Novel, mercury-free synthetic pathway for trifluoromethylthio-substituted metallocenes

A novel synthetic pathway for trifluoromethylthioferrocene (3), which does not involve the use of toxic mercury(II)-based reagents, is described. The novel approach involves first the treatment of the commercially available bromoferrocene (1a) with NaSCN in the presence of copper(+I) to yield thiocyanatoferrocene (1), and then the reaction of 1 with the Rupper-Prakash reagent and tetrabutylammonium fluoride (TBAF) to give 3 in an overall yield of 60%. This approach could be extended for the preparation of thiocyanato-(4) and trifluoromethylthio-ruthenocene (7), which are herein both reported for the first time. Interestingly, diferrocenyl disulfide (2a) and diruthenocenyl disulfide (5) could be isolated as side-products during the synthesis of 3 and 7, respectively. All new compounds were unambiguously characterized by (1)H, (13)C, and (19)F NMR spectroscopy, mass spectrometry, cyclic voltammetry, elemental analysis, as well by X-ray crystallography for 1, 4, 4b, 5, 6, and 7. 1-7 were further tested for their toxic activity on cervical cancer (HeLa) and noncancerous (MRC-5) cell lines. All organometallic compounds were found either to be nontoxic or to have a moderate toxicity toward the cell lines used in this study

In vitro metabolic profile and in vivo antischistosomal activity studies of (η(6)-Praziquantel)Cr(CO)3 derivatives

In vitro metabolic behavior was investigated for two chromium tricarbonyl derivatives of the antischistosomal drug praziquantel (PZQ) with the formula (η(6)-PZQ)Cr(CO)3 (1 and 2), by use of human liver microsomes. The metabolic profiles of the derivatives differ significantly. The optically pure (η(6)-PZQ)Cr(CO)3 derivatives (S, Sp)-1, (R, Rp)-1, (S, Rp)-2, and (R, Sp)-2 were also prepared to assess the eudysmic ratios of 1 and 2 against Schistosoma mansoni in vitro. A strong enantioselective antischistosomal activity was observed. The R-enantiomers are highly active against adult schistosomes in vitro (IC50 0.08-0.13 μM), whereas both S-enantiomers lack activity. The in vivo activity of 1 and 2 was then studied in mice harboring a chronic S. mansoni infection. A single dose of 1 and 2 (400 mg/kg) resulted in low worm burden reductions of 24% and 29% (p > 0.05)

Photo-induced activation of metal complexes in living cells for photodynamic therapy (PDT) and photo-activated chemotherapy (PACT)

Elaboration of new generations of more effective and safer metal-based anticancer agents, has been stimulated by the severe side effects encountered by patients undergoing chemotherapeutic treatments. In this search, ruthenium complexes have shown encouraging potential, demonstrating a wide antiproliferative profile against cancer cells. Seminal studies conducted in our labs have resulted in the development of ruthenium(II)-based new anticancer agents, which showed distinct cytotoxicity mechanisms. First, a substitutionally-inert bis(dppz)-Ru(II) complex has been synthetized that impairs the mitochondrial membrane potential of cells leading to apoptosis. A follow- up structure-activity relationship analysis investigating the impact of lipophilicity, charge and size-based modification revealed the presence of carboxylic acid functionality as indispensable to confer cytotoxicity to the Ru(II) complex. This complex was successfully inactivated by protecting the carboxylate functionality with a photolabile protecting group. The anticancer activity could be regained by UV-A irradiation (2.58 J/cm2). Second, a seemingly harmless ruthenium(II) complex was prepared. It targets the cell nucleus and causes significant damage to DNA, such as single-strand breaks (SSBs) and purines oxidation upon UV-A irradiation (1.29 J/cm2). After 24 h, double- strand breaks (DSBs) are also created that lead overall to cell death. Collectively, these findings are an important progress towards developing a new class of metal-based anticancer agents, which have the potential to overcome the drawbacks of the current platinum-based drugs

Combination of Ru(II) Complexes and Light: New Frontiers in Cancer Therapy

In this perspective article, we present the recent achievements in the application of ruthenium complexes as photosensitizers and as photoactivatable prodrugs.</p

Two-photon uncageable enzyme inhibitors bearing targeting vectors

The activity of two cyclooxygenase-2 enzyme inhibitors, Celecoxib and Lumiracoxib, could be suppressed by coupling to photo-labile protecting groups, so-called photocages. These groups could be further functionalized with a peptide targeting vector for specific cellular delivery. The enzyme inhibition potential of the cyclooxygenase-2 inhibitors could be regained upon two-photon excitation with tissue-transparent near-IR light at 800 nm

