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Abstract: The bis(silylated) alkenes Z-(PhSCH2)Me2SiC(H)2(CH2SPh) (2) and Z-(PhSCH2)Me2SiC(H))SiMe2(CH2SPh) (3) have been prepared by Pd-catalyzed double silylation of ethynylferrocene and 4-ethynyl-1,1′-biphenyl in the presence of 1,1,2,2-tetramethyl-1,2-bis(phenylthiomethyl)disilane (1). A reinvestigation on the interaction of 1 with [PdCl2(PhCN)2] in technical-grade CH2Cl2 as solvent revealed competition between reduction to elemental palladium (due to oxidative addition of the Si–Si bond across Pd(II) and subsequent reductive elimination) and formation of an unusual eight-membered chelate complex cis-[PdCl2{(PhSCH2SiMe2)2O}] (4), which is fluxional in solution. Based on GC–MS analyses revealing both formation of chlorosilane ClSiMe2CH2SPh and the disiloxane (PhSCH2SiMe2)2O, residual water contained in CH2Cl2 is supposed to be the source for the oxygen atom of the siloxane function. The mechanism of the formation of 4 is discussed. The molecular structures of 1 and 4 were determined by single-crystal X-ray diffraction analyses. The energies of several conformational isomers of 4 were computed by means of DFT calculations, the coexistence of a species featuring a weak dative Pd–O interaction due to a hemi-labile coordination of ligand 1 was evidenced. [Copyright &y& Elsevier]

Abstract: The biological evaluation of half-sandwich 99mTc-complexes that surrogate iodobenzamide with a high affinity for melanin tumor tissue is described. We have synthesized via retro Diels–Alder reaction two models of 99mTc complexes which possess the piano stool [Cp99mTc(CO)3] motif instead of a phenyl ring as in the original iodobenzamide 123I-N-(N-benzylpiperidin-4-yl)-2-iodobenzamide (2-IBP) and N-(2-diethylaminoethyl)-4-iodobenzamide (BZA). Diels–Alder products – (HCp-CONHR)2 (, R=2-diethylaminoethyl; , R=benzylpiperidin-4-yl) were prepared and reacted with fac-[99mTc(H2O)3(CO)3)]+ 1 in water to produce the corresponding 99mTc complexes [()99mTc(CO)3)] and [()99mTc(CO)3)] . The structures of the 99mTc complexes on the no-carrier-added level have been confirmed by chromatographic comparison with the corresponding rhenium complexes and , macroscopically characterized by IR, NMR, ESI-MS and X-ray crystallography for [triclinic, P-1, a=7.3518(1) Å, b=8.0309(2) Å, c=17.5536(3) Å, α=99.1260(5)°, β=90.4215(14)°, γ=117.0187(11)°]. The radioconjugate showed good in vitro stability. In murine melanoma B16F1 cells, significant cellular uptake (43.9% of the total applied activity) was attained after 4 h at 37°C with about 50% of the cell-associated radioactivity being internalized in the cells (22% of the applied activity). Furthermore, in melanoma-bearing C57BL6 mice, tumor uptake values of 3.39±0.50 %ID g−1 and 3.21±0.26 %ID g−1 at 1 and 4 h postinjection, respectively, were observed indicating a good retention of in the tumor. [Copyright &y& Elsevier]

Starting from asymmetric Thiele's acid derivatives, two different imaging probes [(99m)Tc(CO)(3)(CpR)] (R=potential targeting vector) are generated simultaneously in one-pot and from one substrate. This extends the previously introduced labeling strategy of metal-mediated retro-Diels-Alder reaction with HCp-R dimers. We demonstrate that chemically active functionalities such as hydroxamic acids are not following this labeling strategy. Adopting the principle of replacing phenyl rings by [Re(CO)(3)(Cp)] entities, potent histone deacetylase (HDAC)-inhibiting Re analogs of suberoylanlilide hydroxamic acid (SAHA; N-hydroxy-N'-phenyloctanediamide) were synthesized and characterized. Cytotoxic evaluation on different tumor cell lines revealed low IC(50) values [μM] for these compounds, comparable to their purely organic congeners., (Copyright © 2012 Verlag Helvetica Chimica Acta AG, Zürich.)

