Synthesis and activity of a trinuclear platinum complex: [{trans-PtCl(NH3)2}2mu-{trans-Pt(3-hydroxypyridine)2(H2N(CH2)6NH2)2}]Cl4 in ovarian cancer cell lines

This paper describes the synthesis, characterisation, and cytotoxicity of a novel trinuclear platinum complex code named TH1. In addition to its activity against human ovarian cancer cell lines: A2780, A2780(cisR), and A2780(ZD0473R), cell uptake, DNA-binding, and the nature of the compound interaction with pBR322 plasmid DNA have been determined. TH1 is found to be significantly more cytotoxic than cisplatin - two times more active than cisplatin against the parent cell line A2780, thirteen times more active against the cisplatin-resistant cell line A2780(cisR) and 11.5 times more active against the cell line A2780(ZD0473R). Whereas the resistance factors for cisplatin as applied to the cell lines A2780 and A2780(cisR), and A2780 and A2780(ZD0473R) are 12.9 and 3.0 respectively, the corresponding values for TH1 are 1.98 and 0.5. The results suggest that TH1 has been able to significantly overcome resistance in A2780(cisR) and A2780(ZD0473R) cell lines. Whereas cisplatin binds with DNA forming mainly intrastrand GG adduct that causes local bending of a DNA strand, TH1 should bind with DNA forming mainly interstrand GG adducts that would cause more of a global change in DNA conformation. Provided it has favourable toxicity profile, TH1 has the potential to be developed into a highly active anticancer drug with a wider spectrum of activity than cisplatin.     

Preclinical Anticancer Activity of an Electron-Deficient Organoruthenium(II) Complex

Ruthenium compounds have been shown to be promising alternatives to platinum(II) drugs. However, their clinical success depends on achieving mechanisms of action that overcome Pt-resistance mechanisms. Electron-deficient organoruthenium complexes are an understudied class of compounds that exhibit unusual reactivity in solution and might offer novel anticancer mechanisms of action. Here, we evaluate the in vitro and in vivo anticancer properties of the electron-deficient organoruthenium complex [(p-cymene)Ru(maleonitriledithiolate)]. This compound is found to be highly cytotoxic: 5 to 60 times more potent than cisplatin towards ovarian (A2780 and A2780cisR), colon (HCT116 p53+/+ and HCT116 p53−/−), and non-small cell lung H460 cancer cell lines. It shows no cross-resistance and is equally cytotoxic to both A2780 and A2780cisR cell lines. Furthermore, unlike cisplatin, the remarkable in vitro antiproliferative activity of this compound appears to be p53-independent. In vivo evaluation in the hollow-fibre assay across a panel of cancer cell types and subcutaneous H460 non-small cell lung cancer xenograft model hints at the activity of the complex. Although the impressive in vitro data are not fully corroborated by the in vivo follow-up, this work is the first preclinical study of electron-deficient half-sandwich complexes and highlights their promise as anticancer drug candidates.     

Impact of the Pd2Spm (Spermine) Complex on the Metabolism of Triple-Negative Breast Cancer Tumors of a Xenograft Mouse Model

The interest in palladium(II) compounds as potential new anticancer drugs has increased in recent years, due to their high toxicity and acquired resistance to platinum(II)-derived agents, namely cisplatin. In fact, palladium complexes with biogenic polyamines (e.g., spermine, Pd₂Spm) have been known to display favorable antineoplastic properties against distinct human breast cancer cell lines. This study describes the in vivo response of triple-negative breast cancer (TNBC) tumors to the Pd₂Spm complex or to cisplatin (reference drug), compared to tumors in vehicle-treated mice. Both polar and lipophilic extracts of tumors, excised from a MDA-MB-231 cell-derived xenograft mouse model, were characterized through nuclear magnetic resonance (NMR) metabolomics. Interestingly, the results show that polar and lipophilic metabolomes clearly exhibit distinct responses for each drug, with polar metabolites showing a stronger impact of the Pd(II)-complex compared to cisplatin, whereas neither drug was observed to significantly affect tumor lipophilic metabolism. Compared to cisplatin, exposure to Pd₂Spm triggered a higher number of, and more marked, variations in some amino acids, nucleotides and derivatives, membrane precursors (choline and phosphoethanolamine), dimethylamine, fumarate and guanidine acetate, a signature that may be relatable to the cytotoxicity and/or mechanism of action of the palladium complex. Putative explanatory biochemical hypotheses are advanced on the role of the new Pd₂Spm complex in TNBC metabolism.     

