73094-99-2Relevant academic research and scientific papers
Crystal structures of N6-modified-amino acid related nucleobase analogs (II): Hybrid adenine-β-alanine and adenine-GABA molecules
García-Raso, Angel,Terrón, Angel,López-Zafra, Adela,García-Viada, Andrés,Barta, Agostina,Frontera, Antonio,Lorenzo, Julia,Rodríguez-Calado, Sergi,Vázquez-López, Ezequiel M.,Fiol, Juan J.
, p. 9680 - 9688 (2019/06/24)
In this manuscript we report the synthesis and X-ray characterization of four N6-amino acid/peptide-adenine-derivatives: N6-βAlaAde·1.5H2O (1) and N6-GABAAde·2H2O (2) and their corresponding protonated forms N6-βAlaAde·HCl (3) and N6-GABAAde·HCl (4). In (1) with a neutral adenine ring, the protonated carboxylate interacts with the N(7) and N(6)H of the neighbouring molecule. The hydrogen bond N9-H?N(3) and the hydrogen bonds between the water molecules are responsible for the planar and parallel disposition of the adenine rings. In (2), two different molecules are present in the crystal structure: (a) a cationic unit in which the N(7)H tautomeric adenine is protonated at N(3) and the carboxylic group interacts with N(6B)-H and N(7B) of the adjacent molecule; (b) an anionic unit, which presents the adenine ring in the N(9)H tautomeric form, where the carboxylate interacts with the N(7A)H and N(6A)H of the neighbouring adenine. In the hydrochloride form of N6-βAlaAde (compound 3) the amino acid chain with the carboxylic acid is almost orthogonal to the ring plane and exhibits protonation at N(3) of the adenine. On the other hand, in compound (4), the side chain is arranged parallel to the ring and anion (Cl-)-π interactions are responsible for a parallel ordering of the final solid state architecture. We have studied the noncovalent interactions observed in the solid state architecture energetically using DFT calculations and rationalized the interactions using Molecular Electrostatic Potential surfaces and Bader's theory of "Atoms-in-Molecules". The main purpose of this study is to explore the competition between homodimer formation by the Hoogsteen site of the adeninium cation, and self-association of the carboxylic group or through the interaction of the carboxylic group with the adeninium cation by X-ray crystallography.
Synthesis and biological activity of analogues of the antidiabetic/antiobesity agent 3-guanidinopropionic acid: Discovery of a novel aminoguanidinoacetic acid antidiabetic agent
Larsen,Connell,Cudahy,Evans,May,Meglasson,O'Sullivan,Schostarez,Sih,Stevens,Tanis,Tegley,Tucker,Vaillancourt,Vidmar,Watt,Yu
, p. 1217 - 1230 (2007/10/03)
3-Guanidinopropionic acid (1, PNU-10483) has been demonstrated to both 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 4. In an effort to identify novel entities that maintain antidiabetic potency without susceptibility to creatine-like metabolism, an analogue program was undertaken to explore the effects of various structural modifications, including homologation, simple substitution, single atom mutations, and bioisosteric replacements for the guanidine and carboxylic acid. Overall, the scope of activity encompassed by the set of new analogues proved to be exceedingly narrow. Notable exceptions demonstrating equivalent or improved antidiabetic activity included the α-amino derivative 29, aminopyridine 47, isothiourea 67, and aminoguanidine 69. On the basis of its superior therapeutic ratio, aminoguanidine 69 was selected for preclinical development and became the foundation for a second phase of analogue work. Furthermore, in vitro studies demonstrated that 69 is markedly less susceptible to phosphorylation by creatine kinase than the lead 1, suggesting that it should have less potential for accumulation in muscle tissue than 1.
