Synthesis, biological activity and mechanism of action of novel allosecurinine derivatives as potential antitumor agents.

Cancer with low survival rates is the second main cause of death among all diseases in the world and consequently, effective antineoplastic agents are urgently needed. Allosecurinine is a plant-derived indolicidine securinega alkaloid shown bioactivity. The object of this study is to investigate synthetic allosecurinine derivatives with considerable anticancer capacity against nine human cancer cell lines as well as mechanism of action. We synthesized twenty-three novel allosecurinine derivatives and evaluated their antitumor activity against nine cancer cell lines for 72 h by MTT and CCK8 assays. FCM was applied to analyze the apoptosis, mitochondrial membrane potential, DNA content, ROS production, CD11b expression. Western blot was selected to analyze the protein expression. Structure-activity relationships were established and potential anticancer lead BA-3 which induced differentiation of leukemia cells towards granulocytosis at low concentration and apoptosis at high concentration was identified. Mechanism studies showed that mitochondrial pathway mediated apoptosis within cancer cells with cell cycle blocking was induced by BA-3. In addition, western blot assays revealed that BA-3 induced expression of the proapoptotic factor Bax, p21 and reduced the levels of antiapoptotic protein such as Bcl-2, XIAP, YAP1, PARP, STAT3, p-STAT3, and c-Myc. Collectively, BA-3 was a lead compound for oncotherapy at least in part, through the STAT3 pathway. These results were an important step in further studies on allosecurinine-based antitumor agent development.

Structure simplification of the Securinine skeleton reveals the importance of BCD ring system for the cytotoxic activity on HCT116 and HL60 cell lines.

Function-oriented molecular editing of the polycyclic scaffold of securinine led to the preparation of a library of simplified analogs that have been evaluated for their cytotoxicity potential against HCT116 and HL60 human cell lines. Chemical diversity at the C14 position (securinine numbering) was generated through the site-selective γ-iodination followed by Pd-catalyzed Sonogashira and Suzuki-Miyaura reactions. To explain the selectivity in the iodination step, a reaction mechanism has been proposed. Surprisingly, the piperidine ring (ring A) of the securinine skeleton has been found to be irrelevant for the cytotoxic activity. Based on this finding, the pharmacophoric core of securinine could be simplified to the key BCD motif. The nature of the substituent at the nitrogen can vary from a methyl or an isobutyl group to a benzyl or a carbamate moiety. Interestingly, the N-benzyl substituted simplified analog exhibited the same cytotoxic activity as the parent compound securinine. This functional group tolerance paves the way for the installation of reactive handles for the synthesis of molecular probes for target identification.

Securinine Induces Differentiation of Human Promyelocytic Leukemic HL-60 Cells through JNK-Mediated Signaling Pathway.

Acute myeloid leukemia is characterized by abnormal differentiation of hematopoietic stem cells, leading to the accumulation of immature myeloid cells. Differentiation therapy has been a successful treatment option for acute promyelocytic leukemia but suffers from adverse effects. Therefore, search for novel differentiation-inducing agents with minimal side effects is desirable. Securinine, a naturally-occurring alkaloid, induces differentiation in various leukemic cells and apoptosis in other types of cancers. However, the underlying molecular mechanism(s) remain elusive. Our study aimed to elucidate the possible molecular mechanism(s) and signaling events involved in securinine-induced differentiation of HL-60 cells. Securinine inhibited proliferation in a time- and dose-dependent manner and triggered differentiation. A higher CD14+ population indicated maturation toward monocytic lineage. Securinine caused cell cycle arrest at the G0/G1 phase and enhanced ROS generation. Quantitative gene expression analysis showed significant down-regulation of C/EBP-α, C/EBP-ε, GAΤΑ, and c-myc and up-regulation of the PU.1 gene. The expression of distinct protein kinases Lyn, Chk-2, Yes, FAK, c-Jun, and JNK were enhanced. Use of specific inhibitors of crucial intracellular signaling proteins indicated that JNK and ERK blockade resulted in a significant decline in differentiation. These data thus confirm that securinine induces differentiation through the activation of the JNK-ERK signaling pathway in HL-60 cells.

Securinine induces mitotic block in cancer cells by binding to tubulin and inhibiting microtubule assembly: A possible mechanistic basis for its anticancer activity.