DNA interstrand cross-linking efficiency and cytotoxic activity of novel cadmium(II)-thiocarbodiazone complexes

We have prepared mono- and binuclear complexes of Zn(II) and Cd(II) with bis(2-pyridyl aldehyde) thiocarbodiazone (H(2)L(1)) and bis(methyl 3-pyridyl ketone) thiocarbodiazone (H(2)L(2)). Cytotoxicity data against the ovarian tumor cell line A2780cisR (acquired resistance to cisplatin) indicate that the mononuclear complex Cd/H(2)L(2) (1) and the binuclear complex Cd(2)/H(2)L(1) (4) are able to circumvent cisplatin resistance and that their cytotoxic activity does not substantially vary after depletion of intracellular levels of glutathione. Moreover, DNA binding studies show that complexes 1 and 4 have higher efficiency than cisplatin at forming DNA interstrand cross-links in both naked pBR322 plasmid and A2780cisR cellular DNA. Interestingly, the thiocarbodiazone ligands alone do not show the biological properties of complexes 1 and 4. Altogether these results suggest that DNA interstrand cross-link formation by compounds 1 and 4 might be related with their cytotoxic activity in cisplatin-resistant cells. We think that compounds 1 and 4 may represent a novel structural lead for the development of cadmium cytotoxic agents capable of improving antitumor activity in cisplatin-resistant tumors.     

Mithplatins: Mithramycin SA-Pt(II) Complex Conjugates for the Treatment of Platinum-Resistant Ovarian Cancers

DNA coordinating platinum (Pt) containing compounds cisplatin and carboplatin have been used for the treatment of ovarian cancer therapy for four decades. However, recurrent Pt-resistant cancers are a major cause of mortality. To combat Pt-resistant ovarian cancers, we designed and synthesized a conjugate of an anticancer drug mithramycin with a reactive Pt(II) bearing moiety, which we termed mithplatin. The conjugates displayed both the Mg²⁺-dependent noncovalent DNA binding characteristic of mithramycin and the covalent crosslinking to DNA of the Pt. The conjugate was three times as potent as cisplatin against ovarian cancer cells. The DNA lesions caused by the conjugate led to the generation of DNA double-strand breaks, as also observed with cisplatin. Nevertheless, the conjugate was highly active against both Pt-sensitive and Pt-resistant ovarian cancer cells. This study paves the way to developing mithplatins to combat Pt-resistant ovarian cancers.     

Ruthenium(II) and Platinum(II) Complexes with Biologically Active Aminoflavone Ligands Exhibit In Vitro Anticancer Activity

