title: Electrophilic Oxidation and [1,2]-Rearrangement of the Biindole Core of Birinapant.
abstract: Birinapant/TL32711 (1) is a bivalent antagonist of the inhibitor of apoptosis (IAP) family of proteins and was designed to mimic AVPI, the N-terminal tetrapeptide of the second mitochondria-derived activator of caspases (Smac/DIABLO). Birinapant bound to the BIR3 domains of cIAP1, cIAP2, and XIAP with K i values of 1, 36, and 45 nM, respectively. Birinapant-mediated activation of cIAP1 resulted in cIAP1 autoubiquitylation and degradation and correlated with inhibition of TNF-mediated NF-κB activation, induction of tumor cell death in vitro, and tumor regression in vivo. Birinapant is being evaluated in Phase 1/2 trials for the treatment of cancer and hepatitis B virus (HBV) infection. After one year at accelerated storage conditions, a formulation of 1 afforded four degradants in >0.1% abundance by HPLC analysis. The primary degradants (2 and 3) were formed via oxidation of the biindole core, while the secondary degradants (5 and 6) arose via [1,2]-rearrangement of 3 and 2, respectively. Forced degradation conditions were developed, which allowed the isolation of 2 and 3 in multigram quantities. Novel deuterated analogues of 1 were prepared to determine the site of oxidation, and NMR experiments confirmed the chemical structures of 5 and 6. The de novo synthesis of 2, 3, 5, and 6 confirmed these experimental findings.
authors.affiliation: TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, Pennsylvania 19355, United States.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Deng
authors.affiliation: TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, Pennsylvania 19355, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Haimowitz
authors.affiliation: TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, Pennsylvania 19355, United States.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: LaPorte
authors.affiliation: TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, Pennsylvania 19355, United States.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Rippin
authors.affiliation: TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, Pennsylvania 19355, United States.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Alexander
authors.affiliation: TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, Pennsylvania 19355, United States.
authors.forename: Pavan Tirunahari
authors.initials: PT
authors.lastname: Kumar
authors.affiliation: TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, Pennsylvania 19355, United States.
authors.forename: Mukta S
authors.initials: MS
authors.lastname: Hendi
authors.affiliation: TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, Pennsylvania 19355, United States.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Lee
authors.affiliation: TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, Pennsylvania 19355, United States.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Condon
keywords: Birinapant; biindole; degradation; drug product; oxidation; rearrangement; stability