Design and synthesis of matrine derivatives for anti myocardial ischemia-reperfusion injury by promoting angiogenesis.

Myocardial ischemia/reperfusion (MI/R) is a common cardiovascular disease that seriously affects the quality of life and prognosis of patients. In recent years, matrine has attracted widespread attention in the treatment of cardiovascular diseases. This study designed, synthesized, and characterized 20 new matrine derivatives and studied their protective effects on ischemia-reperfusion injury through in vivo and in vitro experiments. Based on cellular assays, most newly synthesized derivatives have a certain protective effect on Hypoxia/Reoxygenation (H/R) induced H9C2 cell damage, with compound 22 having the best activity and effectively reducing cell apoptosis and necrosis. In vitro experimental data shows that compound 22 can significantly reduce the infarct size of rat myocardium and improve cardiac function after MI/R injury. In summary, compound 22 is a new potential cardioprotective agent that can promote angiogenesis and enhance antioxidant activity by activating ADCY5, CREB3l4, and VEGFA, thereby protecting myocardial cell apoptosis and necrosis induced by MI/R.

Design, synthesis and biological evaluation of matrine contains benzimidazole derivatives as dual TOPOI and PARP inhibitors for cancer therapy.

TOPOI inhibitors have long been a focal point in the research and development of antitumor drugs. PARP-1 plays a crucial role in repairing DNA damage induced by TOPOI inhibitors. Thus, concurrent inhibition of TOPOI and PARP-1 has the potential to augment drug activity. Matrine, characterized by low toxicity and good water solubility, offers advantageous properties. In this investigation, a series of benzimidazole matrine derivatives were designed and synthesized using matrine as the lead compound with the aim of developing dual inhibitors targeting both TOPOI and PARP-1. Among these derivatives, Compound B6 exhibited potent inhibitory effects on PARP-1 and TOPOI, effectively suppressing cancer cell proliferation and migration. Mechanistic assessments revealed that B6 induced DNA damage in HGC-27 cells, leading to G0/G1 cell cycle arrest and significant apoptosis. Molecular docking experiments demonstrated that B6 can effectively enter the active pocket of target proteins, where it forms stable hydrogen bonds with amino acid residues. In vivo, experiments demonstrated that B6 exhibited antitumor activity comparable to that of the positive control drug. The tumor growth inhibition rates (TGIs) for irinotecan, B6 and matrine were 87.0%, 75.4% and 9.7%, respectively. Importantly, B6 demonstrated lower toxicity than the positive control drug. Our findings suggest that TOPOI and PARP-1 may represent potential targets for matrine and B6 emerges as a promising candidate for cancer therapy.

Novel chiral matrine derivatives as potential antitumor agents: Design, synthesis and biological evaluation.

Since the thalidomide incident, research on chiral drugs has escalated immensely. Differences in drug configuration can lead to significant variations in therapeutic efficacy. Matrine, a natural product esteemed for its low toxicity and high water solubility, has garnered significant attention in research endeavors. Nonetheless, its precise target has proven elusive. In this study, we designed and synthesized a novel chiral matrine derivative. Their cytotoxicity against three types of tumor cells was assessed. Comparing the newly synthesized derivatives to the parent matrine, most compounds exhibited significantly enhanced inhibitory effects on cancer cells. Among them, Q12 exhibited the highest activity, with IC50 values of 8.31 µM against rat glioma cells C6, 6.3 µM against human liver cancer cells HepG2 and 7.14 µM against human gastric cancer cells HGC-27, meanwhile showing low toxicity. Based on IC50 values, we constructed a preliminary structure-activity relationship (SAR). Compound Q12 significantly suppressed the cloning and migration of HepG2 cells. Further mechanistic studies indicated that Q12 inhibited Topo I in HepG2 cells, leading to DNA damage, induction of G0/G1 cell cycle arrest and ultimately causing apoptosis. The molecular docking experiments provided a rational binding mode of Q12 with the Topo I-DNA complex. In vivo, experiments demonstrated that Q12 exhibited a higher tumor growth inhibition rate (TGI) compared to the positive control drug Lenvatinib, while maintaining good safety. In summary, it suggests that Topo I might be a potential target for matrine and Q12 represents a promising candidate for cancer treatment.

Research Progress of Natural Matrine Compounds and Synthetic Matrine Derivatives.

