共查询到20条相似文献,搜索用时 11 毫秒
1.
Chitalu C. Musonda Gavin A. Whitlock Michael J. Witty Reto Brun Marcel Kaiser 《Bioorganic & medicinal chemistry letters》2009,19(2):481-484
A dual activity, conjugated approach has been taken to form hybrid molecules of two known antimalarial drugs, chloroquine (CQ) and the non-sedating H1 antagonist astemizole. A variety of linkers were investigated to conjugate the two agents into one molecule. Compounds 5–8 possessed improved in vitro activity against a CQ-resistant strain of Plasmodium falciparum, and examples 7 and 8 were active in vivo in mouse models of malaria. 相似文献
2.
《Bioorganic & medicinal chemistry letters》2014,24(7):1825-1829
Bisindole analogs 1–17 were synthesized and evaluated for their in vitro β-glucuronidase inhibitory potential. Out of seventeen compounds, the analog 1 (IC50 = 1.62 ± 0.04 μM), 6 (IC50 = 1.86 ± 0.05 μM), 10 (IC50 = 2.80 ± 0.29 μM), 9 (IC50 = 3.10 ± 0.28 μM), 14 (IC50 = 4.30 ± 0.08 μM), 2 (IC50 = 18.40 ± 0.09 μM), 19 (IC50 = 19.90 ± 1.05 μM), 4 (IC50 = 20.90 ± 0.62 μM), 7 (IC50 = 21.50 ± 0.77 μM), and 3 (IC50 = 22.30 ± 0.02 μM) showed superior β-glucuronidase inhibitory activity than the standard (d-saccharic acid 1,4-lactone, IC50 = 48.40 ± 1.25 μM). In addition, molecular docking studies were performed to investigate the binding interactions of bisindole derivatives with the enzyme. This study has identified a new class of potent β-glucouronidase inhibitors. 相似文献
3.
Mohammadhossein Hassanshahi Yu-Wen Su Chia-Ming Fan Samira Khabbazi Alireza Hassanshahi Cory J. Xian 《Journal of cellular biochemistry》2019,120(3):3220-3231
Chemotherapeutic agents are very well evident extrinsic stimuli for causing damage to endothelial cells. Methotrexate is an antimetabolite commonly used to treat solid tumours and paediatric cancers. However, studies on the effect(s) of methotrexate on bone marrow microvascular system are inadequate. In the current study, we observed a significant bone marrow microvascular dilation following methotrexate therapy in rats, accompanied by apoptosis induction in bone marrow sinusoidal endothelial cells, and followed by recovery of bone marrow sinusoids associated with increased proliferation of remaining bone marrow sinusoidal endothelial cells. Our in vitro studies revealed that methotrexate is cytotoxic for cultured sinusoidal endothelial cells and can also induce apoptosis which is associated with upregulation of expression ratio of Bax and Bcl-2 genes and Bax/Bcl-2 expression ratio. Furthermore, it was shown that methotrexate can negatively affect proliferation of cultured sinusoidal endothelial cells and also inhibit their abilities of migration and formation of microvessel like tubes. The data from this study indicates that methotrexate can cause significant bone marrow sinusoidal endothelium damage in vivo and induce apoptosis and inhibit proliferation, migration and tube-forming abilities of sinusoidal endothelial cells in vitro. 相似文献
4.
5.
Previously, we reported that retigeric acid B (RB), a natural pentacyclic triterpenic acid isolated from lichen, inhibited cell growth and induced apoptosis in androgen-independent prostate cancer (PCa) cells. However, the mechanism of action of RB remains unclear. In this study, we found that using PC3 and DU145 cells as models, RB inhibited phosphorylation levels of IκBα and p65 subunit of NF-κB in a time- and dosage-dependent manner. Detailed study revealed that RB blocked the nuclear translocation of p65 and its DNA binding activity, which correlated with suppression of NF-κB-regulated proteins including Bcl-2, Bcl-x(L), cyclin D1 and survivin. NF-κB reporter assay suggested that RB was able to inhibit both constitutive activated-NF-κB and LPS (lipopolysaccharide)-induced activation of NF-κB. Overexpression of RelA/p65 rescued RB-induced cell death, while knockdown of RelA/p65 significantly promoted RB-mediated inhibitory effect on cell proliferation, suggesting the crucial involvement of NF-κB pathway in this event. We further analyzed antitumor activity of RB in in vivo study. In C57BL/6 mice carrying RM-1 homografts, RB inhibited tumor growth and triggered apoptosis mainly through suppressing NF-κB activity in tumor tissues. Additionally, DNA microarray data revealed global changes in the gene expression associated with cell proliferation, apoptosis, invasion and metastasis in response to RB treatment. Therefore, our findings suggested that RB exerted its anti-tumor effect by targeting the NF-κB pathway in PCa cells, and this could be a general mechanism for the anti-tumor effect of RB in other types of cancers as well. 相似文献
6.
