New Antitumor Organotitanium Complexes with a Pendant Biologically Active Diazo Group (original) (raw)
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Inorganic and Nano-Metal Chemistry, 2019
Titanium complexes with composition TiCl 2 (L)(L1) and TiCl 2 (L)(L2) [where, L ¼ benzoylacetone (bzac) and L1 ¼ 1,2-diaminocyclohexane (dach), 1,10-phenanthroline (phen) L2 ¼ 1-adamantylamine (ada)] have been synthesized by reacting titanium tetrachloride with benzoylacetone and nitrogen containing ligands in predetermined molar ratio. The structure of complexes was confirmed by different spectroscopic techniques i.e. FT-IR, UV-visible, 1 H NMR and mass spectrometory. The unit cell parameters of complexes were calculated by using powder XRD software. Cytotoxic studies were done on HeLa (cervical), C6 (glioma), and CHO (Chinese hamster ovarian) cell lines. The complex 3 proved to be most effective than other complexes against human cervical HeLa cancer cell line with IC 50 value of 5.6 mM which is even better than known anticancer drug Camptothecin having IC 50 value of 6.2 mM. The flow cytometric study showed that complexes inhibited cell proliferation by arresting cell cycle in the G 0 phase.
Titanium(IV) carboxylate complexes: Synthesis, structural characterization and cytotoxic activity
Polyhedron, 2010
a b s t r a c t Me 5 )Cl 3 ] and two (for 1-3) or three (for 4) equivalents of mesitylthioacetic acid. Complexes 1-4 have been characterized by spectroscopic methods and the molecular structure of the complexes 1, 2 and 4 have been determined by X-ray diffraction studies. The cytotoxic activity of 1-4 was tested against tumor cell lines human adenocarcinoma HeLa, human myelogenous leukemia K562, human malignant melanoma Fem-x, and normal immunocompetent cells, that is peripheral blood mononuclear cells PBMC and compared with those of the reference complexes [Ti(g 5 -C 5 H 5 ) 2 Cl 2 ] (R1), [Ti(g 5 -C 5 H 4 Me) 2 Cl 2 ] (R2), [Ti(g 5 -C 5 H 5 ) (g 5 -C 5 H 4 SiMe 3 )Cl 2 ] (R3) and cisplatin. In all cases, the cytotoxic activity of the carboxylate derivatives was higher than that of their corresponding dichloride analogues, indicating a positive effect of the carboxylato ligand on the final anticancer activity. Complexes 1-4 are more active against K562 (IC 50 values from 72.2 to 87.9 lM) than against HeLa (IC 50 values from 107.2 to 142.2 lM) and Fem-x cells (IC 50 values from 90.2 to 191.4 lM).
Structural features of antitumor titanium agents and related compounds
Bioinorganic Chemistry and …, 2005
Previous studies established some Ti compounds as having marked activity against tumors of the gastrointestinal tract and lack of side effects common to widely used cytostatic agents. We describe pertinent structural features of known antitumor Ti agents and other potentially active compounds. Particularly noteworthy features are that Ti-O bonds are short and Ti-O-Ti bond angles are large, demonstrating that in these compounds the O binding has high s-character approaching sp hybridization. /'he successful drug development/1/of the antitumor agent cis-diaminodichloroplatinum(II) (cisplatin) 1, generated a search for other active metal compounds and cis-diethoxy-bis(1-phenylbutane-l,3dionato)titanium(IV), [(bzac)2Ti(OEt)2] (budotitane) 2, was the first non-Pt metal antitumor compound that reached clinical trials /2/. The ligand 1-phenylbutane-l,3-dionato bzac benzoylacetonato, is an asymmetric [3-diketone chelator useful tbr establishing one key structural feature tbr activity in budotitane, namely, the existence of two OEt cis leaving groups, which arc analogous to the 2 CI in cisplatin. Another Ti antitumor agent is titanocene dichloride, (Cp)2TiCI2 3, Cp cyclopentadienyl, which possesses 2 CI leaving groups/5/. Among the differences between Ti antitumor drugs and cisplatin is the spectrum of activity, as Ti drugs operate against gastrointestinal tumors whereas Pt drugs do not. On the other hand, P338 and LI210 leukemia are sensitive targets for Pt drugs but not for budotitane/4/. Other differences include a much faster hydrolysis rate of the leaving groups in the former, and the environment where the metal-leaving group bonds cleave: outside the cell for Ti drugs and inside the cell tbr Pt drugs/1/. Titanocenc dichloride shows a larger spectrum of activity compared to budotitane. This is likely due to better solubility in physiological medium and it is currently in phase II clinical tests /5/, whereas the Structural Features of Antitumor Titanium. Agents and Related Compounds development of budotitane is limited by formulation problems /6/. Titanocene dichloride interacts with transferrin, a protein associated with iron transport, and suggests a possible mode of entry into the tumor cell. That is, the protein, with a Ti atom bound to one of its 2 domains/7,8/, could cross the tumor cell wall, which is characterized by greater amount of transferrin receptors than present in normal cells, and allow metal interaction with unknown targets.