Matrine is a quinoline alkaloid extracted and separated from the dried root, fruit, and other parts of the plant Sophora flavescens using an organic solvent. Matrine exhibits a variety of biological activities and is widely used in pharmacy, agronomy, and other fields. Due to its low bioavailability, poor chemical stability, and toxicity to the central nervous system, a large number of researchers have searched for matrine derivatives with higher biological activity and safety by modifying its structure. In this review article, the research progress of matrine derivatives obtained using two methods (extraction from Sophora flavescens and structural modifications) from 2018 to 2022 in terms of pharmacological activity, mechanism of action, and structure-activity relationship are presented. The modification of matrine over the past five years has been mainly on the D-ring. Many new matrine alkaloids have been extracted from natural products, some of which have good pharmacological activity, which broadens the strategy for matrine structural modification in the future.

Synthesis, and biological evaluation of pyrazole matrine derivatives as an insecticide against Spodoptera frugiperda.

As one of the major threats to global food security, Spodoptera frugiperda (S. frugiperda) is highly gaining consideration due to its severe damage. Matrine is a widely and effectively used botanical insecticide in controlling S.frugiperda but lacks a rapidly available effect. To further improved the insecticidal activity of matrine based on combination principles, this work synthesized five new pyrazole matrine derivatives (PMDs) using Michael addition and investigated insecticidal activity against 2nd instar larvae of S. frugiperda(in vivo) and its isolated cell(in vitro). Our result demonstrated that PMDs show higher pesticidal activity than that matrine in both in vitro and in vivo assays. The most toxic derivatives in vitro and in vivo are PMD-3 and PMD-1, with IC50 of 2.49 mM and LC50 of 22.76 mg/L respectively. This research also investigates the anti-proliferation mechanism of PMDs based on isolated cells. PMDs decrease mitochondria membrane potential, arrested cell cycle at the G2/M phase, and upregulated Caspase 3, Caspase 9, and Apaf-1 to induce Caspase-dependent apoptosis. For Caspase-independent apoptosis, AIF and Endo G were found to be upregulated. Besides, pro-apoptotic factors like p53, IBM-1, and anti-apoptotic factors like IAP were upregulated. Moreover, we supposed that there was a linkage between lysosomes and PMD-induced apoptosis according to increased apoptosis rate, activated lysosomes, and upregulated Cathepsin B. This research provides new ideas for the synthesis of matrine derivatives and further demonstrated the anti-proliferation mechanism of PMDs.

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

A large number of studies have shown that matrine (MA) possesses various pharmacological activities and is one of the few natural, plant-derived pesticides with the highest prospects for promotion and application. Fifty-eight MA derivatives were prepared, including 10 intermediates and 48 target compounds in 3 series, to develop novel mosquitocidal agents. Compounds 4b, 4e, 4f, 4m, 4n, 6e, 6k, 6m, and 6o showed good larvicidal activity against Aedes albopictus, which is both a highly aggressive mosquito and an important viral vector that can transmit a wide range of pathogens. Dipping methods and a bottle bioassay were used for insecticidal activity evaluation. The LC50 values of 4e, 4m, and 6m reached 147.65, 140.08, and 205.79 µg/mL, respectively, whereas the LC50 value of MA was 659.34 µg/mL. Structure-activity relationship analysis demonstrated that larvicidal activity could be improved by the unsaturated heterocyclic groups introduced into the carboxyl group after opening the D ring. The MA derivatives with oxidized N-1 lost their mosquitocidal activities, indicating that the bareness of N-1 is crucial to maintain their anti-mosquito activity. However, the activity was not greatly influenced by introducing a cyan group at C-6 or a benzene sulfonyl group at N-16. Additionally, compounds 4e and 4m exhibited good inhibitory activities against acetylcholinesterase with inhibitory rates of 59.12% and 54.30%, respectively, at a concentration of 250 µg/mL, whereas the inhibitory rate of MA was 9.88%. Therefore, the structural modification and mosquitocidal activity of MA and its derivatives obtained here pave the way for those seeking strong mosquitocidal agents of plant origin.

Synthesis of Halopyrazole Matrine Derivatives and Their Insecticidal and Fungicidal Activities.

Matrine is a traditional botanical pesticide with a broad-spectrum biological activity that is widely applied in agriculture. Halopyrazole groups are successfully introduced to the C13 of matrine to synthesize eight new derivatives with a yield of 78-87%. The insecticidal activity results show that the introduction of halopyrazole groups can significantly improve the insecticidal activity of matrine on Plutella xylostella, Mythimna separata and Spodoptera frugiperda with a corrected mortality rate of 100%, which is 25-65% higher than matrine. The fungicidal activity results indicate that derivatives have a high inhibitory effect on Ceratobasidium cornigerum, Cibberella sanbinetti, Gibberrlla zeae and Collectot tichum gloeosporioides. Thereinto, 4-Cl-Pyr-Mat has the best result, with an inhibition rate of 23-33% higher than that of matrine. Therefore, the introduction of halogenated pyrazole groups can improve the agricultural activity of matrine.

