Cyclative cleavage via solid-phase supported stabilized sulfur ylides: synthesis of macrocyclic lactones

A new synthesis of macrolactones bearing a cyclopropyl ring condensed to the macrocycle is reported via a cyclization-release strategy making use of solid-phase supported stabilized sulfur ylides

Synthesis and biological evaluation of dual action cyclo-RGD/SMAC mimetic conjugates targeting αvβ3/αvβ5 integrins and IAP proteins

The rational design, synthesis and in vitro biological evaluation of dual action conjugates 11-13, containing a tumour targeting, integrin a(v)beta(3)/a(v)beta(5) ligand portion and a pro-apoptotic SMAC mimetic portion (cyclo-RGD/SMAC mimetic conjugates) are reported. The binding strength of the two separate units is generally maintained by these dual action conjugates. In particular, the connection between the separate units (anchor points on each unit; nature, length and stability of the linker) influences the activity of each portion against its molecular targets (integrins a(v)beta(3)/a(v)beta(5) for cyclo-RGD, IAP proteins for SMAC mimetics). Each conjugate portion tolerates different substitutions while preserving the binding affinity for each target

Novel SMAC-mimetics synergistically stimulate melanoma cell death in combination with TRAIL and Bortezomib

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 apoptosis-binding 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

DFG-in and DFG-out homology models of TrkB kinase receptor: Induced-fit and ensemble docking

Kinases from the Trk family are important for the regulation of development and for the correct functioning of the neural system. Deregulation (over-expression) of Trks leads to survival and proliferation of different human cancers. Therefore, development of inhibitors for Trks that can disrupt the signal pathway of Trks could lead to cure against cancer as well as to nociception. Homology models built by YASARA have been used as targets for docking various libraries of known Trk inhibitors. The receptor plasticity was compensated with induced fit docking and/or ensemble docking. It was determined that DFG-in and DFG-out conformational states of TrkB kinase must be taken into account in order to get more reasonable relationships between the docking score and the activity measured by pIC 50 for the corresponding ligands

(4S)-p-Hydroxybenzyl-1,3-oxazolidin-2-one as a solid-supported chiral auxiliary in asymmetric 1,3-dipolar cycloadditions

Evans' chiral auxiliary was grafted onto both Merrifield and Wang resins and, after functionalisation, they were used as chiral dipolarophiles in a 1,3-dipolar cycloaddition involving both a nitrile oxide and a nitrone. The cycloadducts were cleaved and analysed by chiral HPLC: the recovered supported chiral oxazolidinone was functionalised and reused in further cycloadditions. The stereochemical results as well as the possibility of recycling the chiral linker supports the applicability of solid-supported chiral auxiliaries. (C) 2000 Elsevier Science Ltd

D-glucose as a regioselectively addressable scaffold for combinatorial chemistry on solid phase

D-Glucose derivatives bearing an anomeric thiophenyl group and orthogonally protections on secondary hydroxyl groups were linked to solid supports (PS/DV polymer, tentagel resin) through an ester bond on C-6. It was investigated the possibility to remove orthogonally protecting groups and functionalize selectively the free hydroxyls groups and the anomeric carbon of sugars in solid phase

A NMR and computational study of Smac mimics targeting both the BIR2 and BIR3 domains in XIAP protein

In this paper we report an extensive NMR anal. of small ligands (Smac mimics) complexed with different constructs of XIAP. The mimics-binding site of XIAP is known as the BIR3 domain - primary, and the linker BIR2 region - secondary site. Interactions between the BIR3 domain and Smac mimics have been extensively studied by X-ray but, as of today, there are scarce data about the interaction between BIR2, or the whole linker-BIR2-BIR3 construct, and Smac mimics. In order to characterize our Smac mimics, we performed a STD NMR study between our 4-substituted, 1-aza-2-oxobicyclo[5.3.0]decane scaffold-based mols. and three different XIAP fragments: single BIR2 and BIR3 domains, and bifunctional linker-BIR2-BIR3. The results were integrated with docking calcns. and mol. dynamics simulations. NMR data, which are consistent with biol. tests, indicated that the two BIR subunits interact differently with our Smac mimics and suggest that the ligands enter into more intimate contact with the linker-BIR2-BIR3. In conclusion, we observe that the SMAC mimics showed with the construct linker-BIR2-BIR3 a series of NOE contacts that were not obsd. in the mono-domain ligand:BIR2 or :BIR3 complexes. So, in agreement with the computational models we believe that the linker moieties of the binding site play a key role in the stability of the protein complex