N6-Substituted 5′-N-Methylcarbamoyl-4′-selenoadenosines as Potent and Selective A3 Adenosine Receptor Agonists with Unusual Sugar Puckering and Nucleobase Orientation

Yu, Jinha; Zhao, Long; Park, Jongmi; Lee, Hyuk Woo; Sahu, Pramod K.; Cui, Minghua; Moss, Steven M.; Hammes, Eva; Warnick, Eugene; Gao, Zhan Guo; Noh, Minsoo; Choi, Sun; Ahn, Hee Chul; Choi, Jungwon; Jacobson, Kenneth A.; Jeong, Lak Shin

doi:10.1021/acs.jmedchem.7b00241

Cited by 23 publications

(10 citation statements)

References 49 publications

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“…For the synthesis of final compounds 9a–l , key intermediates, 4′-seleno purine nucleosides 15a–b were synthesized from D-ribose following the previously reported procedures [ 18 , 19 ] ( Scheme 1 ). Briefly, D-ribose was converted to L-lyxonolactone derivative 10 in three steps (oxidation to lactone, conversion of D-ribo configuration to L-lyxo configuration, and tert -butyldiphenylsililyl (TBDPS) protection).…”

Section: Resultsmentioning

confidence: 99%

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Design and Synthesis of 2,6-Disubstituted-4′-Selenoadenosine-5′-N,N-Dimethyluronamide Derivatives as Human A3 Adenosine Receptor Antagonists

Choi

Jeong

2021

Pharmaceuticals

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A new series of 4′-selenoadenosine-5′-N,N-dimethyluronamide derivatives as highly potent and selective human A3 adenosine receptor (hA3AR) antagonists, is described. The highly selective A3AR agonists, 4′-selenoadenosine-5′-N-methyluronamides were successfully converted into selective antagonists by adding a second N-methyl group to the 5′-uronamide position. All the synthesized compounds showed medium to high binding affinity at the hA3AR. Among the synthesized compounds, 2-H-N6-3-iodobenzylamine derivative 9f exhibited the highest binding affinity at hA3AR. (Ki = 22.7 nM). The 2-H analogues generally showed better binding affinity than the 2-Cl analogues. The cAMP functional assay with 2-Cl-N6-3-iodobenzylamine derivative 9l demonstrated hA3AR antagonist activity. A molecular modelling study suggests an important role of the hydrogen of 5′-uronamide as an essential hydrogen bonding donor for hA3AR activation.

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Section: Resultsmentioning

confidence: 99%

“…On the basis of a bioisosteric rationale, we recently reported that 4′-seleno analogues of 1 and 2 , i.e., 7 and 8 , were discovered as potent and selective hA 3 AR agonists [ 19 ] ( Figure 2 ). They exhibited comparable A 3 AR binding affinity as the corresponding 4′-oxo- and 5′-thio nucleosides 1 and 2 .…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of 2,6-Disubstituted-4′-Selenoadenosine-5′-N,N-Dimethyluronamide Derivatives as Human A3 Adenosine Receptor Antagonists

Choi

Jeong

2021

Pharmaceuticals

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“…The N-terminal and C-terminal were truncated (residues 1‒8 and 305‒318). The hA 3 AR homology model was then constructed using Prime [36], based on the crystal structure of the active-state hA 2A AR bound to the selective agonist UK-432,097 as a template (PDB ID: 3QAK) [37]. The disulphide bridge between Cys83 3.25 and Cys166 45.50 in hA 3 AR was conserved.…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis and Evaluation of New Indolylpyrimidylpiperazines for Gastrointestinal Cancer Therapy

et al. 2019

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Human A3 adenosine receptor hA3AR has been implicated in gastrointestinal cancer, where its cellular expression has been found increased, thus suggesting its potential as a molecular target for novel anticancer compounds. Observation made in our previous work indicated the importance of the carbonyl group of amide in the indolylpyrimidylpiperazine (IPP) for its human A2A adenosine receptor (hA2AAR) subtype binding selectivity over the other AR subtypes. Taking this observation into account, we structurally modified an indolylpyrimidylpiperazine (IPP) scaffold, 1 (a non-selective adenosine receptors’ ligand) into a modified IPP (mIPP) scaffold by switching the position of the carbonyl group, resulting in the formation of both ketone and tertiary amine groups in the new scaffold. Results showed that such modification diminished the A2A activity and instead conferred hA3AR agonistic activity. Among the new mIPP derivatives (3–6), compound 4 showed potential as a hA3AR partial agonist, with an Emax of 30% and EC50 of 2.89 ± 0.55 μM. In the cytotoxicity assays, compound 4 also exhibited higher cytotoxicity against both colorectal and liver cancer cells as compared to normal cells. Overall, this new series of compounds provide a promising starting point for further development of potent and selective hA3AR partial agonists for the treatment of gastrointestinal cancers.

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“…The replacement of the ribose ring O of Cl‐IB‐MECA with S and Se, that is, 19 a and 19 b , is tolerated with only minor changes in A 3 AR affinity [75] . This was surprising because the Se analogue of Cl‐IB‐MECA 3 has a south conformation in its pure crystalline state, but in the AR binding site a north conformation is required, according to multiple A 1 AR and A 2A AR structures.…”

Section: Design Of Ar Agonists and Their Receptor Interactionsmentioning

confidence: 99%

Purinergic Signaling: Impact of GPCR Structures on Rational Drug Design

Salmaso

2020

ChemMedChem

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The purinergic signaling system includes membrane‐bound receptors for extracellular purines and pyrimidines, and enzymes/transporters that regulate receptor activation by endogenous agonists. Receptors include: adenosine (A1, A2A, A2B, and A3) and P2Y (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14) receptors (all GPCRs), as well as P2X receptors (ion channels). Receptor activation, especially accompanying physiological stress or damage, creates a temporal sequence of signaling to counteract this stress and either mobilize (P2Rs) or suppress (ARs) immune responses. Thus, modulation of this large signaling family has broad potential for treating chronic diseases. Experimentally determined structures represent each of the three receptor families. We focus on selective purinergic agonists (A1, A3), antagonists (A3, P2Y14), and allosteric modulators (P2Y1, A3). Examples of applying structure‐based design, including the rational modification of known ligands, are presented for antithrombotic P2Y1R antagonists and anti‐inflammatory P2Y14R antagonists and A3AR agonists. A3AR agonists are a potential, nonaddictive treatment for chronic neuropathic pain.

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N⁶-Substituted 5′-N-Methylcarbamoyl-4′-selenoadenosines as Potent and Selective A₃ Adenosine Receptor Agonists with Unusual Sugar Puckering and Nucleobase Orientation

Cited by 23 publications

References 49 publications

Design and Synthesis of 2,6-Disubstituted-4′-Selenoadenosine-5′-N,N-Dimethyluronamide Derivatives as Human A3 Adenosine Receptor Antagonists

Design and Synthesis of 2,6-Disubstituted-4′-Selenoadenosine-5′-N,N-Dimethyluronamide Derivatives as Human A3 Adenosine Receptor Antagonists

Design, Synthesis and Evaluation of New Indolylpyrimidylpiperazines for Gastrointestinal Cancer Therapy

Purinergic Signaling: Impact of GPCR Structures on Rational Drug Design

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