The effects of salicylate on the activity of rat liver tyrosine–2-oxoglutarate aminotransferase in vitro and in vivo
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A. A.-B. Badawy 《The Biochemical journal》1972,126(2):347-350
1. Salicylate, in concentrations of 0.25mm and above, enhances the basal activity of tyrosine–2-oxoglutarate aminotransferase in homogenates of rat liver incubated in the absence of added pyridoxal 5′-phosphate (endogenous activity). The effect is decreased by increasing the concentration of the cofactor. 2. The intraperitoneal administration of sodium salicylate enhances the activity of rat liver tyrosine aminotransferase; the major effect during the first hour being on the enzyme in the absence of added pyridoxal phosphate. Actinomycin D prevents the induction of the enzyme by cortisol and tryptophan. Induction by pyridoxine or salicylate is 50% inhibited by actinomycin D. The effects of the injections of various combinations of cortisol, pyridoxine and salicylate were also studied in the absence or presence of actinomycin D. 3. It is suggested that salicylate induces rat liver tyrosine aminotransferase by displacing its protein-bound cofactor and that a cofactor-type induction of the hepatic enzyme occurs in pyridoxine-treated rats. 相似文献
7.
Epithelial to mesenchymal transition (EMT) plays a key role in tumor progression and metastasis as a crucial event for cancer cells to trigger the metastatic niche. Transforming growth factor-β (TGF-β) has been shown to play an important role as an EMT inducer in various stages of carcinogenesis. Previous reports had shown that antitumor vanadium inhibits the metastatic potential of tumor cells by reducing MMP-2 expression and inducing ROS-dependent apoptosis. However, the role of vanadium in (TGF-β)-induced EMT remains unclear. In the present study, we report for the first time on the inhibitory effects of vanadium on (TGF-β)-mediated EMT followed by down-regulation of ex vivo cancer stem cell markers. The results demonstrate blockage of (TGF-β)-mediated EMT by vanadium and reduction in the mitochondrial potential of tumor cells linked to EMT and cancer metabolism. Furthermore, combination of vanadium and carboplatin (a) resulted in synergistic antitumor activity in ex vivo cell cultures, and (b) prompted G0/G1 cell cycle arrest and sensitization of tumor cells to carboplatin-induced apoptosis. Overall, the findings highlight the multifaceted antitumor action of vanadium and its synergistic antitumor efficacy with current chemotherapy drugs, knowledge that could be valuable for targeting cancer cell metabolism and cancer stem cell-mediated metastasis in aggressive chemoresistant tumors. 相似文献
8.
Kevin Lewellyn Dobroslawa Bialonska Melissa J. Loria Stephen W. White Kenneth J. Sufka Jordan K. Zjawiony 《Bioorganic & medicinal chemistry》2013,21(22):7083-7090
Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms and have been shown to possess a range of biological activities. In vitro receptor binding assays showed that of the 12 serotonin receptor subtypes, analogues showed a high affinity for the 5-HT2B and 5-HT2C receptor subtypes, with selectivity for 5-HT2B over 5-HT2C. While no conclusions could be drawn about the number and position of N-methylations, bromination at C-4 and C-5 of the indole ring resulted in greater binding affinities, with Ki’s as low as 35 nM. This data, combined with previous knowledge of the CNS activity of aplysinopsin analogs, suggested that these compounds may have potential as leads for antidepressant drugs. Compounds 3c, 3u, and 3x were evaluated in the chick anxiety–depression model to assess their in vivo efficacy. Compound 3c showed a modest antidepressant effect at a dose of 30 nM/kg in the animal model. 相似文献
9.
