Synthesis Of Novel Naphthoquinone Derivatives As Heat Shock Protein 90 Inhibitors And Anti-Breast Cancer Agents
محل انتشار: دومین سمپوزیوم بین المللی سرطان نسترن
سال انتشار: 1395
نوع سند: مقاله کنفرانسی
زبان: انگلیسی
مشاهده: 446
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NASTARANCANSER02_018
تاریخ نمایه سازی: 22 دی 1396
چکیده مقاله:
Naphthoquinone based natural products are known to possess anti-cancer activity. On the otherhand, the discovery of Hsp90 as the target of anticancer activity of geldanamycin devoted muchattention in the inhibition of Hsp90 as a tactic for the treatment of cancer. This interest has led tohuge efforts to develop clinically practical small molecule Hsp90 inhibitors possessing quinonemoiety, in this study we designed, synthesized and characterized different classes ofnaphthoquinone derivatives as Hsp90 inhibitors and anticancer agents. For synthesis of desiredcompounds, initially, 2-hydroxy-1,4-naphthoquinone, aldehyde, amine (in equivalent mole ratio)and InCl3 (20% mole) was refluxed in appropriate solvent for distinct time and the final product waspurified by chromatography methods. Then the structures of synthesized compounds weredetermined by IR, 1H-NMR, 13C-NMR and Mass spectra and finally their anticancer activities wereexamined against two human cell lines including MCF-7 and PC-3 by MTT test. The effects of twopotent anti-breast cancer compounds on Her2 protein expression levels were evaluated in MCF-7cancer cells employing western blot analysis. Molecular docking studies of potent cytotoxic agentsinto the binding site of HSP90 demonstrated possible mode of interaction between these compoundsand HSP90.In summary, we synthesized and characterized novel naphthoquinone derivatives whichcan be classified in four different classes including bis naphthoquinone, 2-arylaminonaphthoquinone, benzoxantene-6,11-dione and benzoacridine-5,6-dione derivatives. Wehave studied the in vitro anti cancer activity of these compounds against MCF-7 and PC3 cell lines byMTT test. The in vitro results revealed that five compounds by the IC50 range of 5.4-47.99 μM arethe most anti breast cancer structures. Her2 degradation assay and molecular modeling studiessuggested that the 8,9,10-trimethoxybenzo[c]acridine-5,6(7H,12H)-dione scaffold affords fortunateinteractions with the binding site of HSP90.
نویسندگان
Razieh Ghodsi
Biotechnology Research Center, Mashhad University Of Medical Sciences, Mashhad, Iran
Sima Golmakaniyon
Biotechnology Research Center, Mashhad University Of Medical Sciences, Mashhad, Iran;Department Of Medicinal Chemistry,School Of Pharmacy, Mashhad University Of Medical Sciences, Mashhad, Iran
VahidReza Askari
Department Of Pharmacology, School Of Medicine, Mashhad University Of Medical Sciences, Mashhad, Iran
Ali Ghasemi
Department Of Pediatric Oncology-Hematology, School Of Medicine, Mashhad University Of Medical Sciences, Mashhad, Iran