Synthesis, characterization and cytotoxic activity of gallium(III) complexes anchored by tridentate pyrazole-based ligands (original) (raw)
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Novel benzyl substituted titanocene anti-cancer drugs
Journal of Organometallic Chemistry, 2005
From the novel reaction of Super Hydride (LiB(Et) 3 H) with 6-(p-N,N-dimethylanilinyl)fulvene (1a) or 6-(p-methoxyphenyl)fulvene (1b) the corresponding lithium cyclopentadienide intermediates (2a, 2b) were obtained. When reacted with TiCl 4 , bis-[(p-dimethylaminobenzyl)cyclopentadienyl]titanium (IV) dichloride (3a) and bis-[(p-methoxybenzyl)cyclopentadienyl]titanium (IV) dichloride (3b) were obtained. Titanocene 3a was reacted with an ethereal solution of HCl, by which its dihydrochloride derivative (3c) was formed and isolated. Titanocenes 3b and 3c were characterised by X-ray crystallography. When the titanocenes 3a-c were tested against pig kidney carcinoma (LLC-PK) cells inhibitory concentrations (IC 50 ) of 1.2 · 10 À4 M, 2.1 · 10 À5 M and 9.0 · 10 À5 M, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, most notably for 3b (Titanocene Y), which is a hundred times more cytotoxic than titanocene dichloride itself.
Cytotoxic studies of substituted titanocene and ansa-titanocene anticancer drugs
Journal of Inorganic Biochemistry, 2008
A variety of substituted titanocene and ansa-titanocene complexes have been synthesized and characterized using traditional methods. The cytotoxic activity of the different titanocene complexes was tested against tumour cell lines human adenocarcinoma HeLa, human myelogenous leukemia K562, human malignant melanoma Fem-x and normal immunocompetent cells, peripheral blood mononuclear cells PBMC. Alkenyl substitution, either on the cyclopentadienyl ring or on the silicon-atom ansa-bridge of the titanocene compounds [Ti{Me 2 Si(g 5 -C 5 Me 4 )(g 5 -C 5 H 3 {CMe 2 CH 2 CH 2 CH@CH 2 })}Cl 2 ] (8), [Ti{Me(CH 2 @CH)Si(g 5 -C 5 Me 4 )(g 5 -C 5 H 4 )}Cl 2 ] (9) and [Ti(g 5 -C 5 H 4 {CMe 2 CH 2 CH 2 CH@CH 2 }) 2 Cl 2 ] (12) showed higher cytotoxic activities (IC 50 values from 24 ± 3 to 151 ± 10 lM) relative to complexes bearing an additional alkenyl-substituted silyl substituent on the silicon bridge [Ti{Me{(CH 2 @CH)Me 2 SiCH 2 CH 2 }Si(g 5 -C 5 Me 4 )(g 5 -C 5 H 4 )}Cl 2 ] (10) and [Ti{Me{(CH 2 @CH) 3 SiCH 2 CH 2 }Si(g 5 -C 5 Me 4 )(g 5 -C 5 H 4 )}Cl 2 ] (11) which causes a dramatic decrease of the cytotoxicity (IC 50 values from 155 ± 9 to >200 lM). In addition, the synthesis of the analogous niobocene complex [Nb(g 5 -C 5 H 4 {CMe 2 CH 2 CH 2 CH=CH 2 }) 2 Cl 2 ] (13), is described. Structural studies based on DFT calculations of the most active complexes 8, 9 and 12 and the X-ray crystal structure of 13 are reported.
Inorganics
Over time platinum-based anticancer drugs have dominated the market, but their side effects significantly impact the quality of life of patients. Alternative treatments are being developed all over the world. The titanocene and auranofin families of compounds, discovered through an empirical search for other metal-based therapeutics, hold tremendous promise to improve the outcomes of cancer treatment. Herein we present a historical perspective of these compounds and review current efforts focused on the evolution of their ligands to improve their physiological solution stability, cancer selectivity, and antiproliferative performance, guided by a clear understanding of the coordination chemistry and aqueous speciation of the metal ions, of the cytotoxic mechanism of action of the compounds, and the external factors that limit their therapeutic potential. Newer members of these families of compounds and their combination in novel bimetallic complexes are the result of years of scienti...
