2,117 research outputs found
Chemical behaviour and crystallographic characterization of ureido 1,2,5-oxadiazole derivatives, related to Stat3 inhibitors
No full textSTAT3 (Signal Transducer and Activator for Transcription 3) is a latent cytosolic protein that directly relates extracellular signals(e.g. growth factors, poly-peptide, cytokines etc.) from the membrane to the nucleus [1]. STAT3 is constitutively
activated by aberrant upstream tyrosine kinase activities in a broad spectrum of human solid and blood tumours. Since STAT3
inhibition leads to apoptosis in tumour cells but not in normal cells, it represents a promising target for cancer therapy [2].
In our research we focused on the discovery of new ureido oxadiazole derivatives related to AVS-2088 (lead compound), as
potential STAT3 inhibitors, with the aim to identify the essential structure-activity requirements for the development of novel
active compounds.
Our previous results [3] indicated that the presence of a phenyl moiety in position 4 of the oxadiazole ring was critical for the
interaction with the biological target, so we planned the synthesis of the styryl derivatives.
On these basis, we analyzed the X-Ray structures of the compounds having the general formula reported in Figure 2 and
structure-activity relationships were derived. The drop in activity of the derivatives with respect to the lead could be due to the
presence of the common flexible benzyl chain linked to the urea that disrupted the flat conformation of the entire molecule,
influencing its orientation and interaction at the receptor site.
The synthetic procedures applied for the preparation of the new derivatives as well as the results of the crystallographic studies
and their biological evaluation will be presented.[1] Yu, H.; Jove, R. The STATs of cancer-new molecular targets come of age. Nat. Rev. Cancer 2004, 4, 97-105.
[2] D. Masciocchi, A. Gelain, S. Villa, F. Meneghetti, D. Barlocco. Signal Transducer and Activator of Transcription 3 (STAT3): a
promising target for anticancer therapy. Future Med. Chem. 2011, 3, 567-597.
[3] Shin, D.-S.; Masciocchi, D.; Gelain, A.; Villa, S.; Barlocco, D.; Meneghetti, F.; Pedretti, A.; Han, Y.-M.; Han, D. C.; Han, M.
Y.; Kwon, B.-M.; Legnani, L.; Toma L. Synthesis, modeling, and crystallographic study of 3,4-disubstituted-1,2,5-oxadiazoles
and evaluation of their ability to decrease STAT3 activity. Med. Chem. Comm. 2010, 1, 156-164
Synthesis, characterization and XRPD studies of metal-organic frameworks containing 1,4 bis(4-pyrazolyl) and 1,4 bis(5-tetrazolyl)benzene ligands
No full textIn the last decade we have been deeply exploring the coordination chemistry of polydentate ligands possessing multiple donor sites. Nowadays we decided to increased the complexity of the polytopic N-ligands aiming at the formation of oligomeric and polymeric species with different functional properties.
Inspires to the 1,4-benzene-dicarboxylate (BDC) the ligand of the highly porous and capable of H2 sorption MOF-5 proposed by Yaghi et al., and planning to employ polytopic longer spacers possessing nitrogen coordination sites (with the possibility of an exobidentate coordination), we turned our attention to the 1,4-bis(5-tetrazolyl)benzene species (C8H6N8, H2btb).
After having tailored high-yield, cheap and atoxic syntheses for H2btb [1], we started coupling this ligand with a transition metal ions aiming at the formation of microcrystalline materials of well defined stoichiometry, structure and functional properties: nanoporosity, cooperative magnetism and catalytic activity.
The isolated materials shows a variety of stoichiometries, each one with its own peculiar structure: homoleptic species [Ag2(btb), Cu(btb) and Co(btb)], hydrated (or solvated) compounds [Co(btb)•2H2O and Zn(btb)•nDMF], and even hydroxo complexes [Cu2(μ3-OH)2(btb)]. These compounds are either dense or moderately porous and, therefore, they are not prone to gas sorption or storage, as originally targeted [2].
