Incorporation of a chiral gem-disubstituted nitrogen heterocycle yields an oxazolidinone antibiotic with reduced mitochondrial toxicity

Article abstract of DOI:10.1016/j.bmcl.2019.07.024

gem-Disubstituted N-heterocycles are rarely found in drugs, despite their potential to improve the drug-like properties of small molecule pharmaceuticals. Linezolid, a morpholine heterocycle-containing oxazolidinone antibiotic, exhibits significant side effects associated with human mitochondrial protein synthesis inhibition. We synthesized a gem-disubstituted linezolid analogue that when compared to linezolid, maintains comparable (albeit slightly diminished) activity against bacteria, comparable in vitro physicochemical properties, and a decrease in undesired mitochondrial protein synthesis (MPS) inhibition. This research contributes to the structure-activity-relationship data surrounding oxazolidinone MPS inhibition, and may inspire investigations into the utility of gem-disubstituted N-heterocycles in medicinal chemistry.

Full text of DOI:10.1016/j.bmcl.2019.07.024

Accepted Manuscript
Incorporation of a chiral gem-disubstituted nitrogen heterocycle yields an oxa-
zolidinone antibiotic with reduced mitochondrial toxicity
Alexander W. Sun, Philip L. Bulterys, Michael D. Bartberger, Peter A. Jorth,
Brendan M. O'Boyle, Scott C. Virgil, Jeff F. Miller, Brian M. Stoltz
PII:
S0960-894X(19)30469-X
https://doi.org/10.1016/j.bmcl.2019.07.024
BMCL 26565
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 April 2019
8 July 2019
13 July 2019
Please cite this article as: Sun, A.W., Bulterys, P.L., Bartberger, M.D., Jorth, P.A., O'Boyle, B.M., Virgil, S.C.,
Miller, J.F., Stoltz, B.M., Incorporation of a chiral gem-disubstituted nitrogen heterocycle yields an oxazolidinone
antibiotic with reduced mitochondrial toxicity, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://
doi.org/10.1016/j.bmcl.2019.07.024
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Incorporation of a chiral gem-disubstituted
nitrogen heterocycle yields an oxazolidinone
antibiotic with reduced mitochondrial
toxicity
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Alexander W. Sun, Philip L. Bulterys, Michael D. Bartberger, Peter A. Jorth, Brendan O’Boyle, Scott C. Virgil,
Jeff F. Miller, and Brian M. Stoltz*

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Incorporation of a chiral gem-disubstituted nitrogen heterocycle yields an
oxazolidinone antibiotic with reduced mitochondrial toxicity
Alexander W. Sun, a Philip L. Bulterys,b Michael D. Bartberger,a Peter A. Jorth,a Brendan M. O’Boyle,a
Scott C. Virgil, a Jeff F. Miller,b and Brian M. Stoltz.a*
a The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California
Institute of Technology, Pasadena, California 91125, United States
b Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
gem-Disubstituted N-heterocycles are rarely found in drugs, despite their potential to improve the
drug-like properties of small molecule pharmaceuticals. Linezolid, a morpholine heterocycle-
containing oxazolidinone antibiotic, exhibits significant side effects associated with human
mitochondrial protein synthesis inhibition. We synthesized a gem-disubstituted linezolid analogue
that when compared to linezolid, maintains comparable (albeit slightly diminished) activity
against bacteria, comparable in vitro physicochemical properties, and a decrease in undesired
mitochondrial protein synthesis (MPS) inhibition. This research contributes to the structure-
activity-relationship data surrounding oxazolidinone MPS inhibition, and may inspire
investigations into the utility of gem-disubstituted N-heterocycles in medicinal chemistry.
Keywords:
Antibiotic
Mitochondria
Allylic Alkylation
Heterocycle
Linezolid
2019 Elsevier Ltd. All rights reserved.
gem-Disubstituted heterocycles are rare in small molecule
pharmaceuticals. However, they exhibit the potential to further
enhance the drug-like properties of small molecules (Figure 1).
For example, gem-disubstitution significantly increases
molecular complexity, which is correlated with decreased
promiscuity and enhanced binding affinity to desired targets.1-3
Furthermore, depending on the chemical identity of the
substitutions, properties such as metabolic stability and polarity
may also be altered (Figure 1).
heterocyclic gem-disubstitution, we selected the morpholine-
containing oxazolidinone antibiotic linezolid (Zyvox) (Figure 1).
Approved by the FDA in 2001, linezolid inhibits bacterial peptide
synthesis. Co-crystal structures show that linezolid binds to the
A-site of the 50S subunit of the ribosome, interacting with an
RNA pocket at the ribosomal peptidyl transferase center.4,5 This
binding mode suggests that linezolid inhibits binding of
aminoacyl tRNA. Linezolid and the recently approved
oxazolidinone Tedizolid are important last resort antibiotics that
are active against drug-resistant pathogens like methicillin-
resistant Staphylococcus aureus (MRSA),6 vancomycin-resistant
Enterococcus faecalis (VRE),7 and multi-drug resistant
Mycobacterium tuberculosis (MDR-TB).8
Figure 1. Biological properties altered by hypothetical gem-disubstitution of
the antibiotic linezolid
Because the bacterial and human ribosomes are highly
homologous, oxazolidinone antibiotics bind
a commonly
conserved site and thus also inhibit mitochondrial protein
synthesis (MPS).9-12 This off-target binding is thought to be
responsible for linezolid’s more significant side-effects, including
myelosuppression, hyperlactatemia, and peripheral neuropathy.13
Other ribosome-targeting antibiotics such as clindamycin and
chloramphenicol also exhibit corresponding myelotoxic side
effects.14,15 If a structure-activity-relationship (SAR) could be
determined for linezolid’s mitochondrial binding ability, then
new oxazolidinones could be designed with reduced MPS
Given this potential, we sought to investigate the practical
utility of gem-disubstituted heterocycles in bioactive small
molecules. After surveying various N-heterocyclic drugs for cases
in which physicochemical attributes could be improved by

