RESUMEN

With the goal of generating hetero-redox levels on metals as well as on nitric oxide (NO), metallodithiolate (N2 S2 )CoIII (NO- ), N2 S2 = N,N- dibenzyl-3,7-diazanonane-1,9-dithiolate, is introduced as ligand to a well-characterized labile [Ni0 (NO)+ ] synthon. The reaction between [Ni0 (NO+ )] and [CoIII (NO- )] has led to a remarkable electronic and ligand redistribution to form a heterobimetallic dinitrosyl cobalt [(N2 S2 )NiII ∙Co(NO)2 ]+ complex with formal two electron oxidation state switches concomitant with the nickel extraction or transfer as NiII into the N2 S2 ligand binding site. To date, this is the first reported heterobimetallic cobalt dinitrosyl complex.

RESUMEN

A series of hybrid thiosemicarbazone-alkylthiocarbamate copper complexes with similar electronic environments but distinct physical structures have been prepared, characterized, and evaluated for antiproliferation activity. The complexes include the constitutional isomers (1-phenylpropane-1-imine-(O-ethylthiocarbamato)-2-one-(N-methylthiosemicarbazonato))copper(II) (CuL1) and (1-phenylpropane-1-one-(N-methylthiosemicarbazonato)-2-imine-(O-ethylthiocarbamato))copper(II) (CuL2) along with (1-propane-1-imine-(O-ethylthiocarbamato)-2-one-(N-methylthiosemicarbazonato))copper(II) (CuL3). Complexes CuL1 and CuL2 differ in the positions of the pendent thiosemicarbazone (TSC) and alkylthiocarbamate (ATC) moieties on the 1-phenylpropane backbone. Complex CuL3 employs a propane backbone with the TSC in the 2-position as in CuL1. The isomer pair CuL1 and CuL2 have equivalent electronic environments with indistinguishable CuII/I potentials (E1/2 = -0.86 V vs. ferrocenium/ferrocene) and electron paramagnetic resonance (EPR) spectra (g∥ = 2.26, g⊥ = 2.08). The electronic structure of CuL3 has a similar E1/2 of -0.84 V and identical EPR parameters to CuL1, 2. Single crystal X-ray diffraction studies confirm a consistent donor environment with no substantial variation in the CuN or CuS bond distances and angles between the complexes. The antiproliferation activities of the CuL1-3 were evaluated against the lung adenocarcinoma cell line (A549) and nonmalignant lung fibroblast cell line (IMR-90) using the MTT assay. CuL1 had the highest A549 activity (A549EC50 = 0.065 µM) and selectivity (IMR-90EC50/A549EC50 = 20). The constitutional isomer CuL2 displayed decreased A549 activity (0.18 µM) and selectivity (10.6). The complex CuL3 displayed activity (0.009 µM) similar to CuL1 but with a lack of selectivity (1.0). Cellular copper loading determined by ICP-MS was consistent with the activity and selectivity trends. The complexes CuL1-3 did not induce reactive oxygen species (ROS) generation.

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A series of isomeric bis(alkylthiocarbamate) copper complexes have been synthesized, characterized, and evaluated for antiproliferation activity. The complexes were derived from ligand isomers with 3-methylpentyl (H2L2) and cyclohexyl (H2L3) backbone substituents, which each yield a pair of linkage isomers. The thermodynamic products CuL2a/3a have two imino N and two S donors resulting in three five-member chelate rings (555 isomers). The kinetic isomers CuL2b/3b have one imino and one hydrazino N donor and two S donors resulting in four-, six-, and five-member rings (465 isomers). The 555 isomers have more accessible CuII/I potentials (E1/2 = -811/-768 mV vs. ferrocenium/ferrocene) and lower energy charge transfer bands than their 465 counterparts (E1/2 = -923/-854 mV). Antiproliferation activities were evaluated against the lung adenocarcinoma cell line (A549) and nonmalignant lung fibroblast cell line (IMR-90) using the MTT assay. CuL2a was potent (A549EC50 = 0.080 µM) and selective (IMR-90EC50/A549EC50 = 25) for A549. Its linkage isomer CuL2b had equivalent A549 activity, but lower selectivity (IMR-90EC50/A549EC50 = 12.5). The isomers CuL3a and CuL3b were less potent with A549EC50 values of 1.9 and 0.19 µM and less selective with IMR-90EC50/A549EC50 ratios of 2.3 and 2.65, respectively. There was no correlation between reduction potential and A549 antiproliferation activity/selectivity.