Gurley L Beloukhina N Boudreau K Klegeris A McNeil WS 《Journal of inorganic biochemistry》2011,105(6):858-866
A series of square planar cobalt(II) compounds bearing tetradentate β-ketoaminato ligands with variation in the number of ―CF3 ligand substituents has been prepared and structurally and spectroscopically characterized. The fluorinated β-ketoamine ligands were prepared utilizing a multistep reaction sequence employing a silylenol protecting group. An additional tetrahedral cobalt compound bearing two bidentate β-ketoaminato ligands was also prepared and characterized.Cytotoxic activity of the cobalt-containing complexes was evaluated using six human cell lines; including two different prostate cancer cell lines (PC-3 and VCaP), acute monocytic leukemia (THP-1), astrocytoma (U-373 MG), hepatocellular carcinoma (HepG2), and neuroblastoma (SH-SY5Y) cells. The cobalt compounds are more active than their corresponding ligands. The activity is cell type specific; the cobalt compounds exhibit strong activity against human prostate cancer and monocytic leukemia cells but weak or no activity against neuroblastoma, astrocytoma, and liver carcinoma cells. Activity generally increases with a greater number of ―CF3 substituents, and square planar complexes exhibit greater activity than the tetrahedral derivative. The mechanisms of activity against human PC-3 prostate cancer cells involve caspase-3 and two different mitogen-activated protein kinases. The addition of a thiol antioxidant reduced cytotoxicity, suggesting the possible involvement of reactive oxygen species. These cobalt complexes may represent a novel class of cytotoxic drugs selective towards certain types of tumors. 相似文献
10.
《Bone and mineral》1991,12(3):181-188
The biological properties of a new synthetic analog of parathyroid hormone-related protein [PTHrP(7–34)NH2] were examined in vivo using a well characterized thyroparathyroidectomized (TPTX) rat model. The phosphaturic and urine cyclic AMP response induced by infusion of PTHrP-(1–34)NH2 (0.16 nmol/h) was inhibited by 70% (P < 0.01, n = 6) by co-infusion of PTHrP-(7–34)NH2 at a 10-fold molar excess (1.6 nmol/h). The 7–34 PTHrP analog also antagonized the PTHrP-(1–34)NH2-induced hypercalcemia and rises in blood 1,25-dihydroxyvitamin D concentrations. However, when infused alone at a higher dose rate (8 nmol/h), PTHrP-(7–34)NH2 displayed significant PTH agonist activity. This profile contrasts to that of [Tyr-34]bPTH-(7–34)NH2 which is comparatively less potent (10–20-fold) with respect to its antagonist activity but has no appreciable agonist activity in vivo. 相似文献
11.
Benjamin Lallemand Marco Masi Lucia Maddau Manuela De Lorenzi Ricard Dam Alessio Cimmino Laetitia Moreno y Banuls Anna Andolfi Robert Kiss Véronique Mathieu Antonio Evidente 《Phytochemistry letters》2012,5(4):770-775
Sphaeropsidins A (1), B (7) and C (10), three fungal phytotoxins, unrearranged pimarane diterpenes produced by Diplodia cupressi and 10 semisynthetic derivatives were evaluated for their in vitro anticancer activities. Among these 13 compounds, sphaeropsidin A and two derivatives (2 and 6) thereof display 50% growth-inhibitory concentration in the low micromolar range for all cell lines analyzed. Structure activity relationship paralleled the phytopathogenic and antimicrobial ones except regarding the vinyl group at C-13 that does not seems to be required as it is for their antipathogenic activity. 相似文献
12.
Brian S. Safina Zachary K. Sweeney Jun Li Bryan K. Chan Angelina Bisconte Diane Carrera Georgette Castanedo Michael Flagella Robert Heald Cristina Lewis Jeremy M. Murray Jim Nonomiya Jodie Pang Steve Price Karin Reif Laurent Salphati Eileen M. Seward Binqing Wei Daniel P. Sutherlin 《Bioorganic & medicinal chemistry letters》2013,23(17):4953-4959
In an effort to identify potent and isoform selective inhibitors of PI3Kδ, GNE-293 (34) was identified. Inhibitor 2 was found to induce micronuclei formation in both the MNT and HCA in vitro assays. Compounds testing negative for genotoxicity were successfully identified through modifications of the 2-benzimidazole substituent and the methylene moiety to disrupt planarity. A variety of heteroatom linkers were explored to examine their effect on potency and isoform selectivity by restricting torsional angles to favor ligand interactions with PI3Kδ’s Trp760. These modifications also resulted in an improved in vivo pharmacokinetic profile. 相似文献
13.
