Design, synthesis and evaluation of new quinazolin-4-one derivatives as apoptotic enhancers and autophagy inhibitors with potent antitumor activity.

European Journal of Medicinal Chemistry
Heba S A ElZahabiReem K Arafa

Abstract

This work presents the design and synthesis of a series of new quinazolin-4-one derivatives, based on the established effectiveness of quinazoline-based small molecules as anticancer agents. Synthesized compounds were more potent against MCF-7 than A-549 with low to submicromolar IC50s. Compound 17 exhibited the best IC50 being equipotent with the positive control doxorubicin (IC50 = 0.06 μM) and better than 5-fluorouracil (IC50 = 2.13 μM). Compound 17 was further tested against MDA-MB-231 and MCF-10A and was found to be > 2 folds more cytotoxic on MCF-7. Significant apoptotic activity was elicited by 17 on MCF-7 where it increased apoptotic cell death along with induction of pre-G1 and G1-phase cell cycle arrest. Similarly, 17 was able to induce apoptosis in MD-MB-231 treated cells associated with a disruption of the cell cycle causing arrest at the pre-G1 and S phases. Investigation of gene expression in MCF-7 demonstrated an increased expression of the proapoptotic genes P53, PUMA, Bax, caspases 3, 8 and 9 and a decrease of the anti-apoptotic gene Bcl2. Also, 17 reduced autophagy giving way for apoptosis to induce cancer cells death. This latter observation was associated with downregulation of EGFR and its downstream effect...Continue Reading

References

Jul 4, 1990·Journal of the National Cancer Institute·P SkehanM R Boyd
Dec 4, 2003·Biological & Pharmaceutical Bulletin·Veerachamy AlagarsamyRamachandran Venkateshperumal
Feb 25, 2005·The New England Journal of Medicine·Susumu KobayashiBalázs Halmos
Sep 23, 2006·Cell Death and Differentiation·M J AbedinA Kelekar
Jul 4, 2007·Genes & Development·Vassiliki Karantza-WadsworthEileen White
Dec 24, 2008·Nature Reviews. Cancer·Jianming ZhangNathanael S Gray
Jul 9, 2009·Chemical Reviews·Donna S Shewach, Robert D Kuchta
Jul 19, 2011·Genes & Development·Huijun WeiJun-Lin Guan
Dec 14, 2011·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hosam A SaadAhmed H Moustafa
Apr 27, 2012·Nature Reviews. Cancer·Eileen White
Sep 8, 2012·Cancer Biology & Therapy·Christopher FungUmamaheswar Duvvuri
Oct 5, 2013·European Journal of Medicinal Chemistry·Reem K ArafaNehad A El-Sayed
Feb 28, 2014·Molecular Pharmacology·Andrew ThorburnDaniel L Gustafson
Jun 27, 2014·BMC Research Notes·Sharon GlaysherIan A Cree
Dec 13, 2016·European Journal of Medicinal Chemistry·Mohamed A IsmailWael M El-Sayed
Mar 9, 2017·Current Topics in Medicinal Chemistry·Vikas SharmaVipin Kumar
May 21, 2017·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Nehal H ElghazawyReem K Arafa
Jul 14, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Mohamed F ZayedSabrin R M Ibrahim
Nov 8, 2018·International Journal of Molecular Sciences·Chul Won Yun, Sang Hun Lee
Jan 27, 2019·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Heba S A El-ZahabiReem K Arafa
May 21, 2019·European Journal of Medicinal Chemistry·Mohamed HishamMohamed Abdel-Aziz
Jan 23, 2020·Journal of Enzyme Inhibition and Medicinal Chemistry·Yi LeLongjia Yan
Apr 15, 2020·Scientific Reports·Abderrahim El GuerrabCorinne Aubel
Nov 28, 2020·European Journal of Medicinal Chemistry·Ranju Bansal, Anjleena Malhotra

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