Continuing our studies on the mechanisms underlying the cytotoxicity of potential drugs, we have described several aspects of the in vitro anticancer activity of ruthenium(II) and platinum(II) complexes with bioactive, synthetic aminoflavone ligands. We examined the mechanism of proapoptotic activity of cis-dichlorobis(3-imino-2-methoxyflavanone)ruthenium(II), cis-dichlorobis(3-imino-2-ethoxyflavanone)ruthenium(II), and trans-dichlorobis(3-aminoflavone)platinum(II). Cisplatin was used as a reference compound. The cytotoxicity was investigated by MTT assay. The mechanism of proapoptotic activity of the tested compounds was investigated by evaluation of caspase-8 activity, cytometric analysis of annexin-V positive cells, and mitochondrial potential loss measurement. The results showed that ruthenium compounds break partially or completely the cisplatin resistance by activating the caspase 8-dependent apoptosis pathway and loss of mitochondrial membrane potential. Platinum compounds also have a cytostatic effect, but their action requires more exposure time. Potential mechanisms underlying drug resistance in the two pairs of cancer cell lines were investigated: total glutathione content, P-glycoprotein activity, and differences in the activity of DNA repair induced by nucleotide excision. Results showed that cisplatin-resistant cells have elevated glutathione levels relative to sensitive cells. Moreover, they indicated the mechanisms enabling cells to avoid apoptosis caused by DNA damage. Pg-P activity has no effect on the development of cisplatin resistance in the cell lines described.     

Facile Synthesis of cis-Dichloro-(1,4,7-Triazacyclononane) Platinum(II) and its Screening Against Human Ovarian Cancer (SK-OV-3) and Leukemia (K-562) Cell Lines

A simple method for the preparation of cis-dichloro(1,4,7-triazacyclononane)platinum(II), cis-Pt(tacn)Cl(2) is presented, together with the results of screening the compound against the K-562 (leukemia) and SK-OV-3 (ovarian) human cancer cell lines. While the compound shows no activity against K-562 cells, there is evidence for some cytotoxicity against SK-OV-3. The compound is much less effective than cisplatin, and its limited solubility restricts the useable concentration range.     

Cell Growth-Inhibiting Properties of Selected Carrier-Bound, Monoamine-Coordinated Platinum(II) Compounds

In contradistinction to the ligand arrangement in coordination compounds of the square-planar cis-diamminedichloroplatinum(II) type as represented by the prototype anticancer drug cisplatin, scant attention has been paid in cancer research to those platinum complexes in which only a single amino group (in addition to different ligands) is coordinated to the metal. In continuation of earlier research in this laboratory focused on macromolecular compounds containing monoamine-coordinated platinum, we have now synthesized a series of such polymeric platinum conjugates and assessed their antiproliferative activity in cell culture tests conducted against several human cancer cell lines. Conjugates containing hydroxylated side groups as hydrosolubilizing entities are found to exhibit poor, or no, activity up to the highest drug concentration tested (50 g Pt/mL). In contrast, those conjugates in which the solubilizing units are characterized by the presence of potentially cationic tert-amine side chain terminals show remarkably high cell-killing activity, with IC₅₀ in the range of 1–6 g Pt/mL against the HeLa cervical epitheloid carcinoma line. Two selected samples tested against the A-2780 human ovarian cancer line and its cisplatin-resistant A-2780-cis counterpart shows lack of cross-resistance with cisplatin (resistance factor 1). These findings augur well for the development of polymer-conjugated monoamine-coordinated platinum compounds with carcinostatic properties.     

Synthesis, Characterization and Antiproliferative Activity of the Co(II), Ni(II), Cu(II), Pd(II) and Pt(II) Complexes of 2-(4-Thiazolyl)Benzimidazole (Thiabendazole)

Complexes of 2-(4-thiazolyi)benzimidazole (thiabendazole, THBD) with Co(II), Ni(II), Cu(ll) of general formula ML(2)(NO(3))(2) H(2)O and complexes of Pd(II) and Pt(II) of general formula ML2Cl(2) H(2)O have been obtained and characterized by elemental analyses, IR and far IR spectroscopy and magnetic measurements. The X-ray crystal structure of the copper(II) complex has been determined. The in vitro cell proliferation inhibitory activity of these compounds was examined against human cancer cell lines A 549 (lung carcinoma), HCV-29 T (urinary bladder carcinoma), MCF-7 (breast cancer), T47D (breast cancer), MES-SA (uterine carcinoma) and HL-60 (promyelocytic leukemia). Pt-THBD has been found to exhibit an antileukemic activity of the HL-60 line cells matching that of an arbitrary criterion.     