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The diaminedithiol (N2S2) tetradentate ligand constitutes a useful chelating molecule for preparing 99mTc-labeled compounds of high in vivo stability in high radiochemical yields. However, since the thiol groups in the N2S2 ligand are easy to be oxidized to disulfide bonds, they need to be protected with an appropriate protecting group, which hinders the broad applications of the N2S2 ligand for radiopharmaceuticals. In this study, a Zn chelate of N2S2 was evaluated as a precursor for purification-free 99mTc-labeled N2S2 under the mild and simple procedure. Zn-N2S2 was prepared by reacting Zn acetate with N2S2, and the Zn-N2S2 remained stable under aerobic conditions at room temperature. 99mTc-N2S2 was obtained over 90% radiochemical yields at room temperature by a one-pot reaction, consisting of Zn-N2S2 (10-5 M), 99mTcO4-, ethylenediaminetetraacetic acid (EDTA), and a reducing agent (Sn2+) at pH = 5.5 to 7.5. 99mTc-N2S2 was also obtained over 90% radiochemical yields when the reaction was conducted in the presence of an equimolar amount of IgG antibody. These findings indicate the Zn complex of N2S2 ligand constitutes a stable and useful precursor to prepare 99mTc-labeled N2S2 compounds in high yields under the mild and simple procedure.

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With the goal of generating anionic analogues to MN2 S2 ⋅Mn(CO)3 Br we introduced metallodithiolate ligands, MN2 S22- prepared from the Cys-X-Cys biomimetic, ema4- ligand (ema=N,N'-ethylenebis(mercaptoacetamide); M=NiII , [VIV ≡O]2+ and FeIII ) to Mn(CO)5 Br. An unexpected, remarkably stable dimanganese product, (H2 N2 (CH2 C=O(µ-S))2 )[Mn(CO)3 ]2 resulted from loss of M originally residing in the N2 S24- pocket, replaced by protonation at the amido nitrogens, generating H2 ema2- . Accordingly, the ema ligand has switched its coordination mode from an N2 S24- cavity holding a single metal, to a binucleating H2 ema2- with bridging sulfurs and carboxamide oxygens within Mn-µ-S-CH2 -C-O, 5-membered rings. In situ metal-templating by zinc ions gives quantitative yields of the Mn2 product. By computational studies we compared the conformations of "linear" ema4- to ema4- frozen in the "tight-loop" around single metals, and to the "looser" fold possible for H2 ema2- that is the optimal arrangement for binucleation. XRD molecular structures show extensive H-bonding at the amido-nitrogen protons in the solid state.

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INTRODUCTION: A lipiodol solution of (188)Re-4-hexadecyl-2,2,9,9-tetramethyl-4,7-diaza-1,10-decanedithiol (HTDD) has been successfully developed for liver cancer therapy; however, its preparation requires a multi-step synthesis and it is characterized by a low labeling yield. METHODS: We synthesized a new compound, 4-hexadecyl-4,7-diaza-1,10-decanedithioacetate (AHDD), without gem dimethyl groups to address these issues. AHDD was formulated into a kit and was labeled with (188)Re. Biodistribution study was performed using normal BALB/c mice. RESULTS: The kit was labeled with (188)Re with a high efficiency (98.8±0.2%). After extraction with lipiodol, the overall yield of (188)Re-HDD/lipiodol was as high as 90.2±2.6%. A comparative biodistribution study of (188)Re-HTDD and (188)Re-HDD was performed in normal mice after intravenous injection. The lungs were identified as the main uptake site due to capillary-blockage. (188)Re-HDD/lipiodol showed a significantly higher lung uptake than that of (188)Re-HTDD/lipiodol (p<0.05). CONCLUSION: The newly synthesized (188)Re-HDD/lipiodol showed improved radiolabeling yield and biodistribution results compared to (188)Re-HTDD/lipiodol, and may therefore be more suitable for liver cancer therapy.

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