Refernces
10.1007/BF00758270
This research presents two distinct studies within the realm of drug development. The first study focuses on the synthesis and antiarrhythmic activity of epimeric 17-amino-5α-androstan-3-ols and their derivatives. The purpose was to create simpler 5α-steroids from plant material and evaluate their potential in treating cardiac arrhythmias. The most active compound identified was the 3β,17β-epimer (I), which led to the development of N-alkyl and N-aminoacyl derivatives. The second study investigates the synthesis and antihypertensive activity of N-acetylmercaptopropionyl-6-(2'-phenylethyl)pipecolic acids, aiming to develop new drugs that target the renin-angiotensin and kallikrein-kinin systems to control blood pressure. The chemicals used in these processes include various steroidal amines, aminoalcohols, aminosteroids, and N-acetylmercaptopropionyl derivatives of pipecolic acids, among others. The conclusions drawn from the antiarrhythmic study suggest that the configuration of hydroxyl and amino groups significantly affects the compounds' activity, with certain epimeric forms showing high activity but also higher toxicity compared to quinidine. The antihypertensive study highlights the potential of N-acetylmercaptopropionylpipecolic acids with specific structural modifications to exhibit significant blood pressure-lowering effects.
10.1016/S0040-4020(01)93166-7
The research investigates the synthesis and properties of N-nitroso derivatives of several amino acids. Sarcosine, azetidine-2-carboxylic acid, hydroxyproline, and pipecolic acid play crucial roles as the primary precursors for the synthesis of their respective N-nitroso derivatives. These derivatives are of significant interest due to their potential carcinogenic properties and their possible formation in the human stomach from dietary nitrites and amino acids. The study aims to understand the formation and characteristics of these nitrosamino acids, which could potentially be relevant to the occurrence of human cancer due to their possible formation in the mammalian stomach from dietary nitrites and amino acids. The researchers prepared these compounds and characterized them using various analytical techniques such as NMR spectroscopy, mass spectrometry, and UV absorption spectroscopy. They found that these compounds are colorless crystalline solids with high yields and are highly soluble in water and most organic solvents. The study also explored the conformational preferences of these compounds in the crystalline state and their behavior in different solvents. The findings suggest that these nitrosamino acids can decarboxylate in dilute alkali to form N-nitrosamines, which are known to be toxic and carcinogenic. The research concludes that the properties of these compounds could have significant implications for understanding the potential carcinogenic activity of nitrosamino acids formed in the human stomach.
10.1016/S0960-894X(98)00231-5
The research aims to develop and evaluate a new series of 4-substituted pipecolic acid derivatives as potential antagonists for the CCK-B receptor. Cholecystokinin (CCK) is a peptide hormone involved in various physiological processes, mediated by two receptors, CCK-A and CCK-B. The study focuses on the CCK-B receptor, which has suggested the existence of two subtypes through experiments using CCK-B ligands. The researchers designed and synthesized a series of dipeptoids with a piperidine ring replacing pyrrolidine, aiming to modify the relative orientation of the aromatic moiety towards the carboxylate while maintaining the essential requirements for CCK-B binding. Key chemicals used in the study include 4-substituted pipecolic acids, 2-Adoc-DL-t-methyltryptophan, and various reagents for synthesis and protection steps, such as Boc2O, NaOH, DEAD, PPh3, and Z-CI. The synthesized dipeptoids were evaluated for their ability to inhibit [3H]pCCK-8 binding to the CCK-B receptor in CHO cells. The results showed a general loss of affinity compared to proline-containing dipeptoids, with the most potent compound (9e) having a Ki value of 175.2 nM for CCK-B receptors. The study concludes that while the piperidine ring does not force the essential features for CCK-B recognition into an optimal fit, the final compounds are better ligands than other similar molecules derived from CCK4. The research also suggests a W-shaped bioactive conformation of peptoid CCK-B antagonists, providing valuable insights for further investigations in this field.
10.1021/ja0587603
The research presents an in-depth study on the biosynthesis of pipecolic acid by RapL, a lysine cyclodeaminase enzyme encoded in the rapamycin gene cluster. The main focus of the study is to validate RapL's ability to convert L-lysine to L-pipecolic acid through a cyclodeamination reaction involving redox catalysis. The researchers heterologously overexpressed and purified RapL, and conducted a series of experiments to confirm its enzymatic activity. They used L-lysine and L-[U-14C]ornithine as substrates, NAD+ as a cofactor, and analyzed the reactions using techniques such as cellulose thin layer chromatography (TLC), chiral radio-HPLC, and mass spectrometry. The study also investigated the enzyme's substrate specificity, cofactor requirements, and inhibitory properties. Additionally, the researchers used isotopically labeled substrates to dissect the mechanistic details of the cyclodeaminase reaction, confirming the loss of the R-amine and retention of the hydrogen atom at the R-carbon. The experiments provided the first in vitro characterization of a lysine cyclodeaminase and contributed to the understanding of the biosynthesis of medically important natural products like rapamycin, FK506, and FK520.
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