Severity: Warning
Message: file_get_contents(https://...@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
Filename: helpers/my_audit_helper.php
Line Number: 143
Backtrace:
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 143
Function: file_get_contents
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 209
Function: simplexml_load_file_from_url
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 994
Function: getPubMedXML
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3134
Function: GetPubMedArticleOutput_2016
File: /var/www/html/application/controllers/Detail.php
Line: 574
Function: pubMedSearch_Global
File: /var/www/html/application/controllers/Detail.php
Line: 488
Function: pubMedGetRelatedKeyword
File: /var/www/html/index.php
Line: 316
Function: require_once
Based on hAAR structures, a hydrophobic C8-heteroaromatic ring in 5'-truncated adenosine analogues occupies the subpocket tightly, converting hAAR agonists into antagonists while maintaining affinity toward hAAR. The final compounds of 2,8-disubstituted--substituted 4'-thionucleosides, or 4'-oxo, were synthesized from d-mannose and d-erythrono-1,4-lactone, respectively, using a Pd-catalyst-controlled regioselective cross-coupling reaction. All tested compounds completely antagonized hAAR, including with the highest affinity ( = 7.7 ± 0.5 nM). The hAAR- X-ray structure revealed that C8-heteroaromatic rings prevented receptor activation-associated conformational changes. However, the C8-substituted compounds still antagonized hAAR. Structural SAR features and docking studies supported different binding modes at AAR and AAR, elucidating pharmacophores for receptor activation and selectivity. Favorable pharmacokinetics were demonstrated, in which displayed high oral absorption, moderate half-life, and bioavailability. Also, significantly improved the antitumor effect of anti-PD-L1 . Overall, this study suggests that the novel dual AAR/AAR nucleoside antagonists would be promising drug candidates for immune-oncology.
Download full-text PDF |
Source |
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10896643 | PMC |
http://dx.doi.org/10.1021/acs.jmedchem.3c00806 | DOI Listing |
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