10.1021/jm00087a012
This research aimed to synthesize and evaluate a series of 5-deazafolate and 5-deazatetrahydrofolate analogues as potential inhibitors of folylpolyglutamate synthetase (FPGS) and glycinamide ribonucleotide formyltransferase (GARFT), enzymes involved in folate metabolism and purine biosynthesis, respectively. The researchers synthesized analogues by replacing the glutamic acid side chain with homocysteic acid (HCysA), 2-amino-4-phosphonobutanoic acid (APBA), and ornithine (Om). The compounds were tested for their inhibitory effects on mouse liver FPGS and GARFT. The results showed that the analogues with HCysA and monoethyl APBA side chains were less active as FPGS inhibitors, while Orn and APBA analogues exhibited competitive inhibition kinetics and were more potent, with Ki values as low as 30 nM.
10.1021/jm00170a005
The research investigates purine derivatives and analogues as competitive inhibitors of human erythrocyte membrane phosphatidylinositol 4-kinase, with the aim of finding a potent, cell-penetrating inhibitor. The study explores the structural requirements for binding to the ATP site of PI 4-kinase and optimizes inhibitory potency. Key chemicals involved include various purine derivatives such as adenine, 6-substituted purines, 8-substituted adenines, and 9-substituted adenines. The most potent inhibitor synthesized was 9-cyclohexyladenine, with an apparent Ki value of 3.7 pM. Other chemicals like benzoic acid, polyphosphoric acid, and formamide were used in the synthesis of these compounds. The research also involved the use of ATP as the substrate in enzyme assays to determine the inhibitory activities of the synthesized compounds.
10.1021/jm00401a018
The research aims to develop more selective A1 adenosine receptor agonists by synthesizing and evaluating a series of 1-deaza analogues of adenosine derivatives. The study synthesized compounds such as p-[(R)-(-)-1-methyl-2-phenethyl]-1-deazaadenosine (1-deaza,R-PIA, 3a), NG-cyclopentyl-1-deazaadenosine (1-deazaCPA, 3b), NG-cyclohexyl-1-deazaadenosine (1-deazaCHA, 3c), and their 2-chloro derivatives, as well as N-ethyl-1'-deoxy-1'-(1-deaza-6-amino-9H-purin-9-yl)-β-D-ribofuranuronamide (1-deazaNECA, 10). The biological evaluation of these compounds in adenylate cyclase and radioligand binding studies revealed that 1-deazaNECA (10) is a nonselective agonist at both A1 and A2 adenosine receptors, being about 10-fold less active than NECA but more active than 1-deazaadenosine. The N6-substituted 1-deazaadenosines largely retain A1 agonist activity but lose some A2 agonist activity, resulting in A1-selective compounds, with p-cyclopentyl-2-chloro-1-deazaadenosine (1-deaza-2-Cl-CPA, 2b) identified as the most selective A1 agonist. The study concludes that the presence of the nitrogen atom at position 1 of the purine ring is not critical for A1 receptor-mediated adenosine actions.
10.1021/jo102579g
This research focuses on the synthesis of fluorinated purine and 1-deazapurine glycosides as potential inhibitors of adenosine deaminase (ADA) and inosine monophosphate dehydrogenase (IMPDH) enzymes. The study explores two synthetic strategies: a de novo approach involving the electrophilic annulation of pyridine and pyrimidine rings using fluorine-containing dielectrophiles, and a salvage approach starting with 5-aminoimidazole. The synthesis involves multiple steps, including glycosylation, deprotection, and the formation of stable hydrates. The resulting compounds are characterized using NMR and X-ray crystallography, providing a foundation for the design of enzyme inhibitors with potential therapeutic applications in treating diseases like cancer and genetic disorders.
10.1021/acs.jmedchem.0c02145
This research focuses on the development of new P2X7 antagonists to treat neuroinflammation associated with neurodegenerative diseases (NDDs). The study introduces a series of novel non-nucleotide purine derivatives designed to be blood-brain barrier (BBB)-permeable, with the goal of identifying potential therapeutic candidates for central nervous system (CNS) disorders. The compounds were synthesized by linking purine or xanthine cores to an aryl group through different short spacers. They were tested through various assays, including YO-PRO-1 uptake assays, intracellular calcium dynamics, two-electrode voltage-clamp recordings, and interleukin-1? release assays. The most potent and selective antagonist identified was compound 6 (ITH15004), which demonstrated significant P2X7 blockade, good BBB permeability, and selectivity for human P2X7 over rat P2X1, P2X2, and P2X4 receptors.
