No abstract

Three ferrocene complexes vectorized with estrogens and vitamin D2 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 IC50, 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.

Efficient radiopharmaceutical design demands an understanding of factors that lead to one isomeric species in one ionization state at physiological pH. Thus, all pK a values must be outside the range of 6−9 for the typical M(V)O(N2S2) (M = 99mTc, 186/188Re) agents. The pendant carboxyl group needed for rapid clearance of renal agents in particular must be either only syn or only anti to the oxo ligand with respect to the N2S2 ligand plane. Monoamide-monoamine-dithiol (monoamide-monoamine = MAMA) ligands useful in preparing radiopharmaceuticals typically form M(V)O(N2S2) complexes with one core ligand pK a of ∼6−7 (secondary amine) and with both syn and anti isomers. We designed a new MAMA ligand, mercaptoacetamide-ethylene-cysteine (MAECH5), with the electron-withdrawing carboxyl group separated by only two bonds from the NH group. Only syn-ReO(MAECH2) was isolated. The structure of the monoanion syn-[ReO(MAECH)]- in the crystal of a [AsPh4]+ salt reveals lattice H-bonding between the CO2H of a tautomer (t2 ) with a CO2H and an amine N- and the CO of a neighboring t2 anion; this interaction results in preferential crystallization of t2 . However, in aqueous solutions of syn-[ReO(MAECH)]-, the predominant monoanionic tautomer (t1 ) has a CO2 - and an amine NH, as indicated by 1H NMR and resonance Raman spectra. The endo-NH configuration favored in M(V)O(N2S2) complexes places the NH and CO2 - groups in t1 spatially close. The NH is less acidic due to the cancellation of the electron-withdrawing and electrostatic effects of the negative CO2 -; as a result, syn-[ReO(MAECH)]- has a pK a value (6.0 ± 0.1) similar to that of the regioisomer syn-[ReO(CACAH)]- in which the carboxyl group and the NH are not close (CACAH5 = cysteine-acetyl-cysteamine). Our results suggest that the carboxyl group position also influences the syn/anti equilibrium. Attachment of the carboxyl group to a puckered ring in syn-[ReO(MAECH)]- appears both to favor the syn isomer and to increase the rate of syn/anti isomerization. ReO(CACAH2), with a carboxyl group attached to a less puckered chelate ring anchored by the amido donor, formed as a noninterconverting roughly equal mixture of syn/anti isomers. Thus, for a MAMA ligand to form a syn isomer with a pK a < 6, it must be designed with a nonionizable electron-withdrawing group near the NH group and a pendant carboxyl on a puckered ring.

Two water-soluble molybdenocene complexes containing oxygen chelating ligands, maltolato and malonate, have been synthesized to elucidate the role of the ancillary ligands in the molybdenocene cytotoxic activity. The structural characterizations of these species by 1 H NMR and IR spectroscopies suggest that both molybdenocene complexes contain the ligands in a bidentate fashion and elemental analysis and mass spectrometry corroborate the proposed formula for the species to be Cp 2 Mo (malonate) and [Cp 2 Mo(maltolato)]Cl (Cp is cyclopentadienyl). Metal-albumin binding studies were pursued using UV-vis spectroscopy and cyclic voltammetric techniques. Whereas metalalbumin binding studies using UV-vis spectroscopy did not show any evidence of interaction, cyclic voltammetry experiments showed that molybdenocene complexes may be involved in weak binding interactions with albumin, most likely in hydrophobic interactions. The cytotoxic activities of Cp 2 Mo(malonate) and [Cp 2 Mo(maltolato)]Cl alone with Cp 2 MoCl 2 were investigated in HT-29 colon cancer and MCF-7 breast cancer cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell viability assay. Cp 2 Mo(malonate) and [Cp 2 Mo(maltolato)]Cl showed slight improvement in terms of cytotoxic activity as compared with Cp 2 MoCl 2 in the HT-29 colon cancer cell line, whereas for MCF-7 all the molybdenocene species exhibited a proliferative profile. The molybdenocene-containing chelating ligands showed stronger proliferative effects than Cp 2 MoCl 2 . There is no correlation between the binding affinity of molybdenocenes for human serum albumin and cytotoxic activity toward HT-29 and MCF-7 cancer cells.