Electrophilic Oxidation and [1,2]-Rearrangement of the Biindole Core of Birinapant

Article abstract of DOI:10.1021/acsmedchemlett.5b00461

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

Full text of DOI:10.1021/acsmedchemlett.5b00461

Letter
pubs.acs.org/acsmedchemlett
Electrophilic Oxidation and [1,2]-Rearrangement of the Biindole Core
of Birinapant
Yijun Deng,* Thomas Haimowitz, Matthew G. LaPorte,† Susan R. Rippin, Matthew D. Alexander,‡
Pavan Tirunahari Kumar, Mukta S. Hendi, Yu-Hua Lee, and Stephen M. Condon*
TetraLogic Pharmaceuticals Corporation, 343 Phoenixville Pike, Malvern, Pennsylvania 19355, United States
S
* Supporting Information
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 Ki 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.
KEYWORDS: Birinapant, biindole, oxidation, degradation, rearrangement, stability, drug product
irinapant/TL32711 (1) is a small-molecule antagonist of
Bthe inhibitor of apoptosis (IAP) family of proteins that is
currently in clinical trials for the treatment of cancer and
hepatitis B virus (HBV) infection.1−3 Structurally, 1 contains
two N(Me)Ala-Abu-Pro peptide chains attached to a central
biindole core (Figure 1A).4 The discovery and development of
birinapant drug substance has been reported.4,5 Birinapant drug
product (1 DP) is currently manufactured as a sterile-filtered,
aqueous formulation, which is administered as an intravenous
infusion. As part of an ongoing chemical development program,
1 DP has been evaluated for long-term stability at multiple
conditions including 25 °C/60% relative humidity (RH) and 40
°C/75% RH. In the course of these investigations, partial
degradation (>0.1%) of 1 was observed on prolonged storage
of 1 DP at the accelerated storage condition of 40 °C/75% RH
(Figure 1B). High performance liquid chromatography
(HPLC) and mass spectral (MS) analysis of these samples
demonstrated that four degradants (i.e., 2, 3, 5, and 6) were
formed by the addition of a single oxygen molecule to 1 (i.e., M
+ 16); degradants arising from the addition of two oxygen
molecules (i.e., 4) were observed in lower quantities.6 In order
to gain insight into the degradation process, we prepared each
oxidative degradant via forced degradation and then confirmed
their structures based on independent synthesis.
To generate sufficient quantities of the oxidative degradants,
air was bubbled through an aqueous solution of 1 containing
0.1% acetic acid (HOAc) for 7 days thus affording a mixture of
2−6 albeit in differing ratios from the degradation of authentic
1 DP (Supplemental Figure S1). Using this process, we were
able to generate gram-quantities of 2 and 3, which allowed for
1
their chemical characterization by H and 13C NMR spectros-
copy and mass spectrometry (MS).
Several possible mechanisms for the oxidation of 1 including
amine oxidation,7 benzylic oxidation,8 and indole oxidation9 are
supported by literature precedent. We observed that mixtures
of 2 and 3 reverted to 1 under standard palladium-catalyzed
hydrogenation conditions thus supporting these proposed
Received: December 1, 2015
Accepted: January 9, 2016
© XXXX American Chemical Society
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Figure 1. (A) Chemical structure of birinapant/TL32711 (1). (B) HPLC profile of 1 DP after extended storage at 40 °C/75% RH indicating the
formation of oxidative degradants 2 through 6. Asterisk (*) indicates a process impurity, which is unrelated to the degradation process.
modes of oxidation (data not shown). The product of N-
terminal amine oxidation was prepared by independent
synthesis and shown not to correlate with any of the observed
degradants by HPLC analysis (Supplemental Scheme S1).
Benzylic oxidation adjacent to an indole moiety is reported
to occur under free-radical conditions when DDQ is employed
as the oxidant.8 In contrast, electrophilic oxidation using
dimethyldioxirane (DMDO) is reported to result in the direct
oxidation of the indole ring to afford 3H-indol-3-ols.9 To
distinguish between these two oxidative pathways, we
incorporated deuterium atoms at the benzylic positions of 1
(Scheme 1).10 Reduction of 7 with NaBH4-d4 furnished 8,
deuterium atoms further confirming the biindole moiety as the
site of oxidation of 1. Removal of the Boc and acetyl protective
groups afforded 2-d4 and 3-d4, which coeluted with authentic 2
and 3 from the 1 DP stability study. The absolute stereo-
chemistry at the C3-indole position of 2-d4 and 3-d4 remains
unknown and thus has been assigned arbitrarily.
These results were confirmed by independent synthesis of 2
and 3 from the Boc-Abu-coupled intermediate (12, Scheme 3).
