The four-membered oxetane ring has been increasingly exploited for its contrasting behaviors: its influence on physicochemical properties as a stable motif in medicinal chemistry and its propensity to undergo ring-opening reactions as a synthetic intermediate. These applications have driven numerous studies into the synthesis of new oxetane derivatives. This review takes an overview of the literature for the synthesis of oxetane derivatives, concentrating on advances in the last five years up to the end of 2015. These methods are clustered by strategies for preparation of the ring and further derivatization of preformed oxetane-containing building blocks. Examples of the use of oxetanes in medicinal chemistry are reported, including a collation of oxetane derivatives appearing in recent patents for medicinal chemistry applications. Finally, examples of oxetane derivatives in ring-opening and ring-expansion reactions are described.
Deregulation of the
transcriptional repressor BCL6 enables tumorigenesis
of germinal center B-cells, and hence BCL6 has been proposed as a
therapeutic target for the treatment of diffuse large B-cell lymphoma
(DLBCL). Herein we report the discovery of a series of benzimidazolone
inhibitors of the protein–protein interaction between BCL6
and its co-repressors. A subset of these inhibitors were found to
cause rapid degradation of BCL6, and optimization of pharmacokinetic
properties led to the discovery of 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260),
which reduces BCL6 levels in a lymphoma xenograft mouse model following
oral dosing.
Functionalization of C(sp(3))-H bonds at the unactivated 3-position of proline derivatives has been achieved using aryl iodides and palladium catalysis. This directly affords cis-2,3-disubstituted pyrrolidines as single stereoisomers. 3-Arylation occurs in high yield under solvent-free conditions with aminoquinoline and methoxyaminoquinoline directing groups. The latter was readily removed to give primary amide derivatives with physicochemical properties appropriate for use as fragments in drug discovery.
Oxetanes offer exciting potential as structural motifs and intermediates in drug discovery and materials science. Here an efficient strategy for the synthesis of oxetane rings incorporating pendant functional groups is described. A wide variety of oxetane 2,2-dicarboxylates were accessed in high yields, including functionalized 3-/4-aryl- and alkyl-substituted oxetanes and fused oxetane bicycles. Enantioenriched alcohols provided enantioenriched oxetanes with complete retention of configuration. The oxetane products were further derivatized, while the ring was maintained intact, thus highlighting their potential as building blocks for medicinal chemistry.
We describe the optimization
of modestly active starting points
to potent inhibitors of BCL6 by growing into a subpocket, which was
occupied by a network of five stably bound water molecules. Identifying
potent inhibitors required not only forming new interactions in the
subpocket but also perturbing the water network in a productive, potency-increasing
fashion while controlling the physicochemical properties. We achieved
this goal in a sequential manner by systematically probing the pocket
and the water network, ultimately achieving a 100-fold improvement
of activity. The most potent compounds displaced three of the five
initial water molecules and formed hydrogen bonds with the remaining
two. Compound
25
showed a promising profile for a lead
compound with submicromolar inhibition of BCL6 in cells and satisfactory
pharmacokinetic (PK) properties. Our work highlights the importance
of finding productive ways to perturb existing water networks when
growing into solvent-filled protein pockets.
The
transcriptional
repressor BCL6 is an oncogenic driver found
to be deregulated in lymphoid malignancies. Herein, we report the
optimization of our previously reported benzimidazolone molecular
glue-type degrader
CCT369260
to
CCT373566
, a highly potent probe suitable for sustained depletion of BCL6
in vivo
. We observed a sharp degradation SAR, where subtle
structural changes conveyed the ability to induce degradation of BCL6.
CCT373566
showed modest
in vivo
efficacy
in a lymphoma xenograft mouse model following oral dosing.
To
identify new chemical
series with enhanced binding affinity
to the BTB domain of B-cell lymphoma 6 protein, we targeted a subpocket
adjacent to Val18. With no opportunities for strong polar interactions,
we focused on attaining close shape complementarity by ring fusion
onto our quinolinone lead series. Following exploration of different
sized rings, we identified a conformationally restricted core which
optimally filled the available space, leading to potent BCL6 inhibitors.
Through X-ray structure-guided design, combined with efficient synthetic
chemistry to make the resulting novel core structures, a >300-fold
improvement in activity was obtained by the addition of seven heavy
atoms.
Di-, tri- and tetra-substituted oxetane derivatives with combinations of ester, amide, nitrile, aryl, sulfone and phosphonate substituents are prepared as fragments or building blocks for drug discovery. The synthesis of these novel oxetane functional groups, in new chemical space, is achieved via rhodium-catalysed O-H insertion and C-C bond forming cyclisation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.