Abstract
Nasopharyngeal carcinoma (NPC) frequently occurs in Southern China. The main treatments of NPC are chemotherapy and radiotherapy. However, chemo-resistance arises as a big obstacle in treating NPC. Therefore, there is a great need to develop new compounds that could reverse tumor drug resistance. In this study, eight matrine derivatives containing thiophene group were designed and synthesized. Structures of these 8 compounds were characterized by 1H-NMR, 13C-NMR, and high-resolution mass spectrometer (HRMS). The cytotoxicity and preliminary synergistic effects of these 8 compounds were detected against nasopharyngeal carcinoma (NPC) cells and cisplatin-resistant NPC cells (CNE2/CDDP), respectively. Furthermore, the in vivo and in vitro tumor resistance reversal effects of compound 3f were evaluated. Moreover, docking studies were performed in Bclw (2Y6W). The results displayed that compound 3f showed synergistic inhibitory effects with cisplatin against CNE2/CDDP cells proliferation via apoptosis induction. Docking results revealed that compound 3f may exert its effects via inhibiting anti-apoptosis protein Bcl-w.
Highlights
Nasopharyngeal carcinoma (NPC) is a common head and neck cancer characterized with remarkable ethnic and geographic distributions which frequently occurs in Southern China, Southeast Asia, and Northern Africa while rarely in Western countries [1]
Matrine (1) was selected as a lead compound and a series of 14-methylene thiomatrine derivatives was synthesized for their potential application as anti-chemoresistance agents
Thiomatrine (2) was transformed into the corresponding thiomatrine derivatives 3a–3h using lithium diisopropylamide (LDA) and aromatic aldehyde in THF [21]. These products 3a–3h were purified by silica gel column chromatography using ethyl acetate and dichloromethane as gradient eluents and their structures were characterized by 1H-nuclear magnetic resonance (NMR), 13C-NMR, and high-resolution mass spectrometer (HRMS) analyses (Supplementary Materials)
Summary
Nasopharyngeal carcinoma (NPC) is a common head and neck cancer characterized with remarkable ethnic and geographic distributions which frequently occurs in Southern China, Southeast Asia, and Northern Africa while rarely in Western countries [1]. The combined chemo-radiotherapy produces a satisfying survival rate (85−90% for 5-year) [4,5], there are still 8−10% patients undergoing a recurrence and developing tumor metastasis [6,7]. For those recurrent NPC, the standard treatment is multi-drug chemotherapy with platinum [8]. Matrine derivative with thiophene group displayed reversal effect in NPC-CDDP resistance cells in vitro [20]. In the present study, we designed and synthesized matrine derivatives with new thiophene side chains to explore potential drugs that would show significant reversal effects in vitro and in vivo
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