New modification strategy of matrine as Hsp90 inhibitors based on its specific L conformation for cancer treatment.

The similarity of spatial structure between radicicol and matrine urged us to perform conformation modification of matrine, followed by L-shaped matrine derivatives, 6, 12, 21a-h and 22a-h were originally designed, synthesized and evaluated for Hsp90N inhibitors as anticancer agents. TSA (Thermal Shift Assay) results indicated that 21e, 22a-c and 22e-g exhibited strong binding force against Hsp90N with∣ΔTm∣ > 3, meanwhile, MTT assay also revealed these compounds displayed potent anticancer activity with IC50 values below 25 µM against HepG2, HeLa and MDA-MB-231 cells lines. Then, compound 22g with a high ΔTm = 10.92 was chosen as a representative to perform further mechanism study. It can induce cell apoptosis, arrest the cell cycle at the S phase and decrease the expression level of Hsp90 in Hela cell. These results originally provided targeted modification strategy for matrine derivatives to serve as Hsp90 inhibitors for cancer therapy.

The Matrine Derivate MASM Inhibits Recruitment of Gr1hi Monocyte and Alleviates Liver Injury.

BACKGROUNDS: (6aS, 10S, 11aR, 11bR, 11cS)-10-methylaminododecahydro-3a, 7a-diaza-benzo (de) anthracene-8-thione (MASM), a novel derivative of matrine, exhibits better anti-inflammatory activity. This study was designed to evaluate the protective effect of MASM on acute and chronic liver injuries and explore the possible mechanisms. METHODS: Acute and chronic liver injury models were established by the CCl4 intraperitoneal injection and the protective effect of MASM was assessed by biochemical and histological examination. The infiltration of different monocyte subsets into the liver was characterized and analyzed by flow cytometry. The in vitro effect of MASM on liver nonparenchymal cells was evaluated by real-time PCR and transwell chemotaxis assays. RESULTS: Administration of MASM markedly attenuated acute liver injury and liver fibrosis induced by CCl4 injection. Meanwhile, the infiltrations of Gr1hi monocytes in injured livers and induced hepatic expression of monocyte chemoattractant protein-1 (MCP-1) were greatly inhibited. Cellular experiments demonstrated that MASM not only decreased the expression of MCP-1 but also inhibited its chemotactic activity. CONCLUSIONS: This study demonstrates that the protective effect of MASM on liver injury could be contributed to the suppression of Gr1hi monocyte infiltration to the liver and the inhibition of MCP-1 production and activity. These findings provide new insights into the protective role of MASM in liver injury.

14-Formyl-15-aryloxy/methoxymatrine and 14-Aryloxymethylidenyl-matrine Derivatives as Anti-HIV-1 Agents.

BACKGROUND: The human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) has always been a global health threat and leading cause of deaths. However, due to the emergence of drug-resistant HIV, an inevitable consequence of increasing use of antiretroviral drugs posed a major threat to antiretroviral therapy success. OBJECTIVE: The discovery of anti-HIV-1 agents will be used for the effective treatment of HIV/AIDS. METHOD: In continuation of our program aimed to discover anti-HIV-1 agents, twelve matrine derivatives, such as 14-formyl-15-aryloxy/methoxymatrines (3a-j) and 14-aryloxymethylidenylmatrines (3k,l), were semi-prepared from matrine, and evaluated against HIV-1 IIIB replication in acutely infected C8166 cells in vitro. RESULTS: Among them, compound 3j showed the most potent anti-HIV-1 activity with EC50 and therapeutic index (TI) values of 1.79 µg/mL, and 98.2, respectively. CONCLUSION: It has been demonstrated that the positions of methyl on the phenyl ring and 14- formylmatrine-15-oxy on the naphthyl ring were very important for the activity. It will lay the foundation for further structural modification and application of matrines as HIV-1 inhibitors.

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

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 G1 phase in a dose-dependent manner.

Synthesis and biological evaluation of matrine derivatives as anti-hepatocellular cancer agents.

We delineate herein the synthesis and anti-cancer effects of 15 matrine derivatives. The in vitro growth inhibitory assays showed that most of the prepared compounds exhibited improved anti-proliferative activities towards cancer cells with IC50 17-109 times lower than that of matrine. Compounds CH6 showed the most potent anti-proliferative activities in the four tested cancer cell lines. Moreover, compound CH6 could induce G1 cell cycle arrest and inhibit cell migration in human hepatocellular cancer cell lines Bel-7402 and HepG2 through up-regulation of P21, P27 and E-cadherin and down-regulation of N-cadherin.