By combining organometallic groups and peptides, a large number of conjugates with interesting new biological properties can be prepared. Especially, attachment to cell-penetrating peptides (CPP) that act as efficient cell delivery vehicles has come to the fore. However, the presence of the metal moiety in such systems can interfere with standard conjugate synthesis procedures which therefore need to be optimized for every new compound. In this work, we report on the preparation of six new cymantrene-sC18 peptide bioconjugates that were prepared by solid phase peptide synthesis (SPPS) techniques. The cymantrene complexes were chosen for their different linker to the peptide, to study the influence of the linker group on cellular uptake and cell viability of the conjugates. Interestingly, the attachment of the metal complex leads to a non-standard cleavage of the Rink amide linker used in the SPPS protocol under trifluoroacetic acid (TFA) treatment, resulting in peptide amides that are N-alkylated at the C-terminus. Furthermore, we found that depending on the type of cymantrene moiety attached, the formation of reactive carbocations which result from decomposition of the resin linker is facilitated and can alkylate the metal complex moiety. Both effects were analyzed by MS/MS studies and cleavage mixtures for efficient elimination of this byproduct formation were identified. Moreover, initial biological testing of the cytotoxicity of one of the bioconjugates gave promising results. Concentration-dependent cell viability studies of Cym1-sC18 on human MCF-7 breast adenocarcinoma cells gave an IC(50) value of 59.8 (+/- 6.7) microM and demonstrate their potential in anticancer chemotherapy.

Cym-CO-CH2-CH2-COOH was prepared in good yield by Friedel-Crafts reaction of cymantrene (Cym, CpMn(CO)3) with succinic anhydride for the IR labelling of peptides and fully characterized, including an X-ray structure analysis (monoclinic space group P2(1)/n, a=5.727(3)A, b=19.865(9)A, c=10.518(5)A, beta=91.211(9) degrees). The compound was isolated in pure form without the need for chromatographic work-up and subsequently used for solution-phase synthesis of a bioconjugate with phenylalanine methyl ester to allow a complete spectroscopic characterization of this model system. The cymantrene keto carboxylic acid also turned out to be a very robust marker in automated microwave-assisted solid phase peptide synthesis (SPPS). [Leu5]-enkephalin (Tyr-Gly-Gly-Phe-Leu) was prepared on a Wang resin and labelled with the cymantrene derivative on the solid support under microwave irradiation in all steps. The metal-carbonyl marker stayed intact during cleavage from the resin with concentrated trifluoroacetic acid. After simple precipitation and lyophilization, the cymantrene-enkephalin bioconjugate could be obtained in analytically pure form without the need of HPLC purification. As required, the compound is non-cytotoxic against MCF-7 cells at up to 100 microM. This protocol thus allows one to introduce organometallic IR spectroscopic labels to peptides in a very straightforward way.

The conjugation of cymantrene CpMn(CO)(3) to cell-penetrating peptide hCT(18-32)-k7 alters the intracellular distribution in MCF-7 cells compared to the unmodified peptide, as visualized by fluorescence microscopy, and leads to an increased nuclear accumulation; the peptide and cymantrene compound themselves are not toxic, but the bioconjugate shows a significant cytotoxicity with an IC(50) value of 36 micromol l(-1).

Cell viability studies of HT29 colon cancer cells treated with the CO-releasing compound [Mn(CO)(3)(tpm)]PF(6) revealed a significant photoinduced cytotoxicity comparable to that of established agent 5-fluorouracil (5-FU), while controls kept in the dark were unaffected at up to 100 microM.