- Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue
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A number of analogues of the marine-derived histone deacetylase inhibitor largazole incorporating major structural changes in the depsipeptide ring were synthesized. Replacing the thiazole-thiazoline fragment of largazole with a bipyridine group gave analogue 7 with potent cell growth inhibitory activity and an activity profile similar to that of largazole, suggesting that conformational change accompanying switching hybridization from sp3 to sp2 at C-7 is well tolerated. Analogue 7 was more class I selective compared to largazole, with at least 464-fold selectivity for class I HDAC proteins over class II HDAC6 compared to a 22-fold selectivity observed with largazole. To our knowledge 7 represents the first example of a potent and highly cytotoxic largazole analogue not containing a thiazoline ring. The elimination of a chiral center derived from the unnatural amino acid R-a-methylcysteine makes the molecule more amenable to chemical synthesis, and coupled with its increased class I selectivity, 7 could serve as a new lead compound for developing selective largazole analogues.
- Almaliti, Jehad,Al-Hamashi, Ayad A.,Negmeldin, Ahmed T.,Hanigan, Christin L.,Perera, Lalith,Pflum, Mary Kay H.,Casero, Robert A.,Tillekeratne, L. M. Viranga
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- Synthesis, Properties and Complexation Studies on 3-Amino-6,6'-dimethyl-2,2'-bipyridine
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The new unsymmetrical bipyridyl ligand 6,6'-dimethyl-3-nitro-2,2'-bipyridine was prepared via coupling of 6-methyl-2-trimethylstanniopyridine and 2-chloro-6-methyl-3-nitropyridine in the presence of .Reduction of the nitro group afforded 3-amino-6,6'-dimethyl-2,2'-bipyridine (L), a model for the central subunit of the antitumour drug streptonigrin.At low temperatures, in acetone, L is planar, held in place by a hydrogen bond from the amino group to the pyridyl nitrogen in the adjacent ring.From 1H NMR lineshape analysis the barrier to rotation about the amino-bipyridyl bond (ΔGb) was estimated to be ca. 38 kJ mol-1 at 200 K.This value is significantly lower than the barrier to rotation about the biaryl bond connecting the aryl rings.In solution, L co-ordinates to Cd(II), Cu(I) and Zn(II) as a bipyridyl ligand; in these complexes the chemical shift of the amino group protons shifts upfield to ca. δ 5 compared to L where they resonate at δ 6.5.The crystal structure of was determined by X-ray diffraction methods and refined to a residual of 0.027 for 1895 independent observed reflections.The crystals are monoclinic, space group P21/n, a = 9.560(2), b = 16.886(2), c = 9.577(3) Angstroem, β = 118.37(2) deg.The complex crystallized as a dimer in which each cadmium binds three chloride ligands and a bipyridyl ligand in a distorted trigonal-bipyramidal arrangement.The relevance of these results to the structure and properties of the antitumour drug streptonigrin is discussed.
- Long, Georgina V.,Boyd, Sue E.,Harding, Margaret M.,Buys, Irmi E.,Hambley, Trevor W.
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- Synthesis and Isomeric Analysis of RuII Complexes Bearing Pentadentate Scaffolds
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A RuII-pentadentate polypyridyl complex [RuII(κ-N5-bpy2PYMe)Cl]+ (1+, bpy2PYMe = 1-(2-pyridyl)-1,1-bis(6-2,2′-bipyridyl)ethane) and its aqua derivative [RuII(κ-N5-bpy2PYMe)(H2O)]2+ (22+) were synthesized and characterized by experimental and computational methods. In MeOH, 1+ exists as two isomers in different proportions, cis (70%) and trans (30%), which are interconverted under thermal and photochemical conditions by a sequence of processes: chlorido decoordination, decoordination/recoordination of a pyridyl group, and chlorido recoordination. Under oxidative conditions in dichloromethane, trans-12+ generates a [RuIII(κ-N4-bpy2PYMe)Cl2]+ intermediate after the exchange of a pyridyl ligand by a Cl- counterion, which explains the trans/cis isomerization observed when the system is taken back to Ru(II). On the contrary, cis-12+ is in direct equilibrium with trans-12+, with absence of the κ-N4-bis-chlorido RuIII-intermediate. All these equilibria were modeled by density functional theory calculations. Interestingly, the aqua derivative is obtained as a pure trans-[RuII(κ-N5-bpy2PYMe)(H2O)]2+ isomer (trans-22+), while the addition of a methyl substituent to a single bpy of the pentadentate ligand leads to the formation of a single cis isomer for both chlorido and aqua derivatives [RuII(κ-N5-bpy(bpyMe)PYMe)Cl]+ (3+) and [RuII(κ-N5-bpy(bpyMe)PYMe)(H2O)]2+ (42+) due to the steric constraints imposed by the modified ligand. This system was also structurally and electrochemically compared to the previously reported [RuII(PY5Me2)X]n+ system (X = Cl, n = 1 (5+); X = H2O, n = 2 (62+)), which also contains a κ-N5-RuII coordination environment, and to the newly synthesized [RuII(PY4Im)X]n+ complexes (X = Cl, n = 1 (7+); X = H2O, n = 2 (82+)), which possess an electron-rich Hκ-N4C-RuII site due to the replacement of a pyridyl group by an imidazolic carbene.
- Gil-Sepulcre, Marcos,Axelson, Jordan C.,Aguiló, Joan,Solà-Hernández, Lluís,Francàs, Laia,Poater, Albert,Blancafort, Lluís,Benet-Buchholz, Jordi,Guirado, Gonzalo,Escriche, Lluís,Llobet, Antoni,Bofill, Roger,Sala, Xavier
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p. 11216 - 11229
(2016/11/17)
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- HDAC Inhibitors as Anti-Cancer Agents
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Largazole analogues, methods of making the same, and methods of using the same, are described.
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Paragraph 0154-0155
(2016/01/15)
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- Electronic influence of the thienyl sulfur atom on the oligomerization of ethylene by cobalt(II) 6-(thienyl)-2-(imino)pyridine catalysis
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The position of the sulfur atom in the thienyl group of 6-(thienyl)-2-(imino)pyridine ligands strongly affects the catalytic activity of the corresponding tetrahedral high-spin dihalide CoII complexes in the oligomerization of ethylene to α-olefins upon activation with methylaluminoxane (MAO). Complexes with the sulfur atom in the 3-position of the thienyl ring catalyze the selective conversion of ethylene to 1-butene, while catalysts containing thien-2-yl groups give C4-C14 a-olefins. In situ EPR experiments showed the occurrence of a spin state changeover with the formation of low-spin CoII species upon activation of the catalyst precursors by MAO. DFT calculations suggest that only thien-2-yl rings allow for the coordination of the sulfur atom to the cobalt center in the MAO-activated systems.
- Bianchini, Claudio,Gatteschi, Dante,Giambastiani, Giuliano,Rios, Itzel Guerrero,Ienco, Andrea,Laschi, Franco,Mealli, Carlo,Meli, Andrea,Sorace, Lorenzo,Toti, Alessandro,Vizza, Francesco
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p. 726 - 739
(2008/10/09)
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