Significado y dimensiones actuales de los tumores estromales gastro-intestinales (GIST)

Desde que en 1983 se utilizara por primera vez el término GISTs hasta hoy, se ha profundizado mucho en su conocimiento, comentándose aquí tres aspectos de actualidad: -Heterogenidad molecular: hasta hace poco se consideraba que los GISTs podían presentar dos tipos de mutaciones excluyentes, en KIT (75%) y PDGFR (10%). Hoy sabemos que existen también mutaciones en SDH, en KRAS/BRAF y en NF1, además de casos con fusiones génicas (s.t. de FGFR-1) y mutaciones puntuales en MAX, BCOR y APe. -Origen de los GISTs y progresión tumoral: Hirota et al (1998) señaló su origen en las células intersticiales de Cajal, aunque las que tienen potencial oncogénico son las sensibles a la transformación por CKIT y expresan el factor de transformación ETV1, cuya trasncripción se regula por KIT activado. Además, en la promoción tumoral es necesario la colaboración de otros factores. El acontecimiento inicial es la activación del oncogen KIT en el subtipo de CIC-ETV1 que conduce solo a una hiperplasia; para que progrese el crecimiento son necesarios cambios adicionales como deleciones del 14q, o del 22q. En la evolución se presentan otras deleciones adicionales en los genes lp,9p 15q Y Xplp 9p y 15q. Entre los genes implicados están MAX que interactúa con el gen MYC y causa desregulación de la expresión de p16 asociándose a progresión a tumor de riesgo intermedio y alto. Otro gen es lNll que regula negativamente el celular. En el segmento del XP está la distrofina que se asocia en el 90% con el desarrollo de metástasis. -GISTs de tipo pediátrico: se caracterizan por malfuncionamiento del complejo SDH y tienen características bioevolutivas diferentes. Afectan a jóvenes, sobre todo mujeres, en estómago, multifocales, con frecuentes metástasis linfáticas, exhiben mutaciones en SDH, expresan CD117 y DOGl, tienen un curso clínico indolente y no responden al imatinib. La mayoría de los casos se asociación a dos síndromes definidos: triada de Carney y síndrome de Carney-Stratakis.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Mechanism of Alkyl Migration in Diorganomagnesium 2,6-Bis(imino)pyridine Complexes: Formation of Grignard-Type Complexes with Square-Planar Mg(II) Centers

Dialkylmagnesium compounds [MgR2L2] (R = n-Bu, L = none or R = Bn, L = THF) react with 2,6-bis(imino)pyridines (BIP) to afford different types of Mg(II) alkyl complexes, depending on the nature of R. For R = n-Bu, thermally stable products resulting from selective alkyl transfer to the pyridine nitrogen (N1) atom are obtained. However, NMR studies showed that the reaction of [Mg(Bn)2THF2] with iPrBIP at −65 °C leads to a thermally unstable product arising from benzyl migration to position C2 in the pyridine ring. Above +5 °C, this compound rearranges, cleanly yielding a mixture of two isomeric complexes, in which the benzyl group has migrated to positions C3 or C4 of the central ring, respectively. Similar isomeric mixtures were obtained when [Mg(Bn)2THF2] was reacted with iPrBIP or MesBIP at room temperature. Such mixtures are thermally stable below 80 °C, but at this temperature, the 3-benzyl isomer converts into the thermodynamically favored 4-benzyl product, albeit not quantitatively. An alternate route was devised for the selective syntheses of the latter type of compounds. The X-ray diffraction structure of one of them provided an unusual example of a square-planar alkylmagnesium(II) center.Ministerio de Economía e Innovación CTQ2015-68978-

Oxygen-Induced Dimerization of Alkyl-Manganese(II) 2,6-Bisiminopyridine Complexes: Selective Synthesis of a New Ditopic NNN-Pincer Ligand

The outcome of the reaction of manganese(II) dialkyls with 2,6-bisiminopyridine (BIP) ligands is dramatically altered by the presence of very small amounts of oxygen (< 0.5 mol %), leading to binuclear species. These arise from the dimerization of the initial product, a Mn(II) 4-alkyl-2,6-bisiminodihydropyridinate alkyl complex. Cleavage of the binuclear Mn products with methanol affords the free dimeric bases, which can be regarded as a special type of ditopic NNN pincer ligand with an unusual tricyclic framework. The coordinative ability of the new ligands has been probed with the syntheses of Zn and Pd organometallic derivativesMinisterio de Economía e Innovación TQ2015- 68978-

Nickel and Palladium Complexes with New Phosphinito-Imine Ligands and Their Application as Ethylene Oligomerization Catalysts

Phosphinito-imines, a new class of P,N donors, are readily generated by reaction of bulky arylamide anions [R2CONAr]− (R2 = Me or t-Bu; Ar = 2,6-i-Pr2C6H4) with chlorophosphines ClP(R1)2. In solution, free phosphinito-imines exist in equilibrium with the corresponding amidophosphine tautomers, containing a nitrogen-bound P(R1)2 group. However, reacting the tautomer mixtures with metal precursor complexes, such as NiBr2(dme) or PdCl2(cod), selectively affords stable phosphinito-imine complexes MX2(P-N) (M = Ni, Pd) in excellent yields. These complexes are diamagnetic and exhibit square-planar structures in the solid state, but in solution, the Ni derivatives exchange with a small amount of the corresponding high-spin tetrahedral isomers. On treatment with MMAO or DEAC, NiX2(P-N) complexes become active ethylene oligomerization catalysts, affording mainly butenes along with smaller amounts of hexenes and octenes. The activity and the selectivity of these catalysts depend on the structure of the phosphinito-imine ligand and the cocatalyst used. When activated with DEAC, complexes containing the P(i-Pr)2 moiety are extremely active, achieving TOFs over 106 mol C2H4/mol Ni·h and high selectivity for butenes.Junta de Andalucía P09- FQM507

