Guanidinium receptors as enantioselective amino acid membrane carriers and HIV-1 protease dimerization inhibitors

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Química Orgánica. Fecha de lectura: 05-10-200

Metallocene-DNA: synthesis molecular and electronic structure and DNA incorporation of C5-ferrocenylthymidine derivatives

Air-stable and readily available ruthenium benzylidene complexes of the general type (RuCl2 (=CHPh)(L)(L')) (L, L' = P(cC5H9)3, PCy3 and/or a N-heterocyclic carbene) constitute a new class of catalyst precursors for atom transfer radical addition (ATRA, also called Kharasch addition) and atom transfer radical polymerisation (ATRP) of methyl methacrylate and styrene, and provide an unprecedented example for the involvement of ruthenium alkylidenes in radical reactions. They promote the addition of carbon tetrachloride to methyl methacrylate and styrene in moderate to high yield (Table 1). They also promote the polymerisation of methyl methacrylate and styrene in a controlled way with good to excellent yields (Table 2). The ligands L (P(cC5H9)3, PCy3 and/or a N-heterocyclic carbene) play a particularly important role in determining the rate of the polymerisation. A similarly pronounced influence is exerted by the substituents on the N-heterocyclic carbene. Our results indicate that: The catalysts decompose quickly under ATRA and ATRP conditions; Polymerisations are mediated by both (RuCl2(=CHPh)(L)(L')) complexes and ruthenium species bereft of the benzylidene moiety

Inter- and Intramolecular Annulation Strategies to a Cyclopentanone Building Block Containing an All-Carbon Quaternary Stereogenic Center

Synthesis of (<i>S</i>)<i>-</i>2-methyl-3-fluorophenyl cyclopentanone methyl ester (1<i>S</i>)-<b>1</b> has been achieved by both inter- and intramolecular alkylation reactions on multigram scale, using chiral pool reagents. The intramolecular variant is a novel example of a chiral <i>bis</i>-electrophile reacting with a carbon nucleophile to form an enantiomerically pure all-carbon quaternary center

Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors

Potent and selective class IIa HDAC tetrasubstituted cyclopropane hydroxamic acid inhibitors were identified with high oral bioavailability that exhibited good brain and muscle exposure. Compound <b>14</b> displayed suitable properties for assessment of the impact of class IIa HDAC catalytic site inhibition in preclinical disease models

Design, Synthesis, and Biological Evaluation of Potent and Selective Class IIa Histone Deacetylase (HDAC) Inhibitors as a Potential Therapy for Huntington’s Disease

Inhibition of class IIa histone deacetylase (HDAC) enzymes have been suggested as a therapeutic strategy for a number of diseases, including Huntington’s disease. Catalytic-site small molecule inhibitors of the class IIa HDAC4, -5, -7, and -9 were developed. These trisubstituted diaryl­cyclopropane­hydroxamic acids were designed to exploit a lower pocket that is characteristic for the class IIa HDACs, not present in other HDAC classes. Selected inhibitors were cocrystallized with the catalytic domain of human HDAC4. We describe the first HDAC4 catalytic domain crystal structure in a “closed-loop” form, which in our view represents the biologically relevant conformation. We have demonstrated that these molecules can differentiate class IIa HDACs from class I and class IIb subtypes. They exhibited pharmacokinetic properties that should enable the assessment of their therapeutic benefit in both peripheral and CNS disorders. These selective inhibitors provide a means for evaluating potential efficacy in preclinical models in vivo

Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of Huntington’s Disease

Huntington’s disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. We report the design of a series of HTT pre-mRNA splicing modulators that lower huntingtin (HTT) protein, including the toxic mutant huntingtin (mHTT), by promoting insertion of a pseudoexon containing a premature termination codon at the exon 49-50 junction. The resulting transcript undergoes nonsense-mediated decay, leading to a reduction of HTT mRNA transcripts and protein levels. The starting benzamide core was modified to pyrazine amide and further optimized to give a potent, CNS-penetrant, and orally bioavailable HTT-splicing modulator 27. This compound reduced canonical splicing of the HTT RNA exon 49-50 and demonstrated significant HTT-lowering in both human HD stem cells and mouse BACHD models. Compound 27 is a structurally diverse HTT-splicing modulator that may help understand the mechanism of adverse effects such as peripheral neuropathy associated with branaplam