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
Novel anti-proliferative agents possessing pyrimidine scaffolds were designed, synthesized and evaluated for their IC values using MTT assay. Most compounds displayed good to excellent activity against the two tested breast cancer lines (MCF-7 and MDA-MB-231) as compared to 5-FU. The observed IC values for active compounds ranged from 0.27 to 10.57 µM in MCF-7 compared to the reference drug 5-FU (IC = 10.80 µM) and from 0.73 to 29.07 µM in MDA-MB-231 (IC for 5-FU = 11.40 µM). SAR analysis indicated that compounds 2c, 3b with hydrazone functionalities and compound 12 possessing pyrazolone ring exhibited superior activities. The most promising compounds were evaluated for their inhibitory activity against epidermal growth factor receptor (EGFR) and aromatase (ARO) enzymes and were further tested for caspase-9 activation, apoptosis and Annexin V/PI staining. Results of enzyme-based experiments indicated that the tested compounds 2c and 12 exert their activities through EGFR inhibition while compound 3b exhibited remarkable ARO inhibition activity. Furthermore, they remarkably induce caspase-9 activation and showed pre G1 apoptosis and cell cycle arrest at G2/M phase. In addition, docked compounds displayed good binding affinities to the target enzymes. Binding interaction details for the most promising inhibitors with the active site of the target enzymes EGFR and ARO utilizing MOE-dock method are also reported.
Download full-text PDF |
Source |
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http://dx.doi.org/10.1016/j.bioorg.2020.103798 | DOI Listing |
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