α-Hydrazino- Acids. I. α-Hydrazinoaliphatic Acids and α-(1-Methylhydrazino)aliphatic Acids

Carmi, A.; Pollak, G.; Yellin, H.

doi:10.1021/jo01071a013

Cited by 33 publications

(14 citation statements)

References 2 publications

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“…a-Hydrazinoacid derivatives 53 can be obtained directly by reaction of N-protected hydrazines 50 with the corresponding a-bromocarboxylic acids 51 (Scheme 10), [225][226][227][228] but, dialkylation products may limit this procedure. 229 Recently, in our group, N b -(free)-a-hydrazinoacids were obtained in 40-48% yields through microwave assisted displacement reactions (70 1C, 50 W, 15-20 min) from chiral a-bromocarboxylic acids.…”

Section: A-hydrazinopeptides and Aza-b 3 -Peptidesmentioning

confidence: 99%

Peptidomimetics via modifications of amino acids and peptide bonds

2014

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Peptidomimetics represent an important field in chemistry, pharmacology and material science as they circumvent the limitations of traditional peptides used in therapy. Self-structural organizations such as turns, helices, sheets and loops can be accessed by chemical modifications of amino acids or peptides. In-depth structural and conformational analysis and structure-activity relationships (SAR) offer a way to establish peptidomimetic libraries. Herein, we review recent developments in peptidomimetics that are formed via heteroatom replacement within the native amino acid backbone. Each sub-section describes structural features, utility and preparative methods.

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Section: A-hydrazinopeptides and Aza-b 3 -Peptidesmentioning

confidence: 99%

Peptidomimetics via modifications of amino acids and peptide bonds

2014

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“…Methods to reduce hydrazines to amines have been known for a long time [190]. In the 1960s, racemic N 1 -methyl a-hydrazino acids had been converted into N-methyl a-amino acids by two methods: quantitative cleavage by nitrous acid or hydrogenolysis using Raney nickel in ethanol [192]. Since the first efficient asymmetric synthesis of a-hydrazino acid derivatives in 1986, basically two methods (hydrogenolysis and reductive cleavage using samarium iodide) have been applied for their conversion into a-amino acids.…”

Section: Cleavage Of the Nàn Bondmentioning

confidence: 99%

Synthesis and Chemistry of α‐Hydrazino Acids

Vidal

2009

Amino Acids, Peptides and Proteins in Organic Chemistry

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“…α-Substituted analogues of 2 could be prepared from the α-bromo acids 83 (eq 1). Treatment with hydrazine produced the hydrazino acids which could be guanylated by reaction with 2-methyl-2-thiopseudourea sulfate to give the α-substituted aminoguanidinoacetic acids 4 − 6 . Preparation of the amino-substituted analogue 7 could be accomplished by reaction of methyl hydrazonothiocarbamate hydroiodide with hydrazinoacetic acid (prepared in situ by saponification of ethylhydrazinoacetate hydrochloride ( 84 , X = NH, R = OEt) (eq 2).…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Biological Activity of Aminoguanidine and Diaminoguanidine Analogues of the Antidiabetic/Antiobesity Agent 3-Guanidinopropionic Acid

Vaillancourt¹,

Larsen

Tanis

et al. 2001

J. Med. Chem.

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3-Guanidinopropionic acid (1) has been demonstrated both to improve insulin sensitivity and to promote weight loss selectively from adipose tissue in animal models of non-insulin-dependent diabetes mellitus (NIDDM). However, 1 has also been shown to be a substrate for both the creatine transporter and creatine kinase, leading to marked accumulation in muscle tissue as the corresponding N-phosphate. The corresponding aminoguanidine analogue 2 was recently discovered to retain the antidiabetic activity of 1 while being markedly less susceptible to creatine-like metabolism, suggesting that it should have less potential to accumulate in muscle. Further structural modification of 2 was undertaken to investigate whether the antidiabetic potency could be augmented while maintaining resistance to creatine-like metabolism. Modifications such as alpha-alkylation, homologation, and bioisosteric replacement of the aminoguanidine all were detrimental to antidiabetic activity. However, the simple regioisomeric aminoguanidinoacetic acid 9 and diaminoguanidinoacetic acid analogue 7 were found to be equipotent to 2, leading eventually to the discovery of the significantly more potent diaminoguanidinoacetic acid regioisomers 52 and 53. Further attempts to modify the more active template represented by 52 led only to reductions in antidiabetic activity. Each of the new active analogues displayed the same resistance to creatine-like metabolism as 2. Further testing of 7, 9, and 53 in obese diabetic ob/ob mice confirmed that weight loss is induced selectively from adipose tissue, similar to the lead 1. Administration of 53 to insulin-resistant rhesus monkeys led to reductions in both fasting and post-prandial plasma glucose levels with concomitant reductions in plasma insulin levels, suggesting that the compound improved the action of endogenous insulin. Compounds 7 and 53 were selected for further preclinical development.

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α-Hydrazino- Acids. I. α-Hydrazinoaliphatic Acids and α-(1-Methylhydrazino)aliphatic Acids

Cited by 33 publications

References 2 publications

Peptidomimetics via modifications of amino acids and peptide bonds

Peptidomimetics via modifications of amino acids and peptide bonds

Synthesis and Chemistry of α‐Hydrazino Acids

Synthesis and Biological Activity of Aminoguanidine and Diaminoguanidine Analogues of the Antidiabetic/Antiobesity Agent 3-Guanidinopropionic Acid

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