In this context, we decided to develop a new strategy to synthesized the analogous 1,4-bis(4-pyrazolyl)benzene (C12H10N4, H2bpb) [1] with the hope to obtain microporous and non-dense species with the coordination of the metal transition elements. Specifically, in our research, we have coupled these ligands with Ni, Cu, Zn, Hg to afford the species Ni(bpb), Zn(bpb), Cu2(bpb) and Hg(bpb). These species are isolated by solvothermal reaction and fully characterized by elemental and thermogravimetric analysis, IR spectroscopy and we attained their full structural characterization resorting to state-of-the-art powder diffraction methods, occasionally coupled to thermodiffractometry analysis.
Adsorption capacities are also studied with preliminary gas sorption analysis, towards N2, and showing attractive adsorption capacities of the compound Ni(bpb) and Zn(bpb) in agreement with their structural characterization that shows a very low density and regulars networks.
[1] A. Maspero, S. Galli, N. Masciocchi, G. Palmisano, Chem. Lett., 2008, in press.
[2] A.Maspero, S. Galli, V.Colombo, G.Peli, N.Masciocchi, S.Stagni, E.Barea, J.A.R. Navarro, Inorg. Chim. ACTA, 2008, in press
Optimation of the lead MD77
No full textThe investigation which led to the identification of our lead MD771 began from a screening (dual-luciferase assay system) of chemical libraries, performed in collaboration with our colleagues of the Korean Research Institute of Bioscience and Biotechnology (KRIBB). From this preliminary screening, several STAT3 inhibitors were identified. Based on the further information gained through conformational and docking studies, a number of derivatives were synthesized, characterized and evaluated by means of different biological assays. The obtained results led to the discovery of a molecule (MD77) as a promising lead compound. MD77 exerted positive results in the dual-luciferase assay, showing 20% inhibition at 5 μM. It was also able to significantly interact with STAT3-SH2 domain, with a dose-dependent profile and an IC50 of 17.7 μM (AlphaScreen-based assay). Moreover, it displayed a significant growth inhibitory activity evaluated on a panel of tumor cell lines with a GI50 around 2 μM for most of them. Modeling, docking and crystallographic studies were also performed and they gave a key support in understanding the binding mode of MD77 to the STAT3-SH2 domain. In light of these results, MD77 became our starting point for the development of new direct STAT3 inhibitors. Initially, the optimized derivatives were designed following the classical methodologies of medicinal chemistry, in which the molecule undergoes a gradual modification on the basis of SAR studies and with the support of molecular modeling studies. In particular, the substitution of the amidic functionality with a bioisosteric thioamidic group and the nature of the substituent at position 5 were considered. In detail, alkyl groups or halogens were introduced at different positions of the aromatic ring. In addition, since docking studies on MD77 suggested that in the binding mode of its favoured conformation to the SH2 domain, which is comparable to that of phosphorylated Tyr-705, the trifluoromethyl group could play an important role by establishing three hydrogen bond interactions with the guanidine moiety of Arg-595 residue, we synthesized the analogue lacking the substituent to verify this hypothesis.
1. Masciocchi D., Villa S., Meneghetti F., Pedretti A., Barlocco D., Legnani L.,Toma L., Kwon BM, Nakano S., Asai A., Gelain A. Biological and computational evaluation of an oxadiazole derivative (MD77) as a new lead for direct STAT3 inhibitors. MedChemComm (2012), 3, 592-59
Crystal structures of N,N'-bis(thiophen-2-ylmethyl)ethane-1,2-diaminium hydrochloride and of its [AuCl4]- salt solved by powder diffraction
No full textPreparation, analytical characterization, and crystal structures of N,N'-bis(thiophen-2-ylmethyl)ethane-1,2-diaminium hydrochloride (1) and of its gold derivative, N,N'-bis(thiophen-2-ylmethyl)ethane-1,2-diaminium tetrachloroaurate(III) (2) are reported. Compound (1) was obtained by reduction of the Schiff base N,N'-bis(thiophen-2-ylmethyl)ethane-1,2-diamine followed by HCl solution addition, whereas compound (2) was prepared reacting (1) with K[AuCl4] in aqueous solution. Compound (1) crystallizes in the orthorhombic system with space group Iba2 and cell parameters a = 29.856(1), b = 5.1372(2), and c = 10.1635(4) Å. Crystals of (2) belong to the monoclinic system with space group P21/c and cell parameters a = 11.0829(1), b = 9.5852(1), c = 11.6054(2) Å, and β = 75.49(1)°. Both structures contain diprotonated organic moieties, counterbalanced by hydrogen-bonded Cl-, or [AuCl4]- ions, in compounds (1) and (2), respectively