Pennington LD Croghan MD Sham KK Pickrell AJ Harrington PE Frohn MJ Lanman BA Reed AB Lee MR Xu H McElvain M Xu Y Zhang X Fiorino M Horner M Morrison HG Arnett HA Fotsch C Tasker AS Wong M Cee VJ 《Bioorganic & medicinal chemistry letters》2012,22(1):527-531
We reveal how a N-scan SAR strategy (systematic substitution of each CH group with a N atom) was employed for quinolinone-based S1P(1) agonist 5 to modulate physicochemical properties and optimize in vitro and in vivo activity. The diaza-analog 17 displays improved potency (hS1P(1) RI; 17: EC(50)=0.020 μM, 120% efficacy; 5: EC(50)=0.070 μM, 110% efficacy) and selectivity (hS1P(3) Ca(2+) flux; 17: EC(50) >25 μM; 5: EC(50)=1.5 μM, 92% efficacy), as well as enhanced pharmacokinetics (17: CL=0.15 L/h/kg, V(dss)=5.1L/kg, T(1/2)=24h, %F=110; 5: CL=0.93L/h/kg, V(dss)=11L/kg, T(1/2)=15 h, %F=60) and pharmacodynamics (17: 1.0mg/kg po, 24h PLC POC=-67%; 5: 3mg/kg po, 24h PLC POC=-51%) in rat. 相似文献
14.
Margaret C. Ackley Colin G. Barry Amanda M. Mounce Michael C. Farmer Beth-Erin Springer Cynthia S. Day Marcus W. Wright Susan J. Berners-Price Suzanne M. Hess Ulrich Bierbach 《Journal of biological inorganic chemistry》2004,9(4):453-461
The synthesis, cytotoxicity, and nucleoside binding of some platinum–acridinylthiourea conjugates derived from the prototypical compound [PtCl(en)(ACRAMTU)](NO3)2 {PT-ACRAMTU; en=ethane-1,2-diamine, ACRAMTU=1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea, protonated form} are reported. To establish structure–activity relationships within this class of compounds, systematic changes were made to the thiourea nonleaving group, which links the intercalator to platinum. Three new derivatives of ACRAMTU, one di-, one tri-, and one tetraalkylated, were generated, where the degree of alkylation indicates the number of alkyl groups attached to the SCN2 framework. Subsequent reaction of the tri- and tetraalkylated derivatives with activated [PtCl2(en)] yielded the corresponding platinum conjugates. The dialkylated thiourea gave an unstable complex, which was not included in the studies. The crystal structure of PT-ACRAMTU·MeOH has been determined. In the solid state, one axial position of the square-planar platinum coordination sphere is partially shielded by the bulky thiourea group, providing a strong rationale for the kinetic inertness of the compound. The cytotoxicity of the prototype, the two new conjugates, and cisplatin was assessed in ovarian (A2780, A2780/CP), lung (NCI-H460), and colon (RKO) cancer cell lines using clonogenic survival assays. The derivatives containing trialkylated thiourea groups showed activity similar or superior to cisplatin, with IC50 values in the low micromolar concentration range. The complex modified with the tetraalkylated (bulkiest) thiourea was significantly less active, possibly due to the greatly decreased rate of binding to nucleobase nitrogen (1H NMR spectroscopy), but was most efficient at overcoming cross resistance to cisplatin in A2780/CP. Possible consequences of the reported structural modifications for the mechanism of action of these agents are discussed.Electronic Supplementary Material Supplementary material is available in the online version of this article at Abbreviations ACRAMTU 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea - Boc t-butyl carbamate - dGuo 2-deoxyguanosine - dien N1-(2-aminoethyl)ethane-1,2-diamine - en ethane-1,2-diamine - HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid - PT-ACRAMTU [PtCl(en)(ACRAMTU)](NO3)2 - TSP 3-(trimethylsilyl)propionate, sodium salt 相似文献
15.
