Novel coumarin- and quinolinone-based polycycles as cell division cycle 25-A and -C phosphatases inhibitors induce proliferation arrest and apoptosis in cancer cells.

Cell division cycle phosphatases CDC25 A, B and C are involved in modulating cell cycle processes and are found overexpressed in a large panel of cancer typology. Here, we describe the development of two novel quinone-polycycle series of CDC25A and C inhibitors on the one hand 1a-k, coumarin-based, and on the other 2a-g, quinolinone-based, which inhibit either enzymes up to a sub-micro molar level and at single-digit micro molar concentrations, respectively. When tested in six different cancer cell lines, compound 2c displayed the highest efficacy to arrest cell viability, showing in almost all cell lines sub-micro molar IC50 values, a profile even better than the reference compound NCS95397. To investigate the putative binding mode of the inhibitors and to develop quantitative structure-activity relationships, molecular docking and 3-D QSAR studies were also carried out. Four selected inhibitors, 1a, 1d, 2a and 2c have been also tested in A431 cancer cells; among them, compound 2c was the most potent one leading to cell proliferation arrest and decreased CDC25C protein levels together with its splicing variant. Compound 2c displayed increased phosphorylation levels of histone H3, induction of PARP and caspase 3 cleavage, highlighting its contribution to cell death through pro-apoptotic effects.

Synthetic polysulfane derivatives induce cell cycle arrest and apoptotic cell death in human hematopoietic cancer cells.

Natural polysulfanes including diallyltrisulfide (DATS) and diallyltetrasulfide (DATTS) from garlic possess antimicrobial, chemopreventive and anticancer properties. However these compounds exhibit chemical instability and reduced solubility, which prevents their potential clinical applicability. We synthesized six DATS and DATTS derivatives, based on the polysulfane motif, expected to exhibit improved physical and chemical properties and verified their biological activity on human leukemia cells. We identified four novel cytotoxic compounds (IC50 values: compound 1, 24.96±12.37 µM; compound 2, 22.82±4.20 µM; compound 3, 3.86±1.64 µM and compound 5, 40.62±10.07 µM, compared to DATTS: IC50: 9.33±3.86 µM). These polysulfanes possess excellent differential toxicity, as they did not affect proliferating mononuclear blood cells from healthy donors. We further demonstrated ability of active compounds to induce apoptosis in leukemia cells by analysis of nuclear fragmentation and of cleavage of effector and executioner caspases. Apoptosis was preceded by accumulation of cells in G2/M phase with a pro-metaphase-like nuclear pattern as well as microtubular alterations. Prolonged and persistent arrest of cancer cells in early mitosis by the benzyl derivative identifies this compound as the most stable and effective one for further mechanistic and in vivo studies.

Comparison between the effects of diallyl tetrasulfide on human retina pigment epithelial cells (ARPE-19) and HCT116 cells.

BACKGROUND: Diallyl mono- and polysulfanes from garlic are known to induce an adaptive cell response and the formation of antioxidants in cancer cells. In the case of a severe ER stress and a failure in the response, cancer cells eventually go into apoptosis. Only little is known about the response of normal cells upon treatment. METHODS: Normal ARPE-19 cells were treated with diallyl tetrasulfide to study their cellular response and the results were compared with those of HCT116 cancer cells. Cell viability was checked by an MTT assay and cytofluorimetry. The formation of superoxide radicals, H2O2 and thiols were determined and proteins involved in the ER stress response were also detected by Western blot analysis. RESULTS: We found that diallyl tetrasulfide induced reactive oxygen species (ROS) in normal cells similar to cancer cells in a time (0 to 60min) and dose dependent manner (0 to 50µM). The level of heme oxigenase-1 (HO-1) was up-regulated in both cell types. Initially, we found a decrease in the total thiol level in both cell types but in contrast to cancer cells, normal cells recovered from the decrease in the total thiol concentration within 60min of treatment. CONCLUSIONS: The recovery of the thiol concentration in normal cells treated with diallyl tetrasulfide seems to be responsible for the failure to induce the ER stress signalling pathway and finally apoptosis in normal cells. GENERAL SIGNIFICANCE: The difference in the recovery of the thiol status might be an explanation for the anti-carcinogenic effects of garlic compounds.

Porphothionolactones: synthesis, structure, physical, and chemical properties of a chemodosimeter for hypochlorite.

The conversion of the lactone functionality of porpholactones, porphyrin analogs in which a porphyrin ß,ß'-double bond was replaced by a lactone moiety, to a thionolactone functionality using Lawesson's reagent is described. The resulting novel thionolactones were spectroscopically characterized and their electronic structure defined using experimental (UV-vis, fluorescence, cyclic voltammetry) and theoretical methods (molecular modelling at the B3LYP/6-31G(d) level). The structures of two benchmark thionolactones were determined by single crystal X-ray diffractometry. The idealized planarity of the chromophores rationalize the bathochromically shifted optical spectra of the thionolactones when compared to the lactones on electronic grounds. The thionolactone moiety can be used as a synthetic handle in the preparation of oxazolochlorins using RANEY® nickel-induced hydrodesulfurization reactions. Importantly, the meso-pentafluorophenyl-based porphothionolactone fluoresces by at least a factor of 60 less compared to the corresponding lactone. The hypochlorite-selective conversion of the thionolactone to the lactone is the basis for the use of this thionolactone as a switch-on chemodosimeter for hypochlorite, a widely used disinfectant and molecule of biological significance in some inflammatory processes.

Antifungal activity of tetrasulfanes against Botrytis cinerea.

Various natural polysulfanes (RS(x)R', x > or = 3, R (double dagger) H), such as diallyltrisulfide and diallyltetrasulfide from garlic, are mostly harmless to humans, higher animals and plants, yet highly active against diverse microbes, including several fungi. Such natural organic sulfur compounds (OSCs) possess considerable practical potential against a wide range of agricultural pests. Unfortunately, their use is often hampered due to the inherently offensive smell, chemical instability and low water solubility. However, since the biological activity of polysulfanes is primarily based on their unique sulfur-sulfur motif, it is possible to preserve this motif and to modify the side-chain(s). Ultimately, such changes result in synthetic polysulfanes which retain or even exceed the activity of their natural analogues, and also show improved physico-chemical properties. The resulting acid-, ether- and ester-based tetrasulfanes synthesized as part of this study are odorless and highly active against the grey mold fungus Botrytis cinerea. Some, but not all, of the synthetic polysulfanes are recognized by an active fungal efflux mechanism mediated by the ABC transporter AtrB. Remarkably, some of them even induce transcription of the AtrB-encoding gene, mediated by transcription factor Mrr1. Taken together, the activity of synthetic polysulfanes against B. cinerea, combined with a likely low ecotoxicity of such sulfur compounds, bodes well for possible future applications against this and eventually other agronomically important plant pathogens.