AIM: Analysis of the anticancer and antimitotic activity of the plant derived alkaloid securinine along with its effect on the organization of cellular microtubules as well as its binding with purified goat brain tubulin in-vitro. MATERIALS AND METHODS: The cytotoxicity of securinine on different cell lines was conducted using SRB assay. The effect of securinine on the cellular microtubules was analyzed using immunofluorescence microscopy. The binding of securinine on purified goat brain tubulin was evaluated using fluorescent spectroscopy. KEY FINDINGS: Securinine effectively prevented the proliferation of cervical, breast and lung cancer cells with an IC50 of 6, 10 and 11 µM respectively and induced minimal toxicity in HEK cell line. Securinine at concentrations higher than IC50 induced significant depolymerization in interphase and mitotic microtubules and it suppressed the reassembly of cold depolymerized spindle microtubules in HeLa cells. In the wound healing assay, securinine effectively suppressed the migration of HeLa cells to close the wound. Securinine bound to tubulin with a Kd of 9.7 µM and inhibited the assembly of tubulin into microtubules. The treatment with securinine induced a mitochondrial dependent ROS response in HeLa cells which enhanced the cytotoxic effect of securinine. The result from gene expression studies indicates that securinine induced apoptosis in MCF-7 cells through p53 dependent pathway. SIGNIFICANCE: Considering the strong anticancer and anti-metastatic property and low toxicity in non-malignant cell lines, we suggest that securinine can be used as a chemotherapeutic drug either alone or in combination with other known anticancer molecules.

Securinine Promotes Neuronal Development and Exhibits Antidepressant-like Effects via mTOR Activation.

Impaired differentiation of newborn neurons or abnormalities at the synapses resulted from stress maladaptation could be the key etiology of depression. Recent studies have shown that mTOR, a crucial factor for neuronal differentiation and synapse development, acts as a common factor that mediates the rapid antidepression effects of several new-class antidepressants. In this study, the antidepressant-like activity of securinine, an alkaloid that has central nervous system stimulation ability, was investigated. Both securinine and its enantiomer virosecurinine exhibited potent in vitro activity on neuronal differentiation and synapse development in Neuro-2a cells and cultured hippocampal neurons, and this activity was dependent on the activation of the AKT-mTOR-S6K pathway. Interestingly, only securinine but not virosecurinine showed mTOR stimulation and antidepressant-like activity in mice. Importantly, a single dose of securinine was capable of alleviating the behavioral deficits induced by both acute and chronic stress models within 30 min of administration, suggesting that securinine has rapid onset of action. Moreover, neither a single dose nor a 3 week treatment of securinine had adverse effects on exploratory locomotion of mice. Together, this study identifies that securinine is a potent agent in promoting neuronal differentiation and synapse formation and shows rapid antidepressant-like activity, without inducing abnormal locomotion, via mTOR activation.

Identification of securinine as vascular protective agent targeting atherosclerosis in vascular endothelial cells, smooth muscle cells, and apolipoprotein E deficient mice.

BACKGROUND: Atherosclerosis is a chronic vascular disease and characterized by accumulation within the intima of inflammatory cells, smooth muscle cells, lipid, and connective tissue. PURPOSE: The purpose of the present study was to identify natural agents that commonly reverse advanced atherosclerotic plaque to early atherosclerotic plaque. METHODS: Differentially expressed genes (DEGs) were analyzed in silico. The differentially expressed genes from 9 intimal thickening and 8 fibrous cap atheroma tissue which were collected from GEO data were assessed by the connectivity map. Natural candidate securinine, a main compound from Securinega suffruticosa, was selected and administrated 1, 5 mg/kg/day in apolipoprotein-E-deficient (ApoE KO) mice for 18 weeks. RESULTS: Securinine significantly showed lowered blood pressure and improvement of metabolic parameters with hyperlipidemia. The impairment in vasorelaxation was remarkably decreased by treatment with securinine. H&E staining revealed that treatment with securinine reduced atherosclerotic lesions. Securinine suppressed the expression of adhesion molecules and matrix metalloproteinase-2/-9 in both ApoE KO and vascular endothelial cells (HUVEC). In HUVEC pretreatment with securinine significantly inhibited ROS generation and NF-κB activation. Growth curve assays using the real-time cell analyzer showed that securinine significantly decreased TNF-α-induced aortic smooth muscle cell proliferation and migration in a dose-dependent manner. CONCLUSION: Securinine may be a potential natural candidate for the treatment of atherosclerosis because it attenuates vascular inflammation and dysfunction as well as vascular lesion.