Well-defined alkylpalladium complexes with pyridine-carboxylate ligands as catalysts for the aerobic oxidation of alcohols

Neophylpalladium complexes of the type [Pd(CH(2)CMe(2)Ph)(N-O)(L)], where N-O is picolinate or a related bidentate, monoanionic ligand (6-methylpyridine-2-carboxylate, quinoline-2-carboxylate, 2-pyridylacetate or pyridine-2-sulfonate) and L is pyridine or a pyridine derivative, efficiently catalyze the oxidation of a range of aliphatic, benzylic and allylic alcohols with oxygen, without requiring any additives. A versatile method is described which allows the synthesis of the above-mentioned complexes with a minimum synthetic effort from readily available materials. Comparison of the rates of oxidation of 1-phenylethanol with different catalysts reveals the influence of the structure of the bidentate N-O chelate and the monodentate ligand L on the catalytic performance of these complexesGobierno de España CTQ2009-11721Junta de Andalucía FQM627

Protonolysis of Fe-C bonds of a diiminopyridineiron(II) dialkyl complex by acids of different strengths: Influence of monoanionic ligands on the spectroscopic properties of diiminopyiridine-FeY2 complexes

The reaction of the dialkyliron complex [Fe(CH2SiMe 3)2(MesBIP)] (MesBIP = 2,6-bis((N-mesityl)acetimidoyl)pyridine) with protic acids (HY) of different strengths (Y = C6F5O, CF3CO2, Cl, CF3SO3) invariably leads to the cleavage of both Fe-C bonds, independent of the Fe/HY ratio used (either 1:2 or 1:1), affording the corresponding complexes [FeY2(MesBIP)]. Relevant spectroscopic features of these compounds, such as paramagnetic 1H NMR shifts and UV-Vis absorption bands, exhibit a marked dependence on the nature of YGobierno de España CTQ2012-30962Junta de Andalucía FQM507

Aluminium(iii) dialkyl 2,6-bisimino-4R-dihydropyridinates(−1): selective synthesis, structure and controlled dimerization

A family of stable and otherwise selectively unachievable 2,6-bisimino-4-R-1,4-dihydropyridinate aluminium (III) dialkyl complexes [AlR’2(4-R-i PrBIPH)] (R = Bn, Allyl; R’ = Me, Et, i Bu) have been synthesized, taking advantage of a method for the preparation of the corresponding 4-R-1,4-dihydropiridine precursors developed in our group. All the dihydropyrdinate(−1) dialkyl aluminium complexes have been fully characterized by 1 H- 13C-NMR, elemental analysis and in the case 2’a, also by X-ray diffraction studies. Upon heating in toluene solution at 110 °C, the dimethyl derivatives 2a and 2’a dimerize selectively through a double cycloaddition. This reaction leads to the formation of two new C–C bonds that involve the both meta positions of the two 4-R-1,4-dihydropyridinate fragments, resulting the binuclear aluminium species [Me2Al(4-R-i PrHBIP)]2 (R = Bn (3a); allyl (3’a)). Experimental kinetics showed that the dimerization of 2’a obeys second order rate with negative activation entropy, which is consistent with a bimolecular rate-determining step. Controlled methanolysis of both 3a and 3’a release the metalfree dimeric bases, (4-Bn-i PrHBIPH)2 and (4-allyl-i PrHBIPH)2, providing a convenient route to these potentially useful ditopic ligands. When the R’ groups are bulkier than Me (2b, 2’b and 2’c), the dimerization is hindered or fully disabled, favoring the formation of paramagnetic NMR-silent species, which have been identified on the basis of a controlled methanolysis of the final organometallic products. Thus, when a toluene solution of [AlEt2(4-Bn-i PrBIPH)] (2b) was heated at 110 °C, followed by the addition of methanol in excess, it yields a mixture of the dimer (4-Bn-i PrHBIPH)2 and the aromatized base 4-Bn-i PrBIP, in ca. 1 : 2 ratio, indicating that the dimerization of 2b competes with its spontaneous dehydrogenation, yielding a paramagnetic complex containing a AlEt2 unit and a non-innocent (4-Bn-i PrBIP)•− radicalanion ligand. Similar NMR monitoring experiments on the thermal behavior of [AlEt2(4-allyl-i PrBIPH)] (2’b) and [Ali Bu2(4-allyl-iPrBIPH)] (2’c) showed that these complexes do not dimerize, but afford exclusively NMR silent products. When such thermally treated samples were subjected to methanolysis, they resulted in mixtures of the alkylated 4-allyl-i PrBIP and non-alkylated i PrBIP ligand, suggesting that dehydrogenation and deallylation reactions take place competitivelyMinisterio de Economía y Competitividad de España (MINECO) y los Fondos europeos FEDER-CTQ2015-68978-P y PRX14/00339United States National Science Foundation-CHE-166491