Evaluating Ligand Modifications of the Titanocene and Auranofin Moieties for the Development of More Potent Anticancer Drugs (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.
Journal of Medicinal Chemistry, 2010
A series of bimetallic titanium-ruthenium complexes of general formula [(η 5-C 5 H 5)(μ-η 5 :κ 1-C 5 H 4-(CR 2) n PR 0 R 00)TiCl 2 ](η 6-p-cymene)RuCl 2 (n = 0, 1, 2 or 4; R = H or Me; R 0 = H, Ph, or Cy; R 00 = Ph or Cy) have been synthesized, including two novel compounds as well as two cationic derivatives of formula [(η 5-C 5 H 5)(μ-η 5 :κ 1-C 5 H 4 (CH 2) n PPh 2)TiCl 2 ] [(η 6-p-cymene)RuCl](BF 4) (n = 0 or 2). The solid state structure of two of these compounds was also established by X-ray crystallography. The complexes showed a cytotoxic effect on human ovarian cancer cells and were markedly more active than their Ti or Ru monometallic analogues titanocene dichloride and RAPTA-C, respectively. Studies of cathepsin B inhibition, an enzyme involved in cancer progression, showed that enzyme inhibition by the bimetallic complexes is influenced by the length of the alkyl chain in between the metal centers. Complementary ESI-MS studies provided evidence for binding of a Ru(II) fragment to proteins.
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.
Organometallics, 2014
Early−late transition metal TiAu 2 compounds [(η-C 5 H 5) 2 Ti{OC(O)CH 2 PPh 2 AuCl} 2 ] (3) and new [(η-C 5 H 5) 2 Ti{OC(O)-4-C 6 H 4 PPh 2 AuCl} 2 ] (5) were evaluated as potential anticancer agents in vitro against renal and prostate cancer cell lines. The compounds were significantly more effective than monometallic titanocene dichloride and gold(I) [{HOC(O)RPPh 2 }AuCl] (R = −CH 2 − 6, −4-C 6 H 4 − 7) derivatives in renal cancer cell lines, indicating a synergistic effect of the resulting heterometallic species. The activity on renal cancer cell lines (for 5 in the nanomolar range) was considerably higher than that of cisplatin and highly active titanocene Y. Initial mechanistic studies in Caki-1 cells in vitro coupled with studies of their inhibitory properties on a panel of 35 kinases of oncological interest indicate that these compounds inhibit protein kinases of the AKT and MAPKAPK families with a higher selectivity toward MAPKAPK3 (IC 50 3 = 91 nM, IC 50 5 = 117 nM). The selectivity of the compounds in vitro against renal cancer cell lines when compared to a nontumorigenic human embryonic kidney cell line (HEK-293T) and the favorable preliminary toxicity profile on C57black6 mice indicate that these compounds (especially 5) are excellent candidates for further development as potential renal cancer chemotherapeutics.
Since the discovery of the cisplatin antitumor activity, great efforts have focused on the rational design of metal-based anticancer agents that can be potentially used in cancer chemotherapy. Over the last four decades, a large number of metal complexes have been extensively investigated and evaluated in vitro and in vivo, and some of them were at different stages of clinical studies. Amongst these complexes, platinum (Pt II and Pt IV ), ruthenium (Ru II and Ru III ), gold (Au I and Au III ) and titanium (Ti IV ) complexes are the most studied metals. We describe here some most recent progresses on Pt IV prodrugs which can be activated once enter tumor cells, polynuclear Pt II complexes which have unique DNA binding ability and mode, anti-metastatic Ru II /Ru III complexes, and Au I /Au III and Ti IV antitumor active complexes. The key focuses of these studies lie in finding novel metal complexes which could potentially overcome the hurdles of current clinical drugs including toxicity, resistance and other pharmacological deficiencies.
European Journal of Medicinal Chemistry, 2019
Organometallic complexes have widely been used for the treatment of various diseases viz., malaria, arthritis, syphilis, pernicious anemia, tuberculosis and particular in cancers. Recent decades have witnessed an upsurging interest in the application of organometallic compounds to treat various phenotypes of cancers with multiple etiologies. The unique and exceptional properties of organometallic compounds, intermediate between classical inorganic and organic materials provide new insight in the progress of inorganic medicinal chemistry. Herein, we have selectively focused on various organometallic sandwich and half-sandwich complexes of ruthenium (Ru), titanium (Ti), gold (Au) and iron (Fe) exhibiting promising activity towards a panel of cancer cell lines and resistant cancer cell lines. These complexes exhibit novel mechanisms of drug action through incorporation of outer-sphere recognition of molecular targets and controlled activation features based on ligand substitution along with monometallic and heterometallic redox processes. Furthermore, they are usually found to be uncharged or neutral possessing metals in a low oxidation state, exhibit kinetic stability, relative lipophilicity and are amenable to a host of various chemical transformations. This review mainly sheds light on the successful advancement of organometallic complexes as anticancer drug aspirants in relation to their versatile structural chemistry and innovative mechanisms of action targeting
ChemMedChem, 2019
Heterometallic titanocene‐based compounds containing gold(I)‐phosphane fragments have been extremely successful against renal cancer in vitro and in vivo. The exchange of phosphane by N‐heterocyclic carbene ligands to improve or modulate their pharmacological profile afforded bimetallic complexes effective against prostate cancer, but less effective against renal cancer in vitro. Herein we report the synthesis of new bimetallic Ti–Au compounds by the incorporation of two previously reported highly active gold(I)‐N‐heterocyclic carbene fragments derived from 4,5‐diarylimidazoles. The two new compounds [(η5‐C5H5)2TiMe(μ‐mba)Au(NHC)] (where NHC=1,3‐dibenzyl‐4,5‐diphenylimidazol‐2‐ylidene, NHC‐Bn 2 a; or 1,3‐diethyl‐4,5‐diphenylimidazol‐2‐ylidene, NHC‐Et 2 b) with the dual linker (‐OC(O)‐p‐C6H4‐S‐) containing both a carboxylate and a thiolate group were evaluated in vitro against renal and prostate cancer cell lines. The compounds were found to be more cytotoxic than previously describe...
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.