A novel curcumin derivative which inhibits P-glycoprotein, arrests cell cycle and induces apoptosis in multidrug resistance cells

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• 作者：Vanessa Lopes-Rodrigues^a ; ^b ; ^c ; ^h ; Ana Oliveira^d ; ^h ; Marta Correia-da-Silva^d ; ^e ; Madalena Pinto^d ; ^e ; Raquel T. Lima^a ; ^b ; ^f ; Emí ; lia Sousa^d ; ^e ; ^{esousa@ff.up.pt} ; M. Helena Vasconcelos^a ; ^b ; ^g ; ^{hvasconcelos@ipatimup.pt}
• 关键词：ABC ; ATP-binding cassette ; DMSO ; dimethyl sulfoxide ; EtOAc ; ethyl acetate ; EtOH ; ethanol ; FBS ; fetal bovine serum ; h ; hours ; HPLC ; high-performance liquid chromatography ; HRMS-ESI ; high resolution mass spectrometry-electrospray ionization ; MDR ; multidrug resistance ; MeOH ; methanol ; min ; minutes ; mp ; melting point ; MW ; microwave ; PBS ; phosphate buffered saline ; P-gp ; P-glycoprotein ; r.t. ; room temperature ; SRB ; sulforhodamine B ; THF ; tetrahydrofuran
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：25
• 期：2
• 页码：581-596
• 全文大小：1983 K
• 卷排序：25

文摘

Cancer multidrug resistance (MDR) is a major limitation to the success of cancer treatment and is highly associated with the overexpression of drug efflux pumps such as P-glycoprotein (P-gp). In order to achieve more effective chemotherapeutic treatments, it is important to develop P-gp inhibitors to block/decrease its activity.Curcumin (1) is a secondary metabolite isolated from the turmeric of Curcuma longa L.. Diverse biological activities have been identified for this compound, particularly, MDR modulation in various cancer cell models. However, curcumin (1) has low chemical stability, which severely limits its application. In order to improve stability and P-gp inhibitory effect, two potential more stable curcumin derivatives were synthesized as building blocks, followed by several curcumin derivatives. These compounds were then analyzed in terms of antitumor and anti-P-gp activity, in two MDR and sensitive tumor lines (from chronic myeloid leukemia and non-small cell lung cancer). We identified from a series of curcumin derivatives a novel curcumin derivative (1,7-bis(3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)hepta-1,6-diene-3,5-dione, 10) with more potent antitumor and anti-P-gp activity than curcumin (1). This compound (10) was shown to promote cell cycle arrest (at the G2/M phase) and induce apoptosis in the MDR chronic myeloid leukemia cell line. Therefore it is a really interesting P-gp inhibitor due to its ability to inhibit both P-gp function and expression.