Phenanthroline derivatives with improved selectivity as DNA-targeting anticancer or antimicrobial drugs

Phenanthroline derivatives are of interest due to their potential activity against cancer, and viral, bacterial, and fungal infections. In a search for highly specific antitumor and antibacterial compounds, we report the activities of 1,10-phenanthroline-5,6-dione (phendione or L(1)), dipyrido[3,2-a:2',3'-c]phenazine (dppz or L(2)), and their corresponding platinum complexes ([PtL(1)Cl2] and [PtL(2)Cl2]), and provide the solid-state 3D structure for [PtL(1)Cl2]. It is generally known that a toxic metal ion coordinated to an active organic moiety leads to a synergistic effect; however, we report herein that the platinum complexes [PtL(1)Cl2] and [PtL(2)Cl2] have weaker activities relative to those of the free ligands, especially against bacteria. Testing these agents against a variety of human cancer cell lines revealed that L(1) and [PtL(1)Cl2] were at least as active as cisplatin against several of the cell lines (including a cisplatin-resistant cell line). The absence of antibacterial activity of [PtL(1)Cl2] removes the detrimental effect of phenanthrolines toward intestinal flora, suggesting a highly promising new strategy for the development of anticancer drugs with reduced side effects.     

A Screening Strategy for Metal Antitumor Agents as Exemplified by Gold(III) Complexes

The use of a screening strategy based on human tumor cell lines, which are also tumorigenic in immune-deprived mice, is described. Activity against the human tumor cells in vitro and in vivo, is complemented with studies on the mechanism of action. This aporoach is demonstrated using 2-[(dimethylamino)-methyl]phenyl (damp) gold(III) compounds of the type [Au X2(damp)], where X = chloride, thiocyanate, acetate, or the bidentate ligands oxalate and malonate. All compounds were shown to be selectively active against a human bladder tumor cell line (HT1376) in vitro, and active in an in vitro panel of ovarian tumor cell lines. The acetato complex was shown to be active in experimental animal models of both the HT1376 bladder tumor, and the CH1 ovarian tumor. Although the [AuX2(damp)] compounds share structural features in common with cisplatin, and exhibit interesting in vivo activity against human tumor cells, the data indicate that they have a very different biochemical mechanism from platinum-based drugs and represent a potentially new class of metal-based antitumor agents.     

Synthesis and Characterization of Asparaginase Bound Silver Nanocomposite Against Ovarian Cancer Cell Line A2780 and Lung Cancer Cell Line A549

Development of new strategies of drug delivery is essential for effective treatment of cancer. In the present work, nanobiocomposite of fungal asparaginase was produced by immobilizing with silver nanoparticles. Asparaginase bound silver nanoparticle has shown higher enzyme activity than crude asparaginase. The primary and secondary amine/amide functional groups were found responsible for binding of asparaginase to silver nanoparticles. The silver nanobiocomposite of asparaginase was found to have smooth surface and crystalline in nature. The size of the nanobiocomposites ranged from 60 to 80 nm. The cytotoxicity of silver nanobiocomposite of asparaginase was found to be higher than free asparaginase on ovarian cancer cell line. The silver nanobiocomposite of asparaginase showed better cytotoxicity against ovarian cancer cell line A2780 than lung cancer cell line A549. Thus the synthesized silver nanobiocomposite of asparaginase can be used as an effective anticancer agent against lung cancer.     

Structures and antitumor activities of planar chiral cyclopalladated ferrocene derivatives

Bis(μ-acetato)-bridged planar chiral cyclopalladated products have been obtained by asymmetric cyclopalladation of the corresponding chiral ferrocenylimines with palladium(II) acetate and sodium acetate in methanol at room temperature. Two diastereomers were isolated in enantiomerically pure form and their absolute configurations have been determined by single-crystal X-ray analysis. It was found that enantiomerically pure cyclopalladated ferrocene displayed the excellent inhibition to two human breast carcinoma cell lines, MDA-MB-231 and MDA-MB-468 and could have good application prospect in pharmaceutical use.     

