Totarol is a non-specific inhibitor of the bacterial cell division protein FtsZ[1]. Totarol directly targets and binds to the FtsZ protein, inhibiting its assembly into the Z-ring, thereby blocking bacterial cell division and proliferation. Totarol is commonly used in research on novel antibacterial drugs, particularly against drug-resistant Gram-positive bacteria (such as Staphylococcus aureus) and Mycobacterium tuberculosis[2]. Totarol can also inhibit Fe(III)-ADP/NADPH-induced lipid peroxidation in rat liver microsomes and mitochondria, as well as the auto-oxidation of linoleic acid[3].
In SGC-7901 human gastric cancer cells and GES-1 cells, Totarol (0-400μM;24h) exhibited dose-dependent cytotoxicity in SGC-7901 cells, while GES-1 cells were less affected. This indicates that tocotrienol targets cancer cells and has less toxicity to normal cells (GES-1) [4]. In the hemolysis assay, Totarol（0.25-1μg/ml；30min） significantly inhibited the hemolytic effect when incubated with rabbit red blood cells at 37℃ for 30 minutes[5]. In RAW264.7 macrophages, when Totarol (0.25-1μg/ml; 16h) was co-cultured with Staphylococcus aureus culture supernatant, the release of TNF-α was reduced[6].
Totarol(0.1-10μg/kg; ip; 2-6h) reduced infarct volume and improved the neurological deficit after acute focal cerebral ischemia[7].
References:
[1]. Kelley C. Design and synthesis of novel FtsZ-targeting antibacterial agents[M]. Rutgers The State University of New Jersey, School of Graduate Studies, 2014.
[2]. Domadia P, Swarup S, Bhunia A, et al. Inhibition of bacterial cell division protein FtsZ by cinnamaldehyde[J]. Biochemical pharmacology, 2007, 74(6): 831-840.
[3]. Haraguchi H, Ishikawa H, Kubo I. Antioxidative action of diterpenoids from Podocarpus nagi[J]. Planta Medica, 1997, 63(03): 213-215.
[4]. Xu T, Huang L, Liu Z, et al. Totarol, a natural diterpenoid, induces selective antitumor activity in SGC-7901 human gastric carcinoma cells by triggering apoptosis, cell cycle disruption and suppression of cancer cell migration[J]. J. BUON., 2019, 24: 686-692.
[5]. Shi C, Zhao X, Li W, et al. Inhibitory effect of totarol on exotoxin proteins hemolysin and enterotoxins secreted by Staphylococcus aureus[J]. World Journal of Microbiology and Biotechnology, 2015, 31(10): 1565-1573.
[6]. Seca A M L, Pinto D, Silva A M S. The current status of bioactive metabolites from the genus Juniperus[J]. Bioactive phytochemicals: Perspectives for modern medicine, 2015, 3: 365-408.
[7]. Gao Y, Xu X, Chang S, et al. Totarol prevents neuronal injury in vitro and ameliorates brain ischemic stroke: Potential roles of Akt activation and HO-1 induction[J]. Toxicology and applied pharmacology, 2015, 289(2): 142-154.
Totarol是一种非特异性细菌细胞分裂蛋白FtsZ的抑制剂[1]。Totarol可直接靶向并与FtsZ蛋白结合，抑制其组装成Z环，从而阻断细菌的分裂与增殖。该化合物通常用于新型抗菌药物的研究，特别是针对耐药性革兰氏阳性菌（如金黄色葡萄球菌）和结核分枝杆菌的研究[2]。此外，Totarol也能抑制Fe(III)-ADP/NADPH诱导的大鼠肝微粒体及线粒体脂质过氧化，以及亚油酸的自氧化[3]。
在人胃癌SGC-7901细胞和正常胃黏膜上皮GES-1细胞中，Totarol（0-400μM；24h）对SGC-7901细胞表现出剂量依赖性细胞毒性，而对GES-1细胞的影响较小，表明其对癌细胞具有靶向性，对正常细胞（GES-1）的毒性较低[4]。在溶血实验中，Totarol（0.25-1μg/ml；30min）与兔红细胞在37℃共孵育30分钟后，能显著抑制溶血作用[5]。在RAW264.7巨噬细胞中，当Totarol（0.25-1μg/ml；16h）与金黄色葡萄球菌培养上清液共培养时，能减少TNF-α的释放[6]。
Totarol（0.1-10μg/kg；ip；2-6h）能够减少大鼠急性局灶性脑缺血后的梗死体积，并改善神经功能缺损[7]。