Yan Lu Zhao Wang Chien-Ming Li Jianjun Chen James T. Dalton Wei Li Duane D. Miller 《Bioorganic & medicinal chemistry》2010,18(2):477-495
A series of (2RS,4R)-2-arylthiazolidine-4-carboxylic acid amide (ATCAA) was synthesized. Antiproliferative activity against melanoma and prostate cancer cells compared with control cells (fibroblast and RH7777, respectively) was evaluated. Compound 3id showed the best selectivity and growth-inhibition activity against three melanoma cell lines (B16-F1, A375, and WM-164). Compounds 15b and 3ac had good selectivity and potency against four prostate cancer cell lines (DU 145, PC-3, LNCaP, and PPC-1). The structure–activity relationship (SAR) of the side chain, the thiazolidine ring, and phenyl substituents is discussed. Cell cycle analysis showed that the percentage of cancer cells undergoing apoptosis (sub-G1 phase) increased after treatment with 1b and 3ad, which also strongly inhibited melanoma colony formation. In vivo studies on nude mice bearing A375 melanoma tumors showed that compound 1b inhibited tumor growth in a dose-dependent manner. At a dose of 10 mg/kg, 1b significantly inhibited melanoma tumor growth and showed higher efficacy than did dacarbazine at 60 mg/kg. 相似文献
16.
Zhi Zhang Rui He Kun Yan Qian-ni Guo Yun-guo Lu Xu-xia Wang Hao Lei Zao-ying Li 《Bioorganic & medicinal chemistry letters》2009,19(23):6675-6678
5-(4-Aminophenyl)-10,15,20-tris(4-sulfonatophenyl) manganese(III) porphyrin conjugated with dextran was synthesized. Its potential of being used as a tumor-targeting magnetic resonance imaging contrast agent was evaluated in vitro and in vivo. The results demonstrated that the compound has a longitudinal relaxivity (R1) higher than Gd-DTPA, low cytotoxicity and binding specificity to tumor cell membrane. 相似文献
17.
Priyanka Pandya Surendra Gattani Pankaj Jain Lokesh Khirwal Sanjay Surana 《AAPS PharmSciTech》2008,9(4):1247-1252
A number of synthesized chemical molecules suffer from low aqueous solubility problems. Enhancement of aqueous solubility,
dissolution rate, and bioavailability of drug is a very challenging task in drug development. In the present study, solubility
and dissolution of poorly aqueous soluble drug simvastatin (SIM) was enhanced using hydrophilic, low viscosity grade polymer
hydroxypropyl methylcellulose (HPMC K3LV). The co-solvent evaporation method was developed for efficient encapsulation of hydrophobic drug in polymer micelles of
HPMC K3LV. Spray drying and rotaevaporation method were applied for solvent evaporation. Co-solvent-evaporated mixture in solid state
was determined by differential scanning calorimetry (DSC), X-ray diffraction studies (XRD), scanning electron microscopy,
and Fourier-transform infrared spectroscopy. In vitro–in vivo studies were performed on co-solvent-evaporated mixture and compared with SIM. In vivo study was conducted on healthy albino rats (Wister strain), and formulations were administered by oral route. Results of
the study show the conversion of crystalline form of SIM into amorphous form. The dissolution rate was remarkably increased
in co-solvent-evaporated mixtures compared to SIM. co-solvent-evaporated mixtures showed better reduction in total cholesterol
and triglyceride levels than the SIM. The low-viscosity grade HPMC acts as a surfactant, which enhances the wetting of drug
and thus improves the solubility of drug. The co-solvent evaporation method provides good encapsulation efficiency and produces
amorphous form of SIM, which gave better solubility and dissolution than the crystalline SIM. 相似文献
18.