Analogs of a Natural Peptaibol Exert Anticancer Activity in Both Cisplatin- and Doxorubicin-Resistant Cells and in Multicellular Tumor Spheroids

Peptaibols, by disturbing the permeability of phospholipid membranes, can overcome anticancer drug resistance, but their natural hydrophobicity hampers their administration. By a green peptide synthesis protocol, we produced two water-soluble analogs of the peptaibol trichogin GA IV, termed K6-Lol and K6-NH2. To reduce production costs, we successfully explored the possibility of changing the naturally occurring 1,2-aminoalcohol leucinol to a C-terminal amide. Peptaibol activity was evaluated in ovarian cancer (OvCa) and Hodgkin lymphoma (HL) cell lines. Peptaibols exerted comparable cytotoxic effects in cancer cell lines that were sensitive—and had acquired resistance—to cisplatin and doxorubicin, as well as in the extrinsic-drug-resistant OvCa 3-dimensional spheroids. Peptaibols, rapidly taken up by tumor cells, deeply penetrated and killed OvCa-spheroids. They led to cell membrane permeabilization and phosphatidylserine exposure and were taken up faster by cancer cells than normal cells. They were resistant to proteolysis and maintained a stable helical structure in the presence of cancer cells. In conclusion, these promising results strongly point out the need for further preclinical evaluation of our peptaibols as new anticancer agents.     

Mitochondrial Fragmentation Is an Important Cellular Event Induced by Ruthenium(II) Polypyridyl Complexes in Osteosarcoma Cells

A series of ruthenium(II) polypyridyl complexes were synthesized and evaluated for their in vitro anticancer activities. The results showed that ruthenium polypyridyl complexes, especially [Ru(bpy)₂(p‐tFPIP)]²⁺ ( 2 a ; bpy=bipyridine, tFPIP=2‐(2‐trifluoromethane phenyl)imidazole[4,5‐f][1,10]phenanthroline), exhibited novel anticancer activity against human cancer cell lines, but with less toxicity to a human normal cell line. The results of flow cytometry and caspase activities analysis indicated that the 2 a ‐induced growth inhibition against MG‐63 osteosarcoma cells was mainly caused by mitochondria‐mediated apoptosis. DNA fragmentation and nuclear condensation as detected by TUNEL–DAPI co‐staining further confirmed 2 a ‐induced apoptotic cell death. Further, fluorescence imaging revealed that ruthenium(II) polypyridyl complexes could target mitochondria to induce mitochondrial fragmentation, accompanied by depletion of mitochondrial membrane potential. Taken together, these findings suggest a potential application of theses ruthenium(II) complexes in the treatment of cancers.     

New Perfluorophtalate Complexes of Platinum(II) With Chemotherapeutic Potential

Two new platinum(II) complexes have been synthesized and their anti-tumour and anti-HIV activities have been evaluated.THE NEW COMPLEXES ARE: (i) cis-tetrafluorophthalate-ammine-morpholine-platinum(II) or MMF3 and (ii) cis-tetrafluorophthalate- ammine-piperidine-platinum(II) or MPF4. They were characterized by elemental analysis, IR spectra and (1)H and (13)C NMR spectra.They were tested against five human ovarian carcinoma cell lines, viz., CH1, CH1cisR, A2780, A2780cisR and SKOV-3. They were less active than cis-platin and showed cross-resistance with cis-platin in the CH1cisR and A2780cisR acquired resistance lines.They were also tested for possible anti-HIV activity using the HIV-I IIIB virus and C8166 cells, but they were inactive compared with AZT.     

