Abstract
Background: Extensive research has been conducted on aspirin, a widely recognized NSAID medication, regarding its potential as an anticancer agent. Studies have revealed its ability to trigger cell death in different types of cancer cells.
Methods: A set of aspirin-chalcone mimic conjugates 5a-k and 6a-d utilizing the freshly prepared acid chloride of aspirin moiety has been designed and synthesized. To evaluate the newly developed compounds, the NCI 60- cell line panel was employed to assess their anti-proliferative properties. Subsequently, cell cycle analysis was conducted along with an examination of the compounds' impact on the levels of p53, Bax, Bcl-2, active caspase- 3, and their inhibition mechanism of tubulin polymerization.
Results: Derivative 6c displayed the best anticancer activity among the tested series while 6d was the best against breast cancer MDA-MB-468, therefore both of them were selected for the 5-dose stage, however, targeting MDA-MB-468, PI-flow cytometry of compound 6d proved the triggered cell growth arrest at the G1/S phase avoiding the mitotic cycle in MDA-MB-468 cells. Similarly, the upregulation of oncogenic parameters such as caspase-3, p53, and Bax/Bcl-2, along with the inhibition of PARP-1 enzyme level, was observed with compound 6d. This compound also exhibited a significant ability to induce apoptosis and disrupt the intracellular microtubule network through a promising activity as a tubulin polymerization inhibitor with IC50 = 1.065 ± 0.024 ng/ml. Furthermore, to examine the manner in which compound 6d binds to the active pocket of the tubulin polymerization enzyme, a molecular docking study was conducted.
Conclusion: The study indicated that compound 6d could be a powerful microtubule-destabilizing agent. Therefore, further research on 6d could be worthwhile.
Graphical Abstract
[http://dx.doi.org/10.1080/13543776.2019.1648433] [PMID: 31353978]
[http://dx.doi.org/10.1177/1758834014539183] [PMID: 25342987]
[http://dx.doi.org/10.1016/C2019-0-00369-X]
[http://dx.doi.org/10.1016/j.bmcl.2017.07.069] [PMID: 28797799]
[http://dx.doi.org/10.3892/br.2019.1196] [PMID: 30972217]
[http://dx.doi.org/10.2174/15748928113089990042] [PMID: 23746164]
[http://dx.doi.org/10.1038/bjc.2014.271] [PMID: 24874482]
[http://dx.doi.org/10.1007/s00203-021-02200-1] [PMID: 33620523]
[http://dx.doi.org/10.1038/cddiscovery.2017.58] [PMID: 28900541]
[http://dx.doi.org/10.3892/or.2014.3373] [PMID: 25109257]
[http://dx.doi.org/10.1158/1541-7786.MCR-15-0360] [PMID: 26685215]
[http://dx.doi.org/10.1038/s41598-020-76824-6] [PMID: 33184378]
[http://dx.doi.org/10.1038/srep45184] [PMID: 28327594]
[http://dx.doi.org/10.1038/cddis.2015.153] [PMID: 26068794]
[http://dx.doi.org/10.1038/s41571-020-00459-9] [PMID: 33469195]
[http://dx.doi.org/10.3390/ijms21239018] [PMID: 33260951]
[http://dx.doi.org/10.3390/molecules25092243] [PMID: 32397626]
[http://dx.doi.org/10.1038/nrc.2016.4] [PMID: 26868177]
[http://dx.doi.org/10.1007/s13277-015-3959-0] [PMID: 26314861]
[http://dx.doi.org/10.1038/emm.2013.91] [PMID: 24113271]
[http://dx.doi.org/10.1038/srep40119] [PMID: 28067282]
[http://dx.doi.org/10.1038/nrc1588] [PMID: 15803156]
[http://dx.doi.org/10.1038/sj.onc.1209658] [PMID: 16878161]
[http://dx.doi.org/10.1038/sj.bjc.6600289] [PMID: 11986787]
[http://dx.doi.org/10.3389/fphar.2017.00145] [PMID: 28377721]
[http://dx.doi.org/10.1097/CMR.0b013e3283107df7] [PMID: 18971789]
[http://dx.doi.org/10.1016/j.bmcl.2012.10.060] [PMID: 23137434]
[http://dx.doi.org/10.1016/j.bmc.2011.01.047] [PMID: 21371895]
[http://dx.doi.org/10.1093/jnci/83.11.757] [PMID: 2041050]
[http://dx.doi.org/10.1038/nrc1951] [PMID: 16990858]
[http://dx.doi.org/10.1002/ddr.430340203]
[http://dx.doi.org/10.1158/1535-7163.MCT-10-0106] [PMID: 20442306]
[http://dx.doi.org/10.1677/erc.0.0060017] [PMID: 10732781]
[PMID: 8183579]
[http://dx.doi.org/10.1067/mai.2001.117819] [PMID: 11586274]
[http://dx.doi.org/10.1080/01926230701320337] [PMID: 17562483]
[http://dx.doi.org/10.1016/j.ejmech.2017.05.017] [PMID: 28494257]
[http://dx.doi.org/10.1016/j.ejmech.2016.12.021] [PMID: 28027532]
[http://dx.doi.org/10.1016/j.bioorg.2017.10.016] [PMID: 29153588]
[http://dx.doi.org/10.1016/B978-0-12-382219-2.00506-8]
[http://dx.doi.org/10.1016/j.ejmech.2017.04.028] [PMID: 28427017]
[http://dx.doi.org/10.3892/or.11.2.421] [PMID: 14719078]
[http://dx.doi.org/10.1038/sj.onc.1207116] [PMID: 14663481]
[http://dx.doi.org/10.1016/j.bmc.2020.115657] [PMID: 32828424]
[http://dx.doi.org/10.1016/j.ejmech.2018.07.037] [PMID: 30041135]
[http://dx.doi.org/10.1080/14737140.2018.1458613] [PMID: 29582690]
[PMID: 23923393]
[http://dx.doi.org/10.1186/s12916-015-0425-1] [PMID: 26268938]
[http://dx.doi.org/10.1016/j.bioorg.2021.105466] [PMID: 34775204]