As expected, oxidation of 12, a previously reported intermediate
in the synthesis of 1,4,5 afforded the hydroxyindolenines 13 and
14 as a separable mixture of stereoisomers. Independent
elaboration of 13 or 14 afforded synthetic 2 or 3, respectively,
which coeluted with authentic 2 and 3 derived from the
degradation of 1 DP (Supplemental Figure S3) and were
Scheme 1. Synthesis of Deuterated Birinapant, 1-d4
1
identical by H and 13C NMR and MS analysis to 2 and 3
formed via forced degradation of 1. Taken together, these
results demonstrated that oxidative degradants 2 and 3 were
formed via the biindole oxidation of 1.
Movassaghi et al. reported that 2-aryl-substituted hydrox-
yindolenines like 2 and 3 rearranged to either 1H-[2,2′]-
biindolyl-3-ones or 1′,3′-dihydro-1H-[2,3′]biindolyl-2′-ones
depending upon the reaction conditions and that these two
regioisomeric rearrangement products could be distinguished
by examining the chemical shift of the nascent carbonyl
resonance in the 13C NMR spectra.9 More recently, Qi et al.13
and Han and Movassaghi14 demonstrated that biindole-derived
hydroxyindolenines rearranged under thermal or acidic
conditions to afford 1H-[2,2′]-biindolyl-3-ones (infra).
To address whether 2 or 3 would undergo this rearrange-
ment, we warmed an aqueous solution of 2 containing 0.1%
HOAc for 24 h at 95 °C. Under this condition, 2 readily
rearranged to 6 (Supplemental Figure S5). In a separate
experiment, we observed that 3 rearranged to 5 under identical
reaction conditions. Taken together, these data demonstrated
that oxidation of 1 occurred at the biindole core to afford
hydroxyindolenines 2 and 3, which further rearranged to 6 and
5, respectively. However, whether 2 or 3 rearranged to provide
1H-[2,2′]-biindolyl-3-ones or the isomeric 1′,3′-dihydro-1H-
[2,3′]biindolyl-2′-ones remained unresolved (Supplemental
Figure S4).
Owing to the structural complexity of 5 and 6, we performed
the oxidation/rearrangement on a simpler biindole substrate in
order to independently confirm the chemical structures of 5
and 6. Biindole 15 is employed in the synthesis of 1.4,5
Treatment of 15 under modified DMDO-mediated oxidation
conditions provided a mixture of hydroxyindolenines 16 and 17
(Scheme 4). As with 2 and 3 (supra), the absolute chemistry at
the C3-indole positions of 16 and 17 is unknown and therefore
has been assigned arbitrarily. This mixture was then subjected
which contained two benzylic deuterium atoms. Following
protection of the hydroxy group, deuterated 9 was subjected to
TFA-mediated indole dimerization;10−12 further elaboration
using known methods afforded 1-d4.4
Under forced oxidation conditions (i.e., 0.1% aqueous
HOAc, 7 days), 1-d4 afforded the same mixture of oxidative
degradants by HPLC analysis (Supplemental Figure S2); the
observed molecular ion for each degradant confirmed the
retention of all four deuterium atoms. Thus, benzylic oxidation,
which would have resulted in the loss of one deuterium atom,
was eliminated as an operative oxidative pathway.
To confirm direct oxidation of the biindole core, we
subjected 1 to electrophilic oxidation using DMDO.9
Unfortunately, this reaction was unsuccessful likely due to the
presence of the two basic nitrogen atoms of 1. Thus, we
performed the oxidation on fully protected intermediate 10
(Scheme 2). Treatment of 10 with DMDO, generated in situ by
the combination of oxone and acetone, provided a mixture of
two diastereomeric hydroxyindolenines (11), each bearing four
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Scheme 2. Preparation of Synthetic Oxidative Degradants 2-d4 and 3-d4 from 10
Scheme 3. Preparation of Oxidative Degradants 2 and 3 from 12
to modified rearrangement conditions (0.1% HOAc in toluene
at 100 °C) to afford a separable mixture of 18 and 19. The
observed 13C chemical shifts for the nascent carbonyl groups of
18 and 19 were δ 200.4 and δ 199.6, respectively, thus
suggesting that hydroxyindolenines 16 and 17 rearranged to
1H-[2,2′]-biindolyl-3-ones 18 and 19 and not to the
structurally related 1′,3′-dihydro-1H-[2,3′]biindolyl-2′-ones
(not shown). In a separate series of experiments, we
demonstrated that, in fact, exposure of 16 to the rearrangement
conditions exclusively afforded 18, while independent treat-
ment of 17 provided 19 thereby demonstrating the stereo-
specific nature of the [1,2]-rearrangement process (data not
shown). Importantly, the absolute stereochemistry at the
quaternary centers of 18 and 19 is unresolved and has thus
been assigned arbitrarily based on the assigned configurations
of 16 and 17, respectively.