Journal of Organometallic Chemistry, 2014
The previously known complexes [Ti{(Me 2 CMe 2 C)(h 5-C 5 H 4) 2 }Cl 2 ] (1), [Ti{Me 2 C(h 5-C 5 H 4) 2 }Cl 2 ] (2), [Ti {Me 2 Si(h 5-C 5 H 4) 2 }Cl 2 ] (4), [Ti{MePhSi(h 5-C 5 H 4) 2 }Cl 2 ] (5) and [Ti{MePhSi(h 5-C 5 Me 4) 2 }Cl 2 ] (6) have been prepared following reported procedures. The novel complex [Ti{MePhC(h 5-C 5 H 4) 2 }Cl 2 ] (3) has been prepared and characterized. The cytotoxic activity of 1e6 has been tested after 72 h on melanoma A375 and B16, prostate cancer DU145 and LNCaP and colon cancer HCT116, SW620 and CT26CL25 cell lines observing a high cytotoxic activity of complexes 1 and 6 compared to the reference compound ([Ti(h 5-C 5 H 5) 2 }Cl 2 ]). 1 and 6 have also been tested against primary normal mouse keratinocytes and lung fibroblasts. While viability of both type of primary cells was significantly less affected by 1 in comparison to the reference compound [Ti(h 5-C 5 H 5) 2 Cl 2 ], compound 6 was completely nontoxic for nonmalignant cells, indicating a potential selectivity of this compound towards cancer cell lines. In addition CFSE staining, cell cycle analysis, AnnexinV-FITC/PI staining, detection of caspase activity and mitochondrial potential showed that 1 and 6 were acting through inhibition of proliferation and subsequent induction of mitochondrial dependent apoptosis in colon cancer cell lines, HCT116 and SW620, which express low sensitivity to cisplatin. Compound 6 was found to be the leading drug in this group since it shows the fastest and most selective anticancer profile.
Synthesis and Antitumor Activity of New Group 3 Metallocene Complexes
Molecules, 2017
The quest for alternative drugs with respect to the well-known cis-platin and its derivatives, which are still used in more than 50% of the treatment regimens for patients suffering from cancer, is highly needed. In this context, organometallic compounds, which are defined as metal complexes containing at least one direct covalent metal-carbon bond, have recently been found to be promising anticancer drug candidates. A series of new metallocene complexes with scandium, yttrium, and neodymium have been prepared and characterized. Some of these compounds show a very interesting anti-proliferative activity in triple negative breast cancer cell line (MDA.MB231) and the non-hormone sensitive prostate cancer cell line (DU145). Moreover, the interaction of some of them with biological membranes, evaluated using liposomes as bio-membrane mimetic model systems, seems to be relevant. The biological activity of these compounds, particularly those based on yttrium, already effective at low concentrations on both cancer cell lines, should be taken into account with regard to new therapeutic approaches in anticancer therapy.
Diarylmethyl substituted titanocenes: Promising anti-cancer drugs
Polyhedron, 2006
From the reaction of tert-butyl lithium with p-bromo-N,N-dimethylaniline (1a), p-bromoanisole (1b) or 1-bromo-3,5-dimethoxybenzene (1c), p-N,N-dimethylanilyl lithium (2a), p-anisyl lithium (2b) or (3,5-dimethoxyphenyl) lithium (2c), respectively, were obtained. When reacted with 6-(p-N,N-dimethylanilinyl)fulvene (3a), 6-(p-methoxyphenyl)fulvene (3b) or 3,5-(dimethoxyphenyl)fulvene (3c), the corresponding lithiated intermediates were formed (4a-c). Titanium tetrachloride was added ''in situ'', obtaining titanocenes 5a-c, respectively. When these titanocenes were tested against pig kidney carcinoma (LLC-PK) cells, inhibitory concentrations (IC 50 ) of 3.8 · 10 À5 M, 4.5 · 10 À5 M, and 7.8 · 10 À5 M, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, compared to their ansa-analogues.
Novel titanocene anti-cancer drugs derived from fulvenes and titanium dichloride
Journal of Organometallic Chemistry, 2004
Starting from 6-(p À N; N-dimethylanilinyl)fulvene (1a) or 6-(pentamethylphenyl)fulvene and their corresponding dithiocyanato complexes (3a, 3b) were synthesized. Titanocene 2b did not show a cytotoxic effect, but when 2a was tested against pig kidney carcinoma cells (LLC-PK) or human ovarian carcinoma cells (A2780/cp70) inhibitory concentrations (IC 50 ) of 2.7 Â 10 À4 and 1.9 Â 10 À4 M, respectively, were observed.