Towards cancer cell-specific phototoxic organometallic rhenium(I) complexes

Over the recent years, several Re(i) organometallic compounds have been shown to be toxic to various cancer cell lines. However, these compounds lacked sufficient selectivity towards cancer tissues to be used as novel chemotherapeutic agents. In this study, we probe the potential of two known N,N-bis(quinolinoyl) Re(i) tricarbonyl complex derivatives, namely Re(i) tricarbonyl [N,N-bis(quinolin-2-ylmethyl)amino]-4-butane-1-amine () and Re(i) tricarbonyl [N,N-bis(quinolin-2-ylmethyl)amino]-5-valeric acid (), as photodynamic therapy (PDT) photosensitizers. and proved to be excellent singlet oxygen generators in a lipophilic environment with quantum yields of about 75%. Furthermore, we envisaged to improve the selectivity of via conjugation to two types of peptides, namely a nuclear localization signal (NLS) and a derivative of the neuropeptide bombesin, to form and , respectively. Fluorescent microscopy on cervical cancer cells (HeLa) showed that the conjugation of to significantly enhanced the compound's accumulation into the cell nucleus and more specifically into its nucleoli. Importantly, in view of PDT applications, the cytotoxicity of the Re complexes and their bioconjugates increased significantly upon light irradiation. In particular, was found to be at least 20-fold more toxic after light irradiation. DNA photo-cleavage studies demonstrated that all compounds damaged DNA via singlet oxygen and, to a minor extent, superoxide production

Towards99mTc-based imaging agents with effective doxorubicin mimetics: a molecular and cellular study

Doxorubicin is a clinical benchmark drug, which is applied in the treatment of numerous cancers. Known for its accumulation in the nucleus and ability to intercalate into DNA, it targets quickly dividing i.e. hypermitotic cells. Through this mechanism, it could be an ideal structural motif for a new class of imaging agents, given that the new entity approximates the in vitro profile of the parent drug. Here we describe design, synthesis and biological activity of a small array of Doxorubicin-metalloconjugates (M = 99mTc, Re). We demonstrate that the conjugates preferably accumulate in the nuclear compartment, tightly bind to DNA and retain an appreciable cytotoxicity. Moreover, the Re conjugates effectively act as inhibitors of the human Topoisomerase II enzyme, which is the widely accepted mechanism of action of the parent drug. Since the conjugates effectively mimic the in vitro behavior of native Doxorubicin, the 99mTc compounds are prospective imaging agents

Dual mode of cell death upon the photo-irradiation of a Ru(II) polypyridyl complex in interphase or mitosis

Photodynamic therapy (PDT) is an attractive, complementary medical technique to chemotherapy. Among the different photosensitizers (PSs) employed, Ru(ii) polypyridyl complexes were found to be valid substitutes to porphyrin-based or phthalocyanine-based PSs. Here, we confirm that one such complex, namely [Ru(bipy)2-dppz-7-methoxy][PF6]2 (Ru65), which localizes in the nucleus of various cancer and normal cells, displays cytotoxicity only upon UV-A irradiation. Importantly, we disclose the molecular mechanism of the UV-A mediated cytotoxic action of Ru65. We demonstrate that Ru65 intercalates in DNA and, upon light irradiation, promotes guanine oxidation, resulting in nicks in the double helix. We confirm this mechanism of action in living cells, showing that the UV-A irradiation of cells loaded with Ru65 results in a transient DNA damage response and cell death. Strikingly, the photo-irradiation of Ru65 triggered distinct mechanisms of cell death in interphase or mitotic cells. The former underwent cell cycle arrest at the G2/M phase and massive cytoplasmic vacuolation, which was paralleled by an unfolded-protein stress response, resulting in a reduction of viability and cell death through a paraptosis-like mechanism. On the other hand, the UV-A irradiation of Ru65 in cells synchronized by G2/M block-release with a selective CDK1 inhibitor led to blocking mitotic entry and rapid cell death through classic apoptotic pathways. Importantly, targeting mitotic cells with Ru65 allowed increasing its photo-toxicity by a factor of 3.6. Overall, our findings show that the use of a combination of a cell cycle inhibitor and a PS targeting the nucleus could open up new avenues in PDT