Design, Synthesis, and Biological Activity of 5\u27-Phenyl-1,2,5,6-tetrahydro-3,3\u27-bipyridine Analogues as Potential Antagonists of Nicotinic Acetylcholine Receptors

Starting from a known non-specific agonist (1) of nicotinic acetylcholine receptors (nAChRs), rationally guided structural-based design resulted in the discovery of a small series of 5′-phenyl-1,2,5,6-tetrahydro-3,3′-bipyridines (3a – 3e) incorporating a phenyl ring off the pyridine core of 1. The compounds were synthesized via successive Suzuki couplings on a suitably functionalized pyridine starting monomer 4 to append phenyl and pyridyl substituents off the 3- and 5-positions, respectively, and then make subsequent modifications on the flanking pyridyl ring to provide target compounds. Compound 3a is a novel antagonist which is highly selective for α3β4 nAChR (Ki = 123 nM) over the α4β2, and α7 receptors

Synthesis of deuterium‐labelled amlexanox and its metabolic stability against mouse, rat, and human microsomes

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149374/1/jlcr3716_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149374/2/jlcr3716.pd

Evolution of eukaryal tRNA-guanine transglycosylase: insight gained from the heterocyclic substrate recognition by the wild-type and mutant human and Escherichia coli tRNA-guanine transglycosylases

The enzyme tRNA-guanine transglycosylase (TGT) is involved in the queuosine modification of tRNAs in eukarya and eubacteria and in the archaeosine modification of tRNAs in archaea. However, the different classes of TGTs utilize different heterocyclic substrates (and tRNA in the case of archaea). Based on the X-ray structural analyses, an earlier study [Stengl et al. (2005) Mechanism and substrate specificity of tRNA-guanine transglycosylases (TGTs): tRNA-modifying enzymes from the three different kingdoms of life share a common catalytic mechanism. Chembiochem, 6, 1926–1939] has made a compelling case for the divergent evolution of the eubacterial and archaeal TGTs. The X-ray structure of the eukaryal class of TGTs is not known. We performed sequence homology and phylogenetic analyses, and carried out enzyme kinetics studies with the wild-type and mutant TGTs from Escherichia coli and human using various heterocyclic substrates that we synthesized. Observations with the Cys145Val (E. coli) and the corresponding Val161Cys (human) TGTs are consistent with the idea that the Cys145 evolved in eubacterial TGTs to recognize preQ1 but not queuine, whereas the eukaryal equivalent, Val161, evolved for increased recognition of queuine and a concomitantly decreased recognition of preQ1. Both the phylogenetic and kinetic analyses support the conclusion that all TGTs have divergently evolved to specifically recognize their cognate heterocyclic substrates

Ready access to 7,8‐dihydro‐ and 1,2,3,4‐tetrahydro‐1,6‐naphthyridine‐5(6 H )‐ones from simple pyridine precursors

Short pathways are described for the synthesis of a representative example of each of the 7,8‐dihydro‐and 1,2,3,4‐tetrahydro‐1,6‐naphthyridine‐5(6 H )‐one ring systems from simple pyridine precursors. An attempted synthesis of the related 4,6‐dihydro‐1,6‐naphthyridin‐5(1 H )‐one ring system from a common intermediate was unsuccessful.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96253/1/5570430525_ftp.pd

Synthesis of azide congeners of preQ1 as potential substrates for tRNA guanine transglycosylase

PreQ1 (2) is a precursor of queuine (1) that in eubacteria is incorporated into transfer RNA (tRNA) by tRNA guanine transglycosylase (TGT) before being further elaborated into queuine. The queuine modification is unusual and occurs across all eukaryotes and eubacteria with few exceptions, but its function remains unclear. As the modified nucleotide occurs through incorporation of a specially synthesized nucleotide instead of via modification of a genetically encoded base, a study of the sites of modification by prepared probes is possible. We report the synthesis of two novel azide congeners (3,4) of preQ1 for this purpose. The evaluation of their interaction with TGT shows that both probes act as weak competitive inhibitors of guanine exchange of guanine(34) tRNATyr with a Ki of ~70 μM. However, we could not show that these are substrates for TGT‐catalyzed incorporation into tRNA. We believe the reason for this is a marked loss of binding due to the azide functionality of 3 and 4 abrogating the possibility of two hydrogen bonds to the carbonyl group of Leu231 and Met260 of TGT, previously observed for the terminal methylene amine of preQ1 by x‐ray crystallography.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167482/1/jhet4220.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167482/2/jhet4220_am.pd

A novel synthesis of substituted 3‐amino and 3‐thio pyrimido[5,4‐e]‐1,2,4‐triazine‐5,7(1H,6H)‐diones

Fervenulin is a natural product that has been extensively studied due to its molecular features and breadth of biological activities. Published studies have reported the generation of numerous analogues of the bicyclic pyrimidotriazinodione core. One underrepresented subclass are compounds with electron releasing atoms bonded directly to the C‐3 position. We report an efficient and straightforward synthesis of compounds with substituted amino and thio functionality attached to the C‐3 position. These are derived from a common 3‐chloro precursor that is made in six steps in 15.8% overall yield from a starting chlorouracil. Our methodology should be applicable to the synthesis of C‐3 ether congeners also, and through previously described chemistry be expandable to incorporating diversity at the N‐6 position of the pyrimidotriazinodione core. The chemistry reported herein expands possibilities for the generation of diverse libraries of substituted pyrimidotriazinediones for future studies.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/169339/1/jhet4263_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/169339/2/jhet4263.pd