Chuanxiongdiolides R4 and R5, phthalide dimers with a complex polycyclic skeleton from the aerial parts of Ligusticum chuanxiong and their vasodilator activity.

Chuanxiongdiolides R4-R6 (1-3), three novel phthalide dimers featuring two classes of unreported monomeric units (ligustilide/senkyunolide A and ligustilide/neocnidilide) with an unprecedented linkage style (3a,7'/7a,7'a), were isolated from the aerial parts of Ligusticum chuanxiong, together with three pairs of enantiomeric phthalide dimers [(-)/(+)-4a/4b, 5a/5b, and 6a/6b]. The bioassays revealed that compounds 1, 3, 4, 5, and 6 showed significant vasodilation effects, and the mechanism may be attributed to Cav1.2 activation blockade. Based on the established compounds library, the structure activity relationship of the phthalides was proposed. Our findings afford possible leads for developing new vasodilator against cardiovascular and cerebrovascular diseases such as hypertension and ischemic stroke.

Antiproliferative and Antimigration Activities of Beauvericin Isolated from Isaria sp. on Pancreatic Cancer Cells.

This study describes the antiproliferative and antimigration effects of beauvericin from a culture broth of Isaria sp. in human pancreatic cancer cells (PANC-1). Activity-guided fractionation of the EtOAc extract of cultured broth of Isaria sp. RD055140 afforded beauvericin (1), a new isariotin derivative, 7-O-methylisariotin C (2), together with the known isariotin analogs, TK-57-164A (3) and B (4). As a result of the measurement of the cell viability, 1 inhibited cell growth (IC50 = 4.8 µM) of PANC-1 cells. Furthermore, 1 was found to inhibit the migration activity of PANC-1 cells by upregulating the expression of the E-cadherin gene and reducing N-cadherin and Snail genes in a dose-dependent manner (0.1-1 µM). These activities of 1 had lower concentrations than the cytotoxic activity. These findings suggest that 1 can be used as an anticancer agent against human pancreatic carcinoma.

Levistilide A reverses rat hepatic fibrosis by suppressing angiotensin II­induced hepatic stellate cells activation.

The renin angiotensin system (RAS) serves an important role in the development of hepatic fibrosis. Therefore, the present study investigated the effect of levistilide A (Lev A) on hepatic fibrosis via regulation of RAS. The effects of Lev A on the proliferation and activation of hepatic stellate cells (HSCs) were measured using a 5­ethynyl­2'­deoxyuridine assay, western blot analysis and immunofluorescence. The in vivo anti­hepatic fibrosis effect of Lev A was examined using a CCL4­induced rat fibrosis model. Lev A significantly prohibited angiotensin (Ang) II­induced proliferation of HSCs, and overexpression of smooth muscle α­actin (α­SMA) and F­actin in HSCs. Lev A partly reversed Ang II­induced angiotensin type 1 receptor (AT1R) upregulation and ERK and c­Jun phosphorylation. In CCL4­induced hepatic fibrosis rats, Lev A treatment significantly decreased the expression of collagen, α­SMA and hydroxyproline in rat liver, and improved liver functions. Lev A treatment also significantly inhibited the CCL4­induced increase in plasma Ang II, and upregulation of AT1R and phosphorylated ERK in rat liver. In conclusion, Lev A is a potential agent for the treatment of hepatic fibrosis by suppressing Ang II/AT1R/ERK/c­Jun activation in HSCs.

Securinine suppresses osteoclastogenesis and ameliorates inflammatory bone loss.

