Synthesis, biological evaluation and mechanism studies of matrine derivatives as anticancer agents

Abstract

Abstract.A total of five matrine derivatives were synthesized and evaluated for their anti-proliferation activity using a panel of four human cancer cell lines, including A549 lung, BT20 breast, MCF-7 breast and U2OS osteosarcoma cells. The YF3-5, YF3-7 and YF3-9, three novel compounds, demonstrated increased anti-proliferation activity compared with matrine, of which YF3-5 revealed the strongest anti-proliferation activity with a half-maximal inhibitory concentration value of 15.49-16.67 µM against the four human cancer cell lines. The anti-proliferation mechanism underlying YF3-5 was investigated in the A549 human lung cancer cell line and the results demonstrated that YF3-5 exerted its anti-proliferation activity through the induction of apoptosis and oxidative stress, in addition to arresting the cell cycle at the G 1 phase in a dose-dependent manner. IntroductionLung cancer is the primary cause of cancer-associated mortalities and is ranked the highest in males and second highest in females for mortality and morbidity rates globally (1). Non-small cell lung cancer (NSCLC), which constitutes 80-85% of lung cancer cases, remains an aggressive type of lung cancer that is associated with poor patient survival (2). Currently, chemotherapy has reached a plateau of effectiveness in improving patient survival, and it is the mainstay of treatment regimens and new drugs, including erlotinib and gefitinib, that they will eventually fail due to drug resistance (3,4); therefore, novel approaches and drugs are urgently required in order to improve the prognosis of patients with lung cancer.Natural compounds remain a predominant source for anticancer drug development. A total of 47% of the 155 anticancer drugs approved from 1950-2006 were natural products or directly derived from them (5). Matrine (C 15 H 24 N 2 O) is the major alkaloid component identified in Sophora alopecuroides roots, which are widely utilized in traditional Chinese medicine and have a wide range of pharmacological effects, including anti-cardiac, anti-arrhythmic, anti-bacterial, anti-asthma, anti-diuretic, immune suppressive and anti-inflammatory activities (6-9). It has also been reported that matrine possesses antitumor activities in vitro and in vivo (10-13). The mechanisms underlying matrine's antitumor activities include the inhibition of cell proliferation and the induction of apoptosis (14-16). However, the low water solubility, bioavailability and bioactivity of matrine, coupled with its considerable side effects, which include general toxicity to the central nervous system, have limited its utility as a therapeutic drug (17,18). Therefore, studies have been focusing on developing derivatives and analogues of matrine by total synthesis or structural modifications in order to improve its activity and bioavailability (19)(20)(21).A previous study demonstrated that the amide bond may be required for the antitumor activities of matrine as following opening of the D-ring and breaking of the amide bond, the anti-proliferative activities of matrine ...

<p>Anti-Tumor Activities of Bioactive Phytochemicals in <em>Sophora flavescens</em> for Breast Cancer</p>

“…106 In addition, three novel compounds (YF3-5, YF3-7 and YF3-9) all demonstrated anti-proliferation activity, of which YF3-5 showed the strongest anti-proliferation properties against the four human cancer cell lines (BT20 breast, MCF-7 breast, A549 lung and U2OS osteosarcoma cells). 107…”

Apoptotic Pathway as the Therapeutic Target for Anticancer Traditional Chinese Medicines

“…Recent studies showed that matrine inhibited cell growth, induced apoptosis, and reversed multidrug resistance through inhibiting PI3K/AKT pathway when it was used alone or in combination with other anticancer agents in human breast, prostate, and bladder cancer cells (Liao et al, 2017; Li Q. et al, 2018a; Zhou et al, 2018). The structure analysis revealed that matrine contains a variety of components in which the carbon–carbon double bond at 14′ of its skeleton is critical for anticancer activity (Jiang et al, 2017). Studies have shown that MASM (6aS, 10S, 11aR, 11bR, 11cS)-10-methylamino-dodecahydro-3a,7a-diazabenzo (de), a novel derivative of matrine, markedly inhibited cell growth and induced apoptosis against human liver cancer Hep3B and Huh-7 cells in vitro and significantly suppressed the tumor growth of Huh-7 xenograft in vivo through inhibiting the PI3K/AKT/mTOR pathway (Liu Y. et al, 2017).…”

Novel Matrine Derivatives as Potential Larvicidal Agents against Aedes albopictus: Synthesis, Biological Evaluation, and Mechanistic Analysis

“…Matrine ( MA ), a quinolizidine alkaloid and an important natural product, is isolated from the plant species of the family Fabaceae, Sophora flavescens Aiton, Sophora tonkinensis Gagnep, Sophora alopecuroides L. [ 1 , 2 , 3 ]. MA and its analogs possess a variety of biological properties, such as anticancer activity, anti-inflammatory activity, insecticidal activity, antimicrobial activity, and antiviral activity; MA alkaloids are excellent precursors for structural modification and thus have attracted great interest from scholars [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. As an insecticide, MA has remarkable insecticidal activity against a variety of agricultural pests, such as Bradysia odoriphaga Yang et Zhang, Cnaphalocroci smedinalis (Guenee, 1854), Ectropis obliqua hypulina Wehrli, Clostera anachoreta Denis and Schiffermüller,1775, Eriosoma lanigerum (Hausmann), Psylla chinensis Yang et Li, Mesonura rufonota Rohwer, and Aceri macrodonis Keifer, with contact toxicity and gastric toxicity as the main modes of action [ 16 , 17 , 18 , 19 , 20 ].…”