Synthesis, characterization and antitumor activity of a series of polypyridyl complexes

A series of polypyridyl complexes have been synthesized. All polypyridyl complexes and some of the soluble ligands have been assayed for antitumor activity in vitro against the HL-60 (the human leucocytoma) cells, BEL-7402 (the human liver carcinoma) cells, KB (the human nasopharyngeal carcinoma) cells and HELA (the human adenocarcinoma of cervix) cells. The results indicate that several complexes have relative activity against different cell lines. Especially, the complexes [Co(bpy)(2)(pip)](3+), [Co(phen)(2)(pip)](3+), [Ru(bpy)(2)(pztp)](2+) and [Ru(pztp)(2)(bpy)](2+) show relative high activity against four tumor cell lines. Moreover, they are slightly more effective than cisplatin. At the concentration of 100 mug/mL, the complexes show inhibitory rate of 72 approximately 86% for the cancer cells and have no toxicity for MDCK and Vero cells. It is indicated that these complexes can inhibit cancer cells selectively.     

6-[2-（1,2,4,5-四嗪-3-基）肼基]-1,3,5-三嗪类化合物的合成和抗肿瘤活性研究

以3,6-二（3,5-二甲基-1H-吡唑-1-基）-1,2,4,5-四嗪为原料,与水合肼反应,得到3-取代-6-肼基-1,2,4,5-四嗪,进一步与三聚氯氰和胺反应,得到6-[2-（1,2,4,5-四嗪-3-基）肼基]-1,3,5-三嗪类化合物,通过元素分析、1HNMR、IR和MS对这些化合物进行了表征;并进一步将此类化合物进行体外人绒毛膜癌细胞株Bewo、子宫内膜癌细胞株Ishikawa、人肺癌细胞株A549、人乳腺癌细胞株MCF-7、人白血病细胞株HL-60的测试,以顺铂为对照,发现此类化合物具有一定的体外抗肿瘤活性,值得进一步研究.     

Anticancer Organometallic Osmium(II)‐p‐cymene Complexes

Osmium compounds are attracting increasing attention as potential anticancer drugs. In this context, a series of bifunctional organometallic osmium(II)‐p‐cymene complexes functionalized with alkyl or perfluoroalkyl groups were prepared and screened for their antiproliferative activity. Three compounds from the series display selectivity toward cancer cells, with moderate cytotoxicity observed against human ovarian carcinoma (A2780) cells, whereas no cytotoxicity was observed on non‐cancerous human embryonic kidney (HEK‐293) cells and human endothelial (ECRF24) cells. Two of these three cancer‐cell‐selective compounds induce cell death largely via apoptosis and were also found to disrupt vascularization in the chicken embryo chorioallantoic membrane (CAM) model. Based on these promising properties, these compounds have potential clinical applications.     

Piperine Targets Different Drug Resistance Mechanisms in Human Ovarian Cancer Cell Lines Leading to Increased Sensitivity to Cytotoxic Drugs

Our goal was to examine the anticancer effects of piperine against the resistant human ovarian cancer cells and to explore the molecular mechanisms responsible for its anticancer effects. Our study used drug-sensitive ovarian cancer cell line W1 and its sublines resistant to paclitaxel (PAC) and topotecan (TOP). We analyzed the cytotoxic effect of piperine and cytostatic drugs using an MTT assay. The impact of piperine on protein expression was determined by immunofluorescence and Western blot. We also examined its effect on cell proliferation and migration. We noticed a different level of piperine resistance between cell lines. Piperine increases the cytotoxic effect of PAC and TOP in drug-resistant cells. We observed an increase in PTPRK expression correlated with decreased pTYR level after piperine treatment and downregulation of P-gp and BCRP expression. We also noted a decrease in COL3A1 and TGFBI expression in investigated cell lines and increased COL3A1 expression in media from W1PR2 cells. The expression of Ki67 protein and cell proliferation rate decreased after piperine treatment. Piperine markedly inhibited W1TR cell migration. Piperine can be considered a potential anticancer agent that can increase chemotherapy effectiveness in cancer patients.