Abstract
For the development of novel anticancer agents, we designed and synthesized a total of 37 perimidine o-quinone derivatives containing the o-quinone group at the A or B ring and different substituents (alkyl groups, aryl groups or heterocycles) at the C ring of the compounds. The structure-activity relationships (SARs) were established based on the cytotoxicity data of compounds from the HL-60, Huh7, Hct116, and Hela cell lines. The cytotoxicity results showed that most compounds exhibited potent cytotoxicity. In particular, compound b-12 showed the best anti-proliferative activity (IC50 ≤ 1 μM) against four cancer cell lines and strong potency against the HL-60/MX2 (0.47 μM) cell line, which is resistant to Topo II poisons. Further studies showed that b-12 exhibited potent Topo IIα inhibitory activity (IC50 = 7.54 μM) compared with Topo I, which acted as a class of non-intercalative Topo IIα catalytic inhibitor by inhibiting the ATP binding site of Topo II. Cell apoptosis and cell cycle assays confirmed that b-12 could induce the apoptosis of Huh7 cells in a dose-dependent manner.
References
Oct 5, 1984·Biochimica Et Biophysica Acta·B S GlissonW E Ross
Dec 16, 1983·Journal of Immunological Methods·T Mosmann
Jun 8, 2001·Annual Review of Biochemistry·J J Champoux
Feb 12, 2002·Bioorganic & Medicinal Chemistry·Maria DzieduszyckaEdward Borowski
Jul 31, 2003·Pharmacology & Therapeutics·Annette K LarsenAndrzej Skladanowski
May 14, 2004·Environmental and Molecular Mutagenesis·Mauricio LehmannHeloísa Helena Rodrigues de Andrade
Jul 17, 2004·Biological & Pharmaceutical Bulletin·Dong WangTakashi Ikejima
Aug 8, 2007·Mutation Research·A Kathleen McClendon, Neil Osheroff
Jun 28, 2008·Free Radical Biology & Medicine·Yu-Jun CaiJian Ding
Dec 2, 2008·Nucleic Acids Research·Joseph E Deweese, Neil Osheroff
Apr 27, 2011·Molecular Nutrition & Food Research·Faiza M KalfalahFritz Boege
Aug 8, 2012·Journal of Medicinal Chemistry·Guoqiang DongChunquan Sheng
Apr 5, 2013·Archiv der Pharmazie·Thoraya A Farghaly, Huda K Mahmoud
Jul 9, 2016·Oncotarget·Paulina RybakJerzy Dobrucki
Aug 4, 2016·European Journal of Medicinal Chemistry·Seojeong ParkYounghwa Na
Jan 18, 2017·Bioorganic & Medicinal Chemistry·Balagani Sathish KumarArvind S Negi