Enrique Meléndez

Titanium(IV) complexes: cytotoxicity and cellular uptake of titanium(IV) complexes on caco-2 cell line.

Replacement of the ancillary ligand in titanocene dichloride by amino acids provides titanocene species with high water solubility. As part of our research efforts in the area of titanium-based antitumor agents, we have investigated the cytotoxic activity of Cp(2)TiCl(2) and three water soluble titanocene-amino acid complexes - [Cp(2)Ti(aa)(2)]Cl(2) (aa=L-cysteine, L-methionine, and D-penicillamine) and one water soluble coordination compound, [Ti(4)(maltolato)(8)(micro-O)(4)] on the human colon adenocarcinoma cell line, Caco-2. At pH of 7.4 all titanocene species decompose extensively while [Ti(4)(maltolato)(8)(micro-O)(4)] is stable for over seven days. In terms of cytotoxicity, the [Cp(2)Ti(aa)(2)]Cl(2) and [Ti(4)(maltolato)(8)(micro-O)(4)] complexes exhibited slightly higher toxicity than titanocene dichloride at 24h, but at 72h titanocene dichloride and [Ti(4)(maltolato)(8)(micro-O)(4)] have higher cytotoxic activity. Cellular titanium uptake was quantified at various time intervals to investigate the possible relationship between Ti uptake and cellular toxicity. Results indicated that there was not a clear relationship between Ti uptake and cytotoxicity. A structure-activity relationship is discussed.

Vectorized ferrocenes with estrogens and vitamin D2: synthesis, cytotoxic activity and docking studies

Three ferrocene complexes vectorized with estrogens and vitamin D(2) were synthesized and fully characterized by spectroscopic, electrochemical and computational methods. The synthesis of these esters was accomplished by reacting ferrocenoyl chloride with the corresponding ROH groups (R = ergocalciferol, estradiol, estrone). The cytotoxicity of these complexes in HT-29 colon cancer and MCF-7 breast cancer cell lines was investigated in vitro. Only ferrocenoyl 17β-hydroxy-estra-1,3,5(10)-trien-3-olate showed good cytotoxic activity in both cell lines, exceeding those of ferrocenium and ferrocene. In MCF-7, ferrocenoyl 17β-hydroxy-estra-1,3,5(10)-trien-3-olate exhibited remarkable IC(50), in the low micromolar range. This may be attributed to the presence of the estradiol vector. Docking studies between alpha-estrogen receptor ligand binding site and ferrocenoyl 17β-hydroxy-estra-1,3,5(10)-trien-3-olate revealed some key hydrophobic interactions that might explain the cytotoxic activity of this ester.

Cytotoxic properties of titanocenyl amides on breast cancer cell line mcf-7.

A new titanocenyl amide containing flavone as pendant group has been synthesized by reaction of titanocenyl carboxylic acid chloride and 7-Aminoflavone and structurally characterized by spectroscopic methods. This species and eight previously synthesized titanocenyl amide complexes have been tested in breast adenocarcinoma cancer cell line, MCF-7. The functionalization of titanocene dichloride with amides enhances the cytotoxic activity in MCF-7. Two sets of titanocenyl amides can be identified, with IC50 <100 μM and IC50>100 μM. The most cytotoxic species is Cp(CpCO-NH-C6H4-(CH2)2CH3)TiCl2 with an IC50 of 24(2) μM, followed by Cp(CpCO-NH-C6H4-Br)TiCl2, IC50 of 46(4) μM and Cp(CpCO-NH-C6H4-OCF3)TiCl2, IC50 of 49(6) μM. There is no correlation between the nature of the para substituent on the phenyl ring and the cytotoxic properties on MCF-7 cell line.

A molecular docking study of the interactions between human transferrin and seven metallocene dichlorides

Human Transferrin (hTf) is a metal-binding protein found in blood plasma and is well known for its role in iron delivery. With only a 30% of its capacity for Fe+3 binding, this protein has the potential ability to transport other metal ions or organometallic compounds from the blood stream to all cell tissues. In this perspective, recent studies have described seven metallocene dichlorides (Cp2M(IV)Cl2, M(IV)=V, Mo, W, Nb, Ti, Zr, Hf) suitable as anticancer drugs and less secondary effects than cisplatin. However, these studies have not provided enough data to clearly explain how hTf binds and transports these organometallic compounds into the cells. Thus, a computational docking study with native apo-hTf using Sybyl-X 2.0 program was conducted to explore the binding modes of these seven Cp2M(IV)Cl2 after their optimization and minimization using Gaussian 09. Our model showed that the first three Cp2M(IV)Cl2 (M(IV)=V, Mo, W) can interact with apo-hTf on a common binding site with the amino acid residues Leu-46, Ile-49, Arg-50, Leu-66, Asp-69, Ala-70, Leu-72, Ala-73, Pro-74 and Asn-75, while the next four Cp2M(IV)Cl2 (M(IV)=Nb, Ti, Zr, Hf) showed different binding sites, unknown until now. A decreasing order in the total score (equal to -log Kd) was observed from these docking studies: W (5.4356), Mo (5.2692), Nb (5.1672), V (4.5973), Ti (3.6529), Zr (2.0054) and Hf (1.8811). High and significant correlation between the affinity of these seven ligands (metallocenes) for apo-hTf and their bond angles CpMCp (r=0.94, p<0.01) and Cl-M-Cl (r=0.95, p<0.01) were observed, thus indicating the important role that these bond angles can play in ligand-protein interactions. Fluorescence spectra of apo-hTf, measured at pH 7.4, had a decrease in the fluorescence emission spectrum with increasing concentration of Cp2M(IV)Cl2. Experimental data has a good correlation between KA (r=0.84, p=0.027) and Kd (r=0.94, p=0.0014) values and the calculated total scores obtained from our docking experiments. In conclusion, these results suggest that the seven Cp2M(IV)Cl2 used for this study can interact with apo-hTf, and their affinity was directly and inversely proportional to their bond angles CpMCp and ClMCl, respectively. Our docking studies also suggest that the binding of the first three Cp2M(IV)Cl2 (M(IV)=V, Mo, W) to hTf could abrogate the formation of the hTf-receptor complex, and as a consequence the metallocene-hTf complex might require another transport mechanism in order to get into the cell.

Structure of Ru(acac)2(ethoxide)(ethanol)·(1/2) trans-stilbene: Intermediate species linked by hydrogen bonds

The reaction of Ru(acac)3 in ethanol in the presence of zinc and trans-stilbene affords Ru(acac)2(EtO)(EtOH) complex, co-crystallized with a half-molecule of trans-stilbene as a by-product, 1. The complex crystallizes in the monoclinic space group P21/n with a = 12.288 (3), b = 28.420(6), c = 13.285 (3) Å, β = 95.63(3)° and Z = 8. The complex exhibits hydrogen bonds between the two Ru(acac)2(EtO)(EtOH) molecules.