45 research outputs found
Preparation of 4 '-spirocyclobutyl nucleoside analogues as novel and versatile adenosine scaffolds
Despite the large variety of modified nucleosides that have been reported, the preparation of constrained 4 '-spirocyclic adenosine analogues has received very little attention. We discovered that the [2+2]-cycloaddition of dichloroketene on readily available 4 '-exo-methylene furanose sugars efficiently results in the diastereoselective formation of novel 4 '-spirocyclobutanones. The reaction mechanism was investigated via density functional theory (DFT) and found to proceed either via a non-synchronous or stepwise reaction sequence, controlled by the stereochemistry at the 3 '-position of the sugar substrate. The obtained dichlorocyclobutanones were converted into nucleoside analogues, providing access to a novel class of chiral 4 '-spirocyclobutyl adenosine mimetics in eight steps from commercially available sugars. Assessment of the biological activity of designed 4 '-spirocyclic adenosine analogues identified potent inhibitors for protein methyltransferase target PRMT5
MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells
Conazoles
This review provides a historical overview of the analog based drug discovery of miconazole and its congeners, and is focused on marketed azole antifungals bearing the generic suffix âconazoleâ. The antifungal activity of miconazole, one of the first broad-spectrum antimycotic agents has been mainly restricted to topical applications. The attractive in vitro antifungal spectrum was a starting point to design more potent and especially orally active antifungal agents such as ketoconazole, itraconazole, posaconazole, fluconazole and voriconazole. The chemistry, in vitro and in vivo antifungal activity, pharmacology, and clinical applications of these marketed conazoles has been described
Directed ruthenium-catalyzed <tex>C(sp^{3})</tex>-alkylation of cyclic amines using dioxolane-protected alkenones
Access to Silylated Pyrazole Derivatives by Palladium-Catalyzed CâH Activation of a TMS group
International audienceA simple and efficient approach to new silylated heterocycles of potential interest in medicinal chemistry is presented. A set of bromophenyl trimethylsilyl pyrazole intermediates can be transformed by direct organometallic routes into two families of regioisomeric iodoaryl substrates; using either arylzinc or aryllithium chemistry, the TMS group remains on the pyrazole ring or translocates to the aryl moiety. These two families can then be efficiently transformed into benzo silino pyrazoles thanks to a singleâstep cyclization relying on the Pdâcatalyzed activation of a nonâactivated C(sp3)âH bond alpha to a silicon atom. The experimental conditions used, which are fully compatible with the pyrazole ring, suggest that this reaction evolves through a concerted metalationâdeprotonation (CMD) mechanism
Synthesis and orthogonal functionalization of oxazolo[5âČ,4âČ:4,5]pyrano[2,3-b]pyridine by intra- and intermolecular Pd-catalyzed direct CâH bond heteroarylation
International audienceThe construction and subsequent orthogonal functionalization of a hitherto unknown oxazolo[5âČ,4âČ:4,5]pyrano[2,3-b]pyridine are reported. A palladium-catalyzed direct CâH bond functionalization methodology was used to build the tricyclic scaffold as well as to achieve the subsequent CâH bond functionalization at the C-2 position of the oxazole unit with various (hetero)aryl iodides. Remarkably, selective CâH construction and functionalization procedures preserve the chorine atom on the pyridine moiety offering a late-stage substitution site to progress drug design
Towards New Sila- or Germa-Derivatives of Motesanib
International audienceDeveloping new access to original silylated heterocycles is an emerging challenge in medicinal chemistry. In this paper, we describe a synthesis of silylated and germylated Motesanib analogues relying on a peptide coupling between a nicotinic acid derivative and silylated or germylated heterocycles, prepared according to our previous reports