Securinine (Sec) is a naturally derived compound separated from the roots of Securinega suffruticosa, which has long been used as a herbal medicine. Sec is widely known as a GABA receptor antagonist, it is also known as an innate immune cell agonist and has been reported to increase macrophage activity and promote monocyte maturation. On the basis of these studies, we investigated the effect of Sec on osteoclast differentiation and bone resorbing function. We have found that Sec inhibits RANKL-induced osteoclast differentiation, fusion, actin ring formation, and bone resorbing function by the inhibition of gene expression associated with each stage. Moreover, Sec significantly suppressed osteoclastogenesis by decreasing the phosphorylation of p38, Akt, JNK, IκB, and PLCγ2, in pathways involved in early osteoclastogenesis as well as through the subsequent suppression of c-Fos and NFATc1. Finally, Sec effectively protected bone loss induced by the excessive inflammatory responses and activity of osteoclasts in vivo by a micro-CT and histological analysis. In conclusion, our findings suggest that Sec may be a promising drug for bone metabolic diseases such as osteoporosis, which is associated with the excessive activity of osteoclasts.

Structure-Based Design of Highly Potent HIV-1 Protease Inhibitors Containing New Tricyclic Ring P2-Ligands: Design, Synthesis, Biological, and X-ray Structural Studies.

We describe here design, synthesis, and biological evaluation of a series of highly potent HIV-1 protease inhibitors containing stereochemically defined and unprecedented tricyclic furanofuran derivatives as P2 ligands in combination with a variety of sulfonamide derivatives as P2' ligands. These inhibitors were designed to enhance the ligand-backbone binding and van der Waals interactions in the protease active site. A number of inhibitors containing the new P2 ligand, an aminobenzothiazole as the P2' ligand and a difluorophenylmethyl as the P1 ligand, displayed very potent enzyme inhibitory potency and also showed excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The tricyclic P2 ligand has been synthesized efficiently in an optically active form using enzymatic desymmetrization of meso-1,2-(dihydroxymethyl)cyclohex-4-ene as the key step. We determined high-resolution X-ray structures of inhibitor-bound HIV-1 protease. These structures revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insights into the binding properties of these new inhibitors.

Bridged α-helix mimetic small molecules.

Herein, we report a strategy for generating conformationally restricted α-helix mimetic small molecules by introducing covalent bridges that limit rotation about the central axis of α-helix mimetics. We demonstrate that the bridged α-helix mimetics have enhanced binding affinity and specificity to the target protein due to the restricted conformation as well as extra interaction of the bridge with the protein surface.

Novel virosecurinine bivalent mimetics as potent reversal agents against P-glycoprotein-mediated multidrug resistance.

Multidrug resistance (MDR) is a main cause of chemotherapy failure and patient death. This situation usually involves a glycoprotein (P-gp) mediated drug efflux, resulting in a low cellular drug concentration and insensitivity. Here we report the design, synthesis and evaluation of novel (+/-)-securinine bivalents as P-gp inhibitors in vitro and in vivo. MTT assays reflected that bivalent mimetics of securinine particularly the virosecurinine bivalent mimetic 8C showed promissing MDR reversal potential in both P-gp highly expressed cell line HepG2/DOX and MCF-7/ADM. At a 10 µM concentration, 8C can entirely reverse the resistance of HepG2/DOX to doxorubicin (DOX), and is more effective than the positive control verapamil (VRP). Fluorescence, flow cytometry, and DOX efflux assays demonstrated that 8C can facilitate the accumulation and diminish the efflux of intracellular DOX. Molecular docking analysis and western blot assays indicated that 8C accomplished this by competitively inhibiting the activity of P-gp rather than by affecting its expression. Compound 8C was also observed to reverse drug resistance effectively in xenograft models when combined with DOX. This study lays a foundation for the discovery of (+/-)-securinine ramifications as P-gp inhibitors and provides a promising lead compound 8C as a P-gp mediated MDR reversal agent.