Final elucidation of the degradation pathway came from the
conversion of 18 into 6 using our standard HATU-mediated
peptide coupling strategy (Scheme 5).4 Hydrogenolytic
removal of the two Cbz protective groups of 18 afforded the
bis-pyrrolidine (20), which was then coupled to Cbz-Abu-OH.
Further elaboration of the peptide chains provided 6 which was
identical by HPLC, MS, 1H, and 13C NMR analyses to
authentic 6 formed either via the degradation of 1 DP
(Supplemental Figure S5) or via acid-mediated rearrangement
of 2 (Supplemental Figure S4).
In an analogous fashion, 1H-[2,2′]-biindolyl-3-one 19 was
converted in several steps to 5, which was identical to the
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Scheme 4. Synthesis and [1,2]-Rearrangement of Hydroxyindolenines 16 and 17
Scheme 5. Transformation of 1H-[2,2′]-Biindolyl-3-one 18 into Oxidative Degradant 6
Figure 2. Proposed pathway for the oxidative degradation of 1.
authentic standard (data not shown). Interestingly, during the
Cbz group removal from 19, an azepine-containing product was
isolated in modest yield together with the desired bis-
pyrrolidine (Supplemental Scheme S2). No effort was made
to optimize this reaction; however, the azepine was likely
formed via the intramolecular reductive amination of the
intermediate bis-pyrrolidine. A similar intramolecular cycliza-
tion was recently described in the synthesis of trigonoliimine
C.13−15
Birinapant drug product (1 DP) is a sterile, aqueous solution,
which is administered in the clinic by intravenous infusion.
During the investigation of long-term storage conditions for 1
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was stirred at 0 °C for 1 h followed by the slow addition of 15 (4.3 g,
5.3 mmol) in DCM (100 mL). After 1 h at 0 °C, the reaction mixture
was diluted with deionized water (100 mL) and DCM (100 mL). The
organic layer was separated, and the aqueous phase was extracted with
DCM (2 × 50 mL). The combined organic extracts were washed with
brine and dried over anhydrous Na2SO4, filtered, and concentrated.
The crude residue was purified by RP-HPLC to provide 1.1 g (26%) of
16 (early eluting product) and 2.7 g (63%) of 17 (late eluting
product) as yellow-colored solids.
Preparation of 18 via [1,2]-Rearrangement of 16. A solution
containing 16 (1.1 g, 1.31 mmol) in toluene (40 mL) and HOAc (0.5
mL) was stirred at 100 °C. After 4 h, HPLC analysis revealed complete
conversion to 18. The solvent was removed in vacuo, and the crude
residue was purified by RP-HPLC to yield 950 mg of 18 (86%) as a
yellow-colored solid.
DP, we observed the formation of four oxidative degradants at
>0.1% occurrence by HPLC analysis. To clarify the degradation
process and support further drug product development, we
isolated 2, 3, 5, and 6 following forced degradation of 1 and
determined their chemical structures via independent synthesis.
This investigation demonstrated that the central biindole
core of 1 reacted with atmospheric oxygen (or a transition
metal oxo species) to afford two primary oxidative degradants 2
and 3, which were diastereomeric at the indole C3 position.14
Forced degradation of 1-d4 confirmed that oxidation did not
occur at the benzylic positions of 1. Both hydroxyindolenines 2
and 3 could be prepared in gram-quantities by forced
degradation of 1 and these synthetic products were identical
by HPLC and mass spectral analysis to those formed on
extended storage of 1 DP at ≥40 °C.
The observation that an acidic solution of hydroxyindolenine
2 transformed with heating to 1H-[2,2′]-biindolyl-3-one 6
further corroborated these results. Notably, diastereomer 3 was
shown to convert to 5 under identical conditions. Contempo-
raneous with this investigation, Qi et al.13 and Han and
Movassaghi14 demonstrated a similar Wagner−Meerwein-type
[1,2]-rearrangement of hydroxyindolenines derived from 2,2′-
bis-tryptamines en route to the total syntheses of the
trigonoliimines. Thus, the oxidative pathway for the degrada-
tion of 1 DP at elevated temperature is summarized in Figure 2.
The ultimate goal of our drug development program was to
develop a formulation of 1, which achieved ambient temper-
ature stability on extended storage. To further aid in this
process, a thorough understanding of the oxidizing species, i.e.,
molecular oxygen, peroxides, etc., effect of the container closure
system, i.e., composition of glass vial, and the application of
pharmaceutically acceptable antioxidants, i.e., BHT, tocopherol,
etc., may be required. The insights gained from this study will
aid in the development of stabilized formulations of 1.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.5b00461.