inhibition. Indeed, reducing myelotoxic side effects while
maintaining antibacterial potency is often cited as one of the
greatest challenges in new oxazolidinone design.16
conditions20 with a variety of gem-disubstituted morpholines
resulting in linezolid analogues 12-19 (Figure 2). Notably, this
synthetic route will facilitate future efforts to modify the C
morpholine ring of linezolid.
Fortunately, the modular structure of oxazolidinones enables
chemical modification of all three rings, A, B, and C, facilitating
SAR studies for mitochondrial ribosome binding (Figure 1).
Some data have already been emerged. In 2006, McKee identified
several oxazolidinones that more potently inhibit MPS yet display
MIC values comparable to that of linezolid (Table 1).17 In these
cases, the morpholine ring was replaced with other heterocycles,
suggesting the C-ring may be the greatest determinant of MPS
inhibition. In spite of these initial results, there are no known
reports of a potent oxazolidinone featuring reduced MPS
inhibition.
Table 1. MIC and MPS IC50 values for linezolid analogues
Scheme 1. Synthesis of gem-disubstituted linezolid analogues via Cu-
catalyzed Ullmann coupling. a. (S)-epichlorohydrin, NH4OH (aq). THF, 40
°C, 12 h, 55% yield; b. LiOt-Bu, CH2Cl2, rt to 40 °C, 87% yield; c.1N HCl,
H2O/EtOAc; d. Ac2O, CH2Cl2, 96% yield over 2 steps; e. NIS, TFA, rt, 92%
yield; f. Substituted morpholine 11a-p, CuBr (10 mol %), BINOL (20 mol %),
K3PO4, DMF, 80 °C.
Two analogues 13 and 14 were prepared using substituted
morpholines 10 and 11, which were synthesized via a
decarboxylative alkylation protocol and subsequent deprotective
and reductive transformations (Scheme 2).20 Other analogues
including the gem-dimethyl compound 12 and spiro compounds
15-19 were prepared from commercially available di-substituted
morpholines. We note that all analogs were synthesized as
racemates.
Scheme 2. Synthesis of gem-disubstituted morpholines by benzoyl cleavage
and reduction of morpholinone decarboxylative alkylation products
a MIC (μg/mL) for S. aureus JC9213. b IC50 (μg/mL) for mitochondrial protein
synthesis
We thus initiated a medicinal chemistry project seeking to
modify the morpholine C-ring of linezolid with the goal of
reducing MPS inhibition. Importantly, crystal structure studies
note that the morpholine ring does not make significant
interactions with the binding pocket, suggesting that the ring can
be modified without compromising binding.5 Because increased
molecular complexity is associated with reduced ligand
promiscuity, we hypothesized that gem-disubstitution of the
morpholine ring could potentially increase selectivity for the
bacterial ribosome and reduce off-target side effects such as MPS
inhibition (Figure 1). To test this hypothesis, we began by
identifying a modular route to enable the synthesis of a library of
gem-disubstituted linezolid analogs (Scheme 1). Cross-coupling
of a gem-disubstituted morpholine with aryl halide 7 was
identified as an efficient route. Thus, aryl halide 7 was
synthesized by adapting a patent procedure.18 Briefly, (S)-
epichlorohydrin (2) was coupled with 4-chlorobenzaldehyde (1)
and ammonia to give imine 3. To forge the oxazolidinone
intermediate 5, imine 3 was then subjected to a base-catalyzed
coupling reaction with carbamate 4,19 which itself was made by
addition of benzyl chloroformate to 3-fluoroaniline. Finally,
imine hydrolysis, N-acetylation, and iodination provided the aryl
iodide 7. 7 was cross-coupled under copper-catalyzed Ullmann
Figure 2. gem-Disubstituted linezolid analogues synthesized via Ullmann
coupling
Additionally, analogues synthesized via Ullman coupling
could be further derivatized (Scheme 3). Taking advantage of the