The combination of Ilexhainanoside D and ilexsaponin A1 reduces liver inflammation and improves intestinal barrier function in mice with high-fat diet-induced non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is becoming a major health concern worldwide. Ilex hainanensis Merr. extract was proved to have anti-inflammation effect on NAFLD, and Ilexhainanoside D (IhD) and ilexsaponin A1 (IsA) were the main triterpenoid saponins extracted from it. PURPOSES: To investigate the hepatoprotective effect of the combination of IhD and IsA (IIC) against NAFLD and discuss the potential mechanisms. METHODS: Male C57BL/6 mice were fed a high-fat diet (HFD) to induce NAFLD and were treated with IIC (60, 120 or 240 mg/kg) for 8 weeks. Growth parameters, abdominal fat content, serum biochemical markers, hepatic lipid accumulation and insulin tolerance were assessed. Quantitative real-time PCR was used to determine the hepatic gene expression of TLR2, TLR4, TNF-α, IL-6, and IL-1ß. Western blot analysis was performed to determine the expression of the epidermal tight junction proteins ZO-1 and occludin. Gut microbiota profiles were established via high-throughput sequencing of the V3-V4 region of the bacterial 16S rRNA gene. RESULTS: IIC significantly reduced the severity of NAFLD induced by HFD in a dose-dependent manner. IIC decreased the ratio of Firmicutes/Bacteroidetes, reduced the relative abundance of Desulfovibrio and increased the relative abundance of Akkermansia. The intestinal barrier was improved as evidenced by the upregulation of the expression of ZO-1 and occludin in the ileum. IIC thus reduced the entry of LPS into the circulation and decreased the hepatic gene expression levels of proinflammatory cytokines. CONCLUSION: This approach demonstrated the positive effects of IIC in a mouse model of NAFLD, indicating that it possibly acts by reducing inflammation and improving the intestinal barrier function.

L-securinine inhibits cell growth and metastasis of human androgen-independent prostate cancer DU145 cells via regulating mitochondrial and AGTR1/MEK/ERK/STAT3/PAX2 apoptotic pathways.

The present study aims to evaluate the anticancer effect of L-securinine on androgen-independent prostate cancer (AIPC) DU145 cells. L-securinine (2.5, 5, and 10 µM) treatment for 24, 48 and 72 h displayed strong growth inhibitory effect on DU145 cells in a concentration and time-dependent fashion but has less toxicity toward normal androgen-dependent LNCaP cells. Hoechst 332582 staining of DU145 cells and Annexin V-FITC/ PI dual-labeling followed by flow cytometry assay identified that this growth inhibition by L-securinine would be due to the induction of apoptosis. Moreover Transwell assay revealed that L-securinine significantly inhibited the cell migration/invasion ability of DU145 cells. Furthermore, results of western blotting showed that the involvement of mitochondrial apoptotic pathway in the L-securinine-induced apoptosis of DU145 cell, as evidenced by an increase in the protein expression of Bax, cleaved caspase-9, cleaved caspase-3, cytosolic cytochrome c, and cleaved PARP, together with a unchanged cleaved caspase-8 and decreased Bcl-2 protein expression. Also, L-securinine-induced antimetastatic activity in DU145 cells was associated with decreased protein expression of MMP-2 and MMP-9 and concurrent reduction of VEGF. In addition, further studies revealed that L-securinine may inhibit the protein expression of AGTR1, p-MEK1/2, p-ERK1/2, p-STAT3, PAX2, and p-PAX2, while the expression of ERK1/2, MEK1/2, and STAT3 protein retains intact. These findings suggest that L-securinine may be a promising chemopreventive agent against AIPC.

Flueggeacosines A-C, Dimeric Securinine-Type Alkaloid Analogues with Neuronal Differentiation Activity from Flueggea suffruticosa.

Flueggeacosines A-C (1-3), three dimeric securinine-type alkaloid analogues with unprecedented skeletons, were isolated from Flueggea suffruticosa. Compounds 1 and 2 are the first examples of C-3-C-15' connected dimeric securinine-type alkaloids. Compound 3 is an unprecedented heterodimer of securinine-type and benzoquinolizidine alkaloids. Biosynthetic pathways for 1-3 were proposed on the basis of the coexisting alkaloid monomers as the precursors. Compound 2 exhibited significant activity in promoting neuronal differentiation of Neuro-2a cells.

Absolute Configuration and Pharmacology of the Poison Frog Alkaloid Phantasmidine.

Phantasmidine, a rigid congener of the well-known nicotinic acetylcholine receptor agonist epibatidine, is found in the same species of poison frog ( Epipedobates anthonyi). Natural phantasmidine was found to be a 4:1 scalemic mixture, enriched in the (2a R,4a S,9a S) enantiomer by chiral-phase LC-MS comparison to the synthetic enantiomers whose absolute configurations were previously established by Mosher's amide analysis. The major enantiomer has the opposite S configuration at the benzylic carbon to natural epibatidine, whose benzylic carbon is R. Pharmacological characterization of the synthetic racemate and separated enantiomers established that phantasmidine is ∼10-fold less potent than epibatidine, but ∼100-fold more potent than nicotine in most receptors tested. Unlike epibatidine, phantasmidine is sharply enantioselective in its activity and the major natural enantiomer whose benzylic carbon has the 4a S configuration is more active. The stereoselective pharmacology of phantasmidine is ascribed to its rigid and asymmetric shape as compared to the nearly symmetric conformations previously suggested for epibatidine enantiomers. While phantasmidine itself is too toxic for direct therapeutic use, we believe it is a useful platform for the development of potent and selective nicotinic agonists, which may have value as pharmacological tools.

