, and finally bleaching of any absorbance at wavelengths longer than 320 nm. Z-2-Amino-5-phosphono-3-pentenoic acid 8 is the unusual amino acid found in the peptide antibiotics of the plumbemicin and rhizocticin families. Racemic 8 irreversibly inhibited TS (Ki = 0.1 mM, kinact = 1.50 min-1) with 1:1 stoichiometry and the concomitant formation of a 482-nm chromophore (epsilon approximately 30,000 M-1 cm-1). DL-E-2-Amino-5-phosphono-3-pentenoic acid was a less potent irreversible inhibitor of TS (Ki = 0.4 mM, kinact = 0.25 min-1), inducing absorption maxima at 462 and 500 nm. The acetylenic amino acid DL-2-amino-5-phosphono-4-pentynoic acid 12 bound to TS (KD = 0.38 mM) forming a quinonoidal chromophore (lambda max = 452 nm, epsilon approximately 30,000 M-1 cm-1), but inhibition of the enzyme by 12 could not be detected under assay conditions even at high inhibitor concentrations. Mechanisms consistent with these observations are proposed.

Preparation of a Serine-Derived Organozinc Reagent in Tetrahydrofuran: Synthesis of Novel, Enantiomerically Pure Allenic, Acetylenic and Heteroaryl Amino Acids

Preparation of a Serine-Derived Organozinc Reagent in Tetrahydrofuran: Synthesis of Novel, Enantiomerically Pure Allenic, Acetylenic and Heteroaryl Amino Acids

ChemInform Abstract: One‐Step Synthesis of Esters of Acetylenic Amino Acids.

AbstractA novel method for the one‐step preparation of the title compounds (IV) is described.

ChemInform Abstract: Synthesis of Analogues of GABA. Part 13. An Alternative Route to (Z)‐4‐Aminocrotonic Acid.

AbstractThe phthaloyl‐protected acetylenic amino alcohol (I) is oxidized to (II) and then hydrogenated to (III).

Synthesis of L‐2‐amino‐4‐hexynoic acid and derivatives

A synthesis is described of optically pure L‐2‐amino‐4‐hexynoic acid and its derivatives, which can serve as potentially useful precursors for the preparation of highly tritium labeled norleucine‐containing peptides, as well as other side‐chain modified peptides. Catalytic tritiation of one derivative of this acetylenic amino acid afforded the (3H)‐L‐norleucine derivative with a specific activity of 115 ± 5 Ci/mmol.