versatile allyl handle of 13, hydroboration-oxidation afforded
hydroxyl analogue 20, which could be acetyl-protected to give
analogue 21. Additionally, a Lemieux–Johnson oxidation
provided the aldehyde intermediate, which was reductively
aminated with dimethylamine to provide analogue 23. Catalytic
hydrogenation afforded the reduced analogue 22. Similarly, the
benzyloxy analogue 14 could also be hydrogenated using
catalytic Pd(OH)2 on carbon to provide the hydroxyl analogue 24.
Finally, Boc-spiro compound 16 was deprotected using HCl
resulting in spiropiperidine 25; subsequent acetyl protection gave
26. Similarly, acid-catalyzed Boc-cleavage of 15 afforded
spiropyrrolidine 27.
biological activity, we used chiral HPLC to obtain both
diastereomers of 19, and then assigned their absolute
stereochemistry using vibrational circular dichroism (VCD) and
optical rotation calculations, both of which were in agreement
(see supporting information for details of synthesis and
purification) (Figure 3). Notably a eudysmic difference between
the two diastereomers 19a and 19b was observed, with the more
active diastereomer 19a displaying an MIC of 6 μg/mL, roughly
sixfold less potent than linezolid (Table 2).
Table 2. MIC values against ATCC 8235-4 (MSSA) or ATCC 43300
(MRSA)
Scheme 3. Additional analogues synthesized by derivatization
Compound
MIC (μg/mL)
Compound
MIC (μg/mL)
a,b
b
Linezolid
1
23
27
17
25
26
> 32
a
b
12
13
22
20
8
> 32
a
b
16
> 32
a
b
16
> 32
a
> 32
6 μg/mL: 18%
c
inhib.
b
21
> 32
18
6 μg/mL: 65%
c
inhib.
b
b
14
24
> 32
19
7
b
6 μg/mL: 48%
19a
6
b,c
inhib.
b
19b
9
MIC: the lowest concentration of molecule preventing visible growth. [a]
Tested against S. aureus ATCC 43300. [b] Tested against S. aureus ATCC
8235-4. [c] 6 μg/mL was the maximal concentration tested.
We further investigated the bioactivity of 19a against other strains
of S. aureus, determining the MIC values to be consistent against
a range of MSSA and MRSA strains (Table 3).
Table 3. MIC values of lead analogue 19a against various S. aureus strains
Strain
Linezolid MIC (μg/mL)
19a MIC (μg/mL)
S. aureus ATCC
1
6
8235-4
With a diverse set of gem-disubstituted linezolid analogues
in hand, we proceeded with broth microdilution assays against S.
aureus to determine minimum inhibitory concentration (MIC)
values (Table 2). The initial three compounds, 12, 13, 24, were
noticeably less potent than linezolid, suggesting that bulky alkyl
di-substitution on the morpholino ring reduces activity. Similarly,
S. aureus 43300
S. aureus 29213
S. aureus 25923
1
1
1
5
5
5
bulky hydroxyl-substituted analogue 20 and protected alcohols 21
and 14 were also inactive. In contrast, hydroxyl analogue 24
retained a moderate amount of activity, displaying 48% growth
inhibition at the maximal tested concentration of 6 µg/mL. The
amine-bearing derivatives, 23, 27, 17, and 25, featuring
methylamino, dimethyl amino, and spiroamine functionalities,
were uniformly inactive up to 32 µg/mL concentrations.
Interestingly, when the basic nitrogen of 25 was masked as an
amide as in 26, an 18% growth inhibition at the maximal tested
concentration of 6 µg/mL was achieved, suggesting that
positively charged substituted morpholines are not tolerated.
Finally, we were excited to observe increased growth inhibition
when the spirofuran 18 and spirotetrahydropyran 19 analogues
were tested, with 19 displaying the greatest potency of all
analogues examined. Since stereoisomers often exhibit differing
We next examined the pharmacokinetic properties of 19a
and 19b, determining most properties were slightly lower but
comparable to that of linezolid (Table 4). For instance, 19a and
19b demonstrated slightly lower aqueous solubility and stability
at low pH. Microsomal stability for was also lower than that of
linezolid, perhaps due to the metabolic susceptibility of the
tetrahydropyran ring. Initial safety data including cytotoxicity and
cytochrome P450 isoform inhibition were satisfactory. One
interesting difference was MPS inhibition, in which linezolid
displayed a relatively potent 8 µM IC50. In contrast, 19a displayed
an IC50 value of 30 µM. This finding correlates with the relative
MIC values of linezolid and 19a; in this case, MPS inhibition is
also roughly three-fold less potent, suggesting that the
spirotetrahydropyran ring of 19a maintains moderate binding