A Tri-O-Bridged Diels-Alder Adduct from Cortex Mori Radicis.

Sanggenon X, an unusual tri-O-bridged Diels-Alder adduct, was isolated from Cortex Mori Radicis. Its structure was established by spectroscopic analysis, including NMR and HR-MS (High Resolution Mass Spectrometry). Sanggenon X contained three O-bridged rings, where the oxygenated bridgeheads were all quaternary carbons. Chemical methylation was carried out to deduce the linkages of the three O-bridges. The absolute configuration was determined by calculating the ECD (Electronic Circular Dichroism) using the TDDFT (Time-Dependent Density Functional Theory) method. Sanggenon X showed significant antioxidant activity against Fe2+-Cys-induced lipid peroxidation in rat liver microsomes, and was as effective as the positive control, curcumin.

Secreted frizzled-related protein 1 (SFRP1) gene methylation changes in the human lung adenocarcinoma cells treated with L-securinine.

Lung cancer remains the leading cause of cancer-related death worldwide. It is important to explore the biomarkers of diagnosis and prognosis in lung cancer. To evaluate the cytotoxicity of L-securinine and the expression and methylation of secreted frizzled-related proteins (SFRPs) genes in the human lung adenocarcinoma cells, cell counting kit-8 (CCK-8) assay was used to assess the proliferation of lung adenocarcinoma cells treated with L-securinine. Quantitative real-time PCR (qRT-PCR) and bisulfite sequencing PCR were used to detect the expression and the DNA methylation of SFRPs genes, respectively. L-securinine inhibited the proliferation of lung adenocarcinoma cells and induced the upregulation of SFRP1 gene expression and the methylation changes at CpG sites in the SFRP1 promoter region. L-securinine was a potential agent in the treatment of lung cancer by upregulation of SFRP1 gene expression and changing the SFRP1 gene methylation.

Synthesis, Structure, and Cytotoxicity of a New Sulphanyl-Bridged Thiadiazolyl-Saccharinate Conjugate: The Relevance of S⋠⋠⋠N Interaction.

Reports showing that the copper concentration is considerably higher in neoplasms than in normal tissues prompted the need to develop selective copper chelators. We disclosed recently that some N-linked tetrazole-saccharinates bind selectively to copper, forming complexes that are highly cytotoxic towards cancer cells. Because tetrazole-saccharinates are photolabile, due to the photoreactivity of tetrazoles, we proposed thiadiazolyl-saccharinates as an alternative. Herein we describe the synthesis, structure, and monomeric photochemistry of a sulphanyl-bridged thiadiazolyl-saccharinate, 3-[(5-methyl-1,3,4-thiadiazol-2-yl)sulphanyl]-1,2-benzothiazole 1,1-dioxide (MTSB). The monomeric structure, charge density analysis, and characteristic infrared spectrum of MTSB were investigated theoretically, using quantum chemical calculations, and also experimentally, using matrix-isolation infrared spectroscopy. The crystal structure was investigated by combining X-ray crystallography with infrared and Raman spectroscopies. Results show that the structure of isolated MTSB is similar to that found in the crystal, with an S⋅⋅⋅N interaction clearly contributing to the structure of the molecule and of the crystal. Matrix irradiation revealed a high photostability of MTSB, compared to parent tetrazole-saccharinates and to the 5-methyl-1,3,4-thiadiazole building block, emphasizing the photostabilizing effect of the saccharyl system. Finally, in vitro toxicity assays of MTSB showed a copper concentration-dependent toxicity against cancer cells, without affecting normal cells. In particular, MTSB was most effective towards the hepatic (HepG2), neuroblastoma (SH-SY5), and lymphoma cell lines (U937). Thus, MTSB represents a promising lead for cancer chemotherapy based on chelating agents.