Chiral sulfoxides are an important class of compounds that find increasing use as chiral auxiliaries in asymmetric synthesis. [1,2] Current interest also reflects the existence of products with biological properties containing a sulfinyl group with a defined configuration. [3] Several methods for the asymmetric oxidation of prochiral sulfides have been reported, including the use of chiral oxidants, such as chiral oxaziridines, [4] chiral hydroperoxides, [5] and enzymes. [6,7] The majority of investigations have concentrated on the use of chiral metal complexes [1,3,[8][9][10][11] following the initial reports by Kagan and co-workers [12,13] and Modena and co-workers [14] on the use of variously modified Sharpless reagents for this reaction.One of the most widely studied metal-based systems has been that discovered by Bolm and Bienewald, [15,16] who employed a combination of Schiff bases 1 derived from chiral amino alcohols and [VO(acac) 2 ] (1.0 mol %; acac = acetylacetanoate), with aqueous hydrogen peroxide as the oxidant, in a two-phase system using dichloromethane as the solvent at 20 8C (Scheme 1). The advantages of the system developed by Bolm et al. include high activity, the very simple reaction conditions, and the use of hydrogen peroxide as the oxidant. The only drawback associated with the initial ligands tested was that the levels of enantiomeric excess were good, rather than excellent. Other research groups sought to optimize the system, by variation of the aromatic aldehyde, [17][18][19] the amino alcohol, [20] and the manner of addition of hydrogen peroxide, [21] and in many cases it is striking that the best outcome was usually obtained when the reaction was conducted in dichloromethane at 0 8C. A very nice application of the system developed by Bolm et al. was the asymmetric oxidation of ditert-butyl disulfide, reported by Ellman and co-workers, [22] who have since reported the results of spectroscopic studies with a view to understanding the nature of the active catalytic species better.[23] The nature of the active species is still not completely established, but while spectroscopic studies indicate the presence of a vanadium(v)oxomonoperoxo species, [24] recent calculations suggest that the active species may be a vanadium(v)oxohydroperoxide. [25] Recently, the use of analogous salan ligands has been reported to give high levels of enantioselectivity (95 % ee) in the oxidation of methyl phenyl sulfide, but lower levels of enantioselectivity were observed with other substrates. [26] Anson and co-workers screened a variety of chiral Schiff base ligands, and found that the 3,5-diiodo ligand (S)-2, in combination with [VO(acac) 2 ] gave excellent results in the catalytic asymmetric sulfoxidation of alkyl aryl sulfides with hydrogen peroxide, again in dichloromethane at 0 8C.[27] For example, methyl phenyl sulfide was oxidized to (S)-methyl phenyl sulfoxide (81 %, 90 % ee). Recently, Bolm and coworkers reported that a combination of this ligand with iron is also very effective for the asymmetric ox...

BACKGROUND: XIAP (X-linked inhibitor of apoptosis protein) is an anti-apoptotic protein exerting its activity by binding and suppressing caspases. As XIAP is overexpressed in several tumours, in which it apparently contributes to chemoresistance, and because its activity in vivo is antagonised by second mitochondria-derived activator of caspase (SMAC)/direct inhibitor of apoptosisbinding protein with low pI, small molecules mimicking SMAC (so called SMAC-mimetics) can potentially overcome tumour resistance by promoting apoptosis. METHODS: Three homodimeric compounds were synthesised tethering a monomeric SMAC-mimetic with different linkers and their affinity binding for the baculoviral inhibitor repeats domains of XIAP measured by fluorescent polarisation assay. The apoptotic activity of these molecules, alone or in combination with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and/or Bortezomib, was tested in melanoma cell lines by MTT viability assays and western blot analysis of activated caspases. RESULTS: We show that in melanoma cell lines, which are typically resistant to chemotherapeutic agents, XIAP knock-down sensitises cells to TRAIL treatment in vitro, also favouring the accumulation of cleaved caspase-8. We also describe a new series of 4-substituted azabicyclo[5.3.0]alkane monomeric and dimeric SMAC-mimetics that target various members of the IAP family and powerfully synergise at submicromolar concentrations with TRAIL in inducing cell death. Finally, we show that the simultaneous administration of newly developed SMAC-mimetics with Bortezomib potently triggers apoptosis in a melanoma cell line resistant to the combined effect of SMAC-mimetics and TRAIL. CONCLUSION: Hence, the newly developed SMAC-mimetics effectively synergise with TRAIL and Bortezomib in inducing cell death. These findings warrant further preclinical studies in vivo to verify the anticancer effectiveness of the combination of these agents.

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