affinity to the bacterial ribosome while reducing inhibition of the
mitochondrial ribosome.
19a, that displays slightly reduced potency compared to linezolid
against various S. aureus strains while also having reduced
mitochondrial inhibition. These results contribute to the existing
SAR of MPS inhibition (Table 1). Although the mitochondrial
and bacterial ribosomes share homology, they have structural
differences that may be exploited to design molecules with
reduced selectivity for the mitochondrial ribosome.9 Our research
further contributes to the body of data suggesting that the
morpholine ring is
a key structural component whose
modification can reduce mitochondrial inhibition while
maintaining bacterial ribosome inhibition. Continued efforts are
needed to identify a molecule as potent as linezolid but with
reduced MPS inhibition. This ability of gem-disubstituted
heterocycles to alter selectivity for a target such as the bacterial
ribosome highlights one of the many useful properties of
heterocyclic substitution. In recent years, powerful methods have
been developed to stereoselectively synthesize gem-disubstituted
heterocycles. For instance, our laboratory has pioneered the
development of Pd-catalyzed decarboxylative asymmetric allylic
alkylation methodologies to synthesize a range of gem-
disubstituted lactams of ring size 5 to 7.21–24 Such lactams can be
deprotected and reductively transformed into the corresponding
gem-disubstituted N-heterocycles. These methods and others to
access gem-disubstituted heterocycles will greatly enable the
investigation of the medicinal utility of such heterocycles. Efforts,
such as those underway in our laboratory to incorporate gem-
disubstituted heterocycles into other small molecule scaffolds will
undoubtedly shed light on the broader medicinal utility of gem-
disubstituted heterocycles.
Figure 3. Diastereomers of analogue 19. Absolute configuration of the
spirocyclic stereocenter determined by both VCD and optical rotations (See
supporting information for details).
Table 4. Pharmacokinetic properties, inhibitory activity, and physicochemical
properties
Linezolid
>67.47
98%
19a
>52.15
94%
19b
>48.49
89%
Aq. Solubility (μg/mL)
Stability at gastric pH (%
remaining 24 h)
a
t1/2 microsomes (min)
>216.8
>30
170.0
> 30
> 100
30
128.3
>30
b
Cytotoxicity EC50 (μM)
c
CYP inhibition (μM)
>100
8.19
>100
> 30
Mt protein synthesis
d
inhibition IC50 (μM)
a Metabolic stability performed with mouse liver microsomes
b Cytotoxicity against HepG2 cells using CellTiter Glo
c Measured against CYP1A2, 2C9, 2C19, 2D6, 3A4
d MitoBiogenesis In-Cell ELISA assay for COXI and SDH-A mitochondrial
proteins
In conclusion, we identified a gem-disubstituted morpholine
analogue of linezolid bearing a spirotetrahydropyran substitution,
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A.W.S. and B.M.S conceived of the project. A.W.S., B.M.O,
M.D.B., and S.C.V. performed experimental chemistry. P.L.B.,
P.A.J., and WuXi AppTec performed biological assays. M.D.B.
performed VCD experiments. A.W.S., P.L.B., M.D.B., P.A.J.,
B.M.O., J.F.M., and B.M.S. wrote the manuscript.
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The NIH-NIGMS (R01GM080269), Caltech, the Paul and Daisy
Soros Foundation, and the UCLA-Caltech Medical Scientist
Training Program are thanked for support of our research program.
(Grants R01GM080269 to B.M.S., F30GM120836 and
T32GM008042 to A.W.S., F30AI118342, T32GM008042 and
P.D. Soros Fellowship to P.L.B.). Dr. David VanderVelde is
thanked for assistance with structural assignments via NMR
analysis. Dr. Justin Hilf is thanked for helpful discussions.
Professor Dianne K. Newman is thanked for MIC testing. The CO-
ADD is thanked for MIC testing. The UCLA Microbiology
Laboratory is thanked for providing bacterial strains.
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