Structural Characterization of Anhydrous and Bishydrated Calcium Hexafluorosilicate by Powder Diffraction Methods
No full textX-ray powder diffraction characterizaton of polymeric metal diazolates
No full textPolymeric metal diazolates typically appear as insoluble and intractable powders, the structure of which could only be retrieved by the extensive use of ab-initio X-ray powder diffraction (XRPD) methods from conventional laboratory data. A number of selected examples from the metal pyrazolate, imidazolate, pyrimidin-2-olate and pyrimidin-4-olate classes are presented, highlighting the specific crystallochemical properties, material functionality and methodological aspects of the structure determination process. Linear and helical one-dimensional polymers, layered systems and three-dimensional networks are described, with particular emphasis on polymorphism and on the thermal, optical, magnetic and sorption properties. A brief outline of the method, as it has been tailored in our laboratories during the last decade, is also offered
X-ray Powder Diffraction Study of Organometallic Polymers: [Ru(L)(CO)2]n (L = 2,2’-Bipyridine or 1,10 Phenanthroline)
No full textA combination of rather unconventional XRPD methods has been used to assess the polymeric nature of the [Ru(L)(CO)(2)](n) (L = 2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, and 1,10-phenanthroline) derivatives. The polymeric chains pack pseudohexagonally in the ab plane and grow along c with Ru-Ru distances close to 3.0 Angstrom. The very poor diffraction patterns of these electrogenerated polymers suggest that the flat Ru(L)(CO)(2) monomers are staggered by 45degrees or 135degrees rotations (as in [Ru(CO)(4)](n)) but stack in random sequence along the chains
Ab initio X-ray powder diffraction characterisation of molecule-based magnetic materials
No full textUse of ab initio X-ray powder diffraction (XRPD) methods in the study of magnetically active species of covalent nature is presented. Selected cases are chosen in order to underline the power of XRPD methodologies, highlighting the importance of independent physico-chemical information from ancillary techniques
FURTHER INVESTIGATIONS OF THE REACTIVITY OF ETA-2-BONDED NITROSO COMPLEXES OF PLATINUM - THE CRYSTAL-STRUCTURE OF PT(PPH3)2(PHNO)
No full textThe crystal structure of Pt(PPh3)2(PhNO) (I) has been determined. This is the first example of a structure determination for a monomeric complex of a metal in a low oxidation state and bearing an η2-bonded nitroso ligand. Compound I crystallizes in the monoclinic space group P21/c (no.14) with a 14.228(4), b 13.914(3), c 17.855(4) Å, β 100.31 (2)°, V 3478(3) Å3 and Z = 4. Final R and Rw indices are 0.026 and 0.030 for 3609 observed reflections (I ≥ 3 σ(I)). The new complexes Pt(PPh3)2(RNO) (R = But (II), CF3 (III)) have been synthesized and their reactions with CO2, CS2, PhNCO, PhNCS, CO, alkenes and dimethyl acetylenedicarboxylate have been investigated and compared with those of the previously studied compound I. Preliminary observations on the synthesis and reactivity of Pd(PPh3)2(CF3NO) (IV) are also reported
[Cu(imidazole)2(CO3)]*H2O: An intermediate in the formation of the copper bis-imidazolate polymer (blue phase)
No full textThe crystal structure of [Cu(Him)2(CO3)].H2O, determined from conventional X-ray powder diffraction methods, allowed to clarify, on the basis of a structural interpretation of the chemical transformation, the role of the title compound in the formation of the blue phase of Cu(im)2 [Cu(Him)(2)(CO3)].H2O is triclinic, P-1; a = 8.8565(7), b = 8.9579(5), c = 8.3705(6) Angstrom, alpha = 105.728(4)°, beta = 105.318(3)°, gamma = 114.369(4)°; final R-wp, R-p and R-F agreement factors, for 4700 data collected in the 11-105° range, are 0.053, 0.036 and 0.078, respectively
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