NMR (1H, 13C) and mass spectral characterization of 1-
d4, 2, 3, 5, 6, 16, 17, 18, and 19 (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*Phone: 001-610-889-9900. Fax: 001-610-889-9994. E-mail:
yijun.deng@tetralogicpharma.com.
*E-mail: stephen.condon@tetralogicpharma.com.
Present Addresses
†Department of Chemistry, Chemical Methodologies and
Library Development, University of Pittsburgh, Pittsburgh,
Pennsylvania 15260, United States.
‡Celgene Corp., 10300 Campus Point Drive, Suite 100, San
Diego, California 92121, United States.
EXPERIMENTAL PROCEDURES
Author Contributions
Y.D., T.H., M.G.L., S.R.R., M.D.A., P.T.K., M.S.H., Y.-H.L., and
S.M.C. contributed to the design and synthesis of compounds.
■
Chemistry. Birinapant (1), 12, and 15 were prepared following
reported procedures.4,5 Deuterated intermediates 8, 9, 10, and 1-d4
were prepared using standard modifications of those methods.10 1H
and 13C NMR and mass spectral characterization of 2, 3, 5, 6, 16, 17,
18, and 19 are provided in the Supporting Information.
Notes
The authors declare no competing financial interest.
Representative procedures for the forced degradation of 1, the
DMDO-mediated oxidation of [2,2′]-biindoles, and rearrangement to
the resultant 1H-[2,2′]-biindolyl-3-ones are provided below.
Isolation of 2 and 3 Following the Forced Degradation of
Birinapant (1). Birinapant (1, 5.0 g, 6.2 mmol) was dissolved in water
containing 0.1% HOAc (250 mL). Air was gently bubbled through the
colorless solution at ambient temperature. After 7 days, HPLC analysis
revealed 85% conversion of 1 to afford 2 (41 area %), 3 (25 area %), 4
(mixture of isomers, 6 area %), 5 (5 area %), and 6 (2 area %). The
yellow-colored solution was concentrated, and the residue was purified
by RP-HPLC to provide 1.4 g of 2 (27%) and 0.7 g of 3 (14%) as
yellow-colored solids.
Preparation of 6 via the [1,2]-Rearrangement of 2. Primary
degradant 2 (140 mg, 0.17 mmol) was dissolved in water containing
0.1% HOAc (10 mL). The resulting yellow-colored solution was
warmed to 95 °C for 24 h at which time HPLC analysis revealed >95%
conversion of 2 to 6. The reaction mixture was concentrated, and the
residue was purified by RP-HPLC to afford 110 mg of 6 (79%) as a
yellow-colored solid.
ACKNOWLEDGMENTS
■
The authors wish to acknowledge the support from our
colleagues at TetraLogic Pharmaceuticals (Malvern, PA).
ABBREVIATIONS USED
■
Abu, α-aminobutyric acid; AVPI, alanine-valine-proline-isoleu-
cine tetrapeptide; BHT, butylated hydroxytoluene; BIR3,
baculovirus IAP repeat domain 3; Cbz, benzyloxycarbonyl;
cIAP, cellular IAP1 or cIAP2; DDQ, 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone; DIABLO, direct IAP binding protein with
low pI (also, Smac); DMDO, dimethyldioxirane; DMSO,
dimethyl sulfoxide; DP, drug product; HPLC, high-perform-
ance liquid chromatography; HOAc, acetic acid; IAP, inhibitor
of apoptosis proteins; LC/MS, liquid chromatography coupled
to mass spectrometry; ML-IAP, melanoma IAP; MS, mass
spectrum or spectrometry; NaBH4, sodium borohydride; NMR,
nuclear magnetic resonance; [O], oxidation; oxone, potassium
peroxymonosulfate; RH, relative humidity; Smac, second
mitochondria-derived activator of caspases (also, DIABLO);
TFA, trifluoroacetic acid; TNF, tumor necrosis factor; TNFR1,
TNF receptor 1; XIAP, X chromosome-linked IAP
Preparation of 16 and 17 via DMDO-Mediated Oxidation of 15.
To suppress overoxidation of the biindole moiety, a biphasic
modification of the DMDO-mediated oxidation was applied.9 To a
heterogeneous mixture of saturated aqueous NaHCO3 (30 mL) and
acetone (30 mL) was slowly added oxone (3.6 g, 5.8 mmol) in
deionized water (50 mL) at 0 °C. The resulting homogeneous mixture
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