Ramón Hernández José Lamboy Li Ming Gao Jaime Matta Félix R. Román Enrique Meléndez 《Journal of biological inorganic chemistry》2008,13(5):685-692
As part of our research efforts in the area of titanium-based antitumor agents, we have investigated the cytotoxic activity of [Ti(4)(maltolato)(8)(mu-O)(4)], (Cp-R)(2)TiCl(2) and (Cp-R)CpTiCl(2) (R = CO(2)CH(3) and CO(2)CH(2)CH(3)), and three water-soluble titanocene-amino acid complexes-[Cp(2)Ti(aa)(2)]Cl(2) (aa = L: -cysteine, L: -methionine, and D: -penicillamine)-on the human colon adenocarcinoma cell line, HT-29. The capacity of [Ti(4)(maltolato)(8)(mu-O)(4)] to donate Ti(IV) to human apo-transferrin and its hydrolytic stability have been investigated and compared to the previously reported data on modified titanocenes with either hydrophilic ancillary ligands or the functionalized cyclopentadienyl ligands. Notably, the titanium-maltolato complex does not transfer Ti(VI) to human apo-transferrin at any time within the first seven days of its interaction, demonstrating the inert character of this species. Stability studies on these complexes have shown that titanocene complexes decompose at physiological pH while the [Ti(4)(maltolato)(8)(mu-O)(4)] complex is stable at this pH without any notable decomposition for a period of ten days. The antitumor activity of these complexes against colon cancer HT-29 cells was determined using an MTT cell viability assay at 72 and 96 h. The titanocene-amino acid and the (Cp-R)(2)TiCl(2)/(Cp-R)CpTiCl(2) (R = CO(2)CH(3)) complexes were not biologically active when human transferrin was absent; they also were inactive when human transferrin was present at dose-equivalent concentrations. (Cp-R)(2)TiCl(2) and (Cp-R)CpTiCl(2) (R = CO(2)CH(2)CH(3)) showed cytotoxic activity in HT-29 cells comparable to that which is displayed by titanocene dichloride. The titanium-maltolato complex had higher levels of cytotoxic activity than any other titanocene complex investigated. Transferrin may be important in protecting the titanium center from hydrolysis, but this may be achieved by selecting ligands that could result in hydrolytically stable, yet active, complexes. 相似文献
19.
《Bioorganic & medicinal chemistry letters》2014,24(21):5123-5126
Extensive structure–activity relationship (SAR) and structure–kinetic relationship (SKR) studies in the bicyclic heteroaromatic series of CRTh2 antagonists led to the identification of several molecules that possessed both excellent binding and cellular potencies along with long receptor residence times. A small substituent in the bicyclic core provided an order of magnitude jump in dissociation half-lives. Selected optimized compounds demonstrated suitable pharmacokinetic profiles. 相似文献
20.
Liane M. Rossi Adailton J. Bortoluzzi Bruno Szpoganicz Antônio S. Mangrich Eduardo E. Castellano 《Inorganica chimica acta》2005,358(6):1807-1822
The unsymmetric dinucleating ligand N-(2-hydroxybenzyl)-N,N′,N′-tris(2-pyridylmethyl)-1,3-diaminopropan-2-ol (L = H2btppnol) and the corresponding copper(II) complex [Cu2(Hbtppnol)(μ-CH3COO)](ClO4)2 (1) have been recently reported in part in a short communication [Inorg. Chem. Commum. 8 (1999) 334]. In this study, we investigated the ability of complex 1 to promote the hydrolysis of P-O phosphate diester bonds in bis(2,4-dinitrophenyl) phosphate (2,4-BDNPP) and the cleavage of genomic and plasmid DNA molecules. Reaction of 1 with excess of the diester 2,4-BDNPP, at pH 7.0, results in the formation of the monoester phosphate coordinated [Cu2(Hbtppnol)(μ-((NO2)2-C6H3)PO4)]ClO4 (3) complex, which was also characterized by X-ray crystallography. In addition, the stable μ-phosphate complex [Cu2(Hbtppnol)(μ-(NO2-C6H4)PO4)](ClO4) (2) obtained from the reaction of 4-nitrophenyl phosphate with complex 1 was also characterized by X-ray crystallography, indicating that 1 is unable to cleave monoester-phosphate bonds. The kinetics for the promotion of bis(2,4-dinitrophenyl) phosphate (2,4-BDNPP) hydrolysis by complex 1 was investigated as a function of pH, catalyst concentration and substrate concentration. On the basis of kinetic and potentiometric studies, the deuterium isotope effect (kH/kD ∼ 1) and the X-ray structure of the monoester phosphate coordinated [Cu2(Hbtppnol)(μ-((NO2)2-C6H3)PO4)]ClO4 (3) complex as the product of the reaction, we demonstrated that the aquo/hydroxo complex is the active species and the reaction occurs through the formation of a ternary complex in which one CuII binds the substrate and the second copper center has a terminal bound hydroxide to attack the phosphorus atom, at physiological pH. A rate enhancement factor of ∼100 was calculated relative to that measured for the uncatalyzed reaction under identical conditions. Complex 1 effectively promotes the cleavage of double-stranded genomic and plasmid DNA, at physiological pH, probably through a hydrolytic mechanism in agreement with that proposed for the reaction of 1 with 2,4-BDNPP. Finally, cytotoxic activity of 1 in a human small cell lung carcinoma cell line (GLC4) and its cisplatin resistant subline (GLC4/CDDP) was studied and the IC50 values were determined. 相似文献