Novel 1,2,4-triazole derivatives as apoptotic inducers targeting p53: Synthesis and antiproliferative activity

[Display omitted] •Novel thiazolo[3,2-b][1,2,4] triazoles 3a-n has been synthesized and evaluated in vitro as antiproliferative agents.•The most potent antiproliferative activity was found in compounds 3a, 3b, 3c and 3d.•Compounds 3b, 3c and 3d showed an increase of 15–27 in p53 level compared to th...

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Published in:Bioorganic chemistry 2020-12, Vol.105, p.104369-104369, Article 104369
Main Authors: Gomaa, Hesham A.M., El-Sherief, Hany A.M., Hussein, Shaimaa, Gouda, Ahmed M., Salem, Ola I.A., Alharbi, Khalid Saad, Hayallah, Alaa M., Youssif, Bahaa G.M.
Format: Article
Language:English
Subjects:
1,2,4-Triazole
Antiproliferative
Cell cycle and apoptosis
P53
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Summary:[Display omitted] •Novel thiazolo[3,2-b][1,2,4] triazoles 3a-n has been synthesized and evaluated in vitro as antiproliferative agents.•The most potent antiproliferative activity was found in compounds 3a, 3b, 3c and 3d.•Compounds 3b, 3c and 3d showed an increase of 15–27 in p53 level compared to the test cells.•In pre-G1 and G2/M phases compound 3b demonstrated the cell cycle arrest.•Compound 3b showed the highest affinity toward p53 binding domain in MDM2. A series of novel thiazolo[3,2-b][1,2,4]-triazoles 3a-n has been synthesized and evaluated in vitro as potential antiproliferative. Compounds 3b-d exhibited significant antiproliferative activity. Compound 3b was the most potent with Mean GI50 1.37 µM comparing to doxorubicin (GI50 1.13 µM). The transcription effects of 3b, 3c and 3d on the p53 were assessed and compared with the reference doxorubicin. The results revealed an increase of 15–27 in p53 level compared to the test cells and that p53 protein level of 3b, 3c and 3d was significantly inductive (1419, 571 and 787 pg/mL, respectively) in relation to doxorubicin (1263 pg/mL). The docking study of the new compounds 3a-n revealed high binding scores for the new compounds toward p53 binding domain in MDM2. The docking analyses revealed the highest affinities for compounds 3b-d which induced p53 activity in MCF-7 cancer cells. Compound 3b which exhibited the highest antiproliferative activity and induced the highest increase in p53 level in MCF-7 cells showed also the highest affinity to MDM2.
ISSN:0045-2068
1090-2120
DOI:10.1016/j.bioorg.2020.104369