41191-92-8Relevant articles and documents
Expedient Synthesis of Thioether-Functionalized Hydrotris(indazolyl)borate as an Anchoring Platform for Rotary Molecular Machines
Erbland, Guillaume,Gisbert, Yohan,Rapenne, Gwéna?l,Kammerer, Claire
, p. 4731 - 4739 (2018)
Major improvements in the synthesis of surface-mounted rotary molecular machines based on ruthenium(II) complexes are reported. The development of a one-pot indium(III)-mediated “N-deprotection/ester reductive sulfidation” sequence allowed step economy, reproducibility and high efficiency in the synthesis of the thioether-functionalized tripodal ligand. Switching to the thallium salt of hydrotris(indazolyl)borate and to microwave heating further optimized the preparation of the common intermediate in the modular synthesis of symmetric and dissymmetric molecular motors and gears. The penta(4-bromophenyl)cyclopentadienyl ruthenium(II) key precursor is now reproducibly synthesized in 5 steps and 31 % overall yield on the longest linear sequence. Subsequent fivefold Suzuki–Miyaura coupling with ferroceneboronic acid led to a new C5-symmetric pentaferrocenyl molecular motor.
Divergent Synthesis of Molecular Winch Prototypes
Abid, Seifallah,Gisbert, Yohan,Kammerer, Claire,Rapenne, Gwéna?l
supporting information, p. 16242 - 16249 (2021/10/16)
We report the synthesis of conceptually new prototypes of molecular winches with the ultimate aim to investigate the work performed by a single ruthenium-based molecular motor anchored on a surface by probing its ability to pull a load upon electrically-driven directional rotation. According to a technomimetic design, the motor was embedded in a winch structure, with a long flexible polyethylene glycol chain terminated by an azide hook to connect a variety of molecular loads. The structure of the motor was first derivatized by means of two sequential cross-coupling reactions involving a penta(4-halogenophenyl)cyclopentadienyl hydrotris(indazolyl)borate ruthenium(II) precursor and the resulting benzylamine derivative was next exploited as key intermediate in the divergent synthesis of a family of nanowinch prototypes. A one-pot method involving sequential peptide coupling and Cu-catalyzed azide-alkyne cycloaddition was developed to yield four loaded nanowinches, with load fragments encompassing triptycene, fullerene and porphyrin moieties.
Investigations into the potential role of metabolites on the anti-leukemic activity of imatinib, nilotinib and midostaurin
Manley, Paul W.
, p. 561 - 570 (2019/09/03)
The efficacy and side-effects of drugs do not just reflect the biochemical and pharmacodynamic properties of the parent compound, but often comprise of cooperative effects between the properties of the parent and active metabolites. Metabolites of imatinib, nilotinib and midostaurin have been synthesised and evaluated in assays to compare their properties as protein kinase inhibitors with the parent drugs. The N-desmethylmetabolite of imatinib is substantially less active than imatinib as a BCR-ABL1 kinase inhibitor, thus providing an explanation as to why patients producing high levels of this metabolite show a relatively low response rate in chronic myeloid leukaemia (CML) treatment. The hydroxymethylphenyl and N-oxide metabolites of imatinib and nilotinib are only weakly active as BCR-ABL1 inhibitors and are unlikely to play a role in the efficacy of either drug in CML. The 3-(R)-HO-metabolite of midostaurin shows appreciable accumulation following chronic drug administration and, in addition to mutant forms of FLT3, potently inhibits the PDPK1 and VEGFR2 kinases (IC50 values 100 nM), suggesting that it might contribute to drug efficacy in acute myeloid leukaemia patients. The case studies discussed here provide further examples of how the synthesis and characterisation of metabolites can make important contributions to understanding the clinical efficacy of drugs.