JBIC Journal of Biological Inorganic Chemistry, 2008
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 (μ-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 (μ-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 (μ-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
Synthesis, Structure, and Antitumor Activity of a Novel Tetranuclear Titanium Complex
Journal of Medicinal Chemistry, 2000
The [RhCl 3 (N-N)(DMSO)] complexes, the N-N being 2,2 0 -bipyridine (1), 1,10-phenanthroline (2), 4,7diphenyl-1,10-phenanthroline (3), 4,4 0 -dimethyl-2,2 0 -bipyridine (4) and 1,10-phenanthroline-5,6-dione (5), have been synthesized and characterized with spectroscopic methods. The compounds 2-5 adopt mer-and complex 1 fac-structure. The molecular and electronic structure studies of mer-and fac-complexes with bpy and phen ligands at the DFT B3LYP level with 3-21G ** basis set showed that mer-isomers are more stable. The cytostatic activity of the [RhCl 3 (N-N)(DMSO)] complexes against Caco-2 and A549 tumor cells have been studied. Their antibacterial activity have also been investigated. It has been found that the very promising biological activity show complexes 2, 3 and 4.
Inorganic Chemistry, 2011
Metal-based drugs are nowadays among the most effective therapeutic agents for the treatment of cancer, with cisplatin, carboplatin, and oxaliplatin being widely used in clinics. 1 However, their effectiveness is still hindered by clinical problems, including acquired or intrinsic resistance, a limited spectrum of activity, and high toxicity leading to side effects. 2 Therefore, anticancer platinum compounds continue to be designed and synthesized through several different approaches in order to improve the therapeutic effects and to overcome the disadvantages of current platinum-based drugs. 3À6 The use of transition metal compounds other than platinum has also attracted attention in metallodrugs' development. 7À9 Among the thousands of inorganic derivatives synthesized and tested so far, only three nonplatinum-based complexes have reached phase II of clinical trials, namely, the organometallic compound titanocene dichloride (Ti(η 5-C 5 H 5) 2 Cl 2) 10 and the Ru-based coordination compounds KP1019 11 and NAMI-A 12 (Chart 1). Recent studies have shown that compounds based on gold are also promising anticancer drugs, and a conspicuous number of gold(III) and gold(I) complexes, with highly different chemical structures, have proven Chart 1. Nonplatinum-Based Anticancer Complexes Having Reached Phase II of Clinical Trials
Metal complexes in cancer therapy – an update from drug design perspective
Drug Design, Development and Therapy, 2017
In the past, metal-based compounds were widely used in the treatment of disease conditions, but the lack of clear distinction between the therapeutic and toxic doses was a major challenge. With the discovery of cisplatin by Barnett Rosenberg in 1960, a milestone in the history of metal-based compounds used in the treatment of cancers was witnessed. This forms the foundation for the modern era of the metal-based anticancer drugs. Platinum drugs, such as cisplatin, carboplatin and oxaliplatin, are the mainstay of the metal-based compounds in the treatment of cancer, but the delay in the therapeutic accomplishment of other metal-based compounds hampered the progress of research in this field. Recently, however, there has been an upsurge of activities relying on the structural information, aimed at improving and developing other forms of metal-based compounds and nonclassical platinum complexes whose mechanism of action is distinct from known drugs such as cisplatin. In line with this, many more metal-based compounds have been synthesized by redesigning the existing chemical structure through ligand substitution or building the entire new compound with enhanced safety and cytotoxic profile. However, because of increased emphasis on the clinical relevance of metal-based complexes, a few of these drugs are currently on clinical trial and many more are awaiting ethical approval to join the trial. In this review, we seek to give an overview of previous reviews on the cytotoxic effect of metal-based complexes while focusing more on newly designed metal-based complexes and their cytotoxic effect on the cancer cell lines, as well as on new approach to metal-based drug design and molecular target in cancer therapy. We are optimistic that the concept of selective targeting remains the hope of the future in developing therapeutics that would selectively target cancer cells and leave healthy cells unharmed.