Parallel Solution-Phase Synthesis of an Adenosine Antibiotic Analog Library

A library of eighty one adenosine antibiotic analogs was prepared under the Pilot Scale Library Program of the NIH Roadmap initiative from 5′-amino-5′-deoxy-2′,3′-<i>O</i>-isopropylidene-adenosine <b>3</b>. Diverse aldehyde, sulfonyl chloride and carboxylic acid reactant sets were condensed to <b>3</b>, in solution-phase fashion, leading after acid-mediated hydrolysis to the targeted compounds in good yields and high purity. No marked antituberculosis or anticancer activity was noted on preliminary cellular testing, but these nucleoside analogs should be useful candidates for other types of biological activity

Parallel Solution-Phase Synthesis and General Biological Activity of a Uridine Antibiotic Analog Library

A small library of ninety four uridine antibiotic analogs was synthesized, under the Pilot Scale Library (PSL) Program of the NIH Roadmap initiative, from amine <b>2</b> and carboxylic acids <b>33</b> and <b>77</b> in solution-phase fashion. Diverse aldehyde, sulfonyl chloride, and carboxylic acid reactant sets were condensed to <b>2</b>, leading after acid-mediated hydrolysis, to the targeted compounds <b>3</b>–<b>32</b> in good yields and high purity. Similarly, treatment of <b>33</b> with diverse amines and sulfonamides gave <b>34</b>–<b>75</b>. The coupling of the amino terminus of d-phenylalanine methyl ester to the free 5′-carboxylic acid moiety of <b>33</b> followed by sodium hydroxide treatment led to carboxylic acid analog <b>77</b>. Hydrolysis of this material gave analog <b>78</b>. The intermediate <b>77</b> served as the precursor for the preparation of novel dipeptidyl uridine analogs <b>79</b>–<b>99</b> through peptide coupling reactions to diverse amine reactants. None of the described compounds show significant anticancer or antimalarial acivity. A number of samples exhibited a variety of promising inhibitory, agonist, antagonist, or activator properties with enzymes and receptors in primary screens supplied and reported through the NIH MLPCN program

Discovery of novel delta opioid receptor (Dor) inverse agonist and irreversible (non-competitive) antagonists

The delta opioid receptor (DOR) is a crucial receptor system that regulates pain, mood, anxiety, and similar mental states. DOR agonists, such as SNC80, and DOR-neutral antagonists, such as naltrindole, have been developed to investigate the DOR in vivo and as potential therapeutics for pain and depression. However, few inverse agonists and non-competitive/irreversible antagonists have been developed, and none are widely available. This leaves a gap in our pharmacological toolbox and limits our ability to investigate the biology of this receptor. Thus, we designed and synthesized the novel compounds SRI-9342 as an irreversible antagonist and SRI-45127/SRI-45128 as inverse agonists. Then, these compounds were evaluated in vitro for their binding affinity by radioligand binding and functional activity by35 S-GTPγS coupling and cAMP accumulation in cells expressing the human DOR. All three compounds demonstrated high binding affinity and selectivity at the DOR, and all three displayed their hypothesized molecular pharmacology of irreversible antagonism (SRI-9342) or inverse agonism (SRI-45127/SRI-45128). Together, these results demonstrate that we have designed new inverse agonists and irreversible antagonists of the DOR based on a novel chemical scaffold. These new compounds will provide new tools to investigate the biology of the DOR or even new potential therapeutics. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]