Belinostat (PXD101)

Description

Belinostat is a drug which was developed by Spectrum Pharmaceuticals and is currently marketed by Onxeo as Beleodaq®. The drug, which received fast track designation by the United States Food and Drug Administration (US FDA) and was approved for the treatment of hematological malignancies and solid tumors associated with peripheral T-cell lymphoma (PTCL) in 2014, is a histone deacetylase (HDAC) inhibitor and is the third such treatment to receive accelerated approval for PTCL, the others being vorinostat (Zolinza®) and pralatrexate (Folotyn®). Although belinostat was not yet approved in Europe as of August 2014, the compound exhibits a safety profile considered to be acceptable for HDAC inhibitors–less than 25% of patients reported adverse effects and these most frequently were nausea, fatigue, pyrexia, anemia, and emesis.

Uses

Belinostat is a novel histone deacetylase 3 selective inhibitor, which protects the β cells from cytokine-induced apoptosis.

Definition

ChEBI: A hydroxamic acid-type histone deacetylase (HDAC) inhibitor with antineoplastic activity.

Synthesis

Commercially available 3-bromobenzenesulfonyl chloride (41) was reacted with aniline in the presence of aqueous sodium carbonate to deliver sulfonamide 42 in 94% yield. Next, this aryl bromide was subjected to a Heck reaction involving ethyl acrylate to give rise to cinnamate ester 43, which was immediately saponified under basic conditions and acidic workup to furnish the corresponding acid 44. This acid was activated as the corresponding acid chloride prior to subjection to hydroxylamine under basic conditions to form the hydroxamic acid, which was then recrystallized from an 8:1 ethanol/water mixture in the presence of a catalytic amount of sodium bicarbonate to furnish crystalline belinostat (VI) in 87% overall yield from acid 44.

target

pan-HDAC