Desmethyl macrolides: Synthesis and evaluation of 4,8-didesmethyl telithromycin

Article abstract of DOI:10.1021/ml300230h

There is an urgent need for novel sources of antibiotics to address the incessant and inevitable onset of bacterial resistance. To this end, we have initiated a structure-based drug design program that features a desmethylation strategy (i.e., replacing m

Full text of DOI:10.1021/ml300230h

Letter
pubs.acs.org/acsmedchemlett
Desmethyl Macrolides: Synthesis and Evaluation of 4,8-Didesmethyl
Telithromycin
Bharat Wagh,† Tapas Paul,† Ian Glassford,† Charles DeBrosse,† Dorota Klepacki,‡ Meagan C. Small,§
Alexander D. MacKerell, Jr.,§ and Rodrigo B. Andrade*,†
†Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States
‡Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, Illinois 60607, United States
§Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201, United States
S
* Supporting Information
ABSTRACT: There is an urgent need for novel sources of
antibiotics to address the incessant and inevitable onset of
bacterial resistance. To this end, we have initiated a structure-
based drug design program that features a desmethylation
strategy (i.e., replacing methyl groups with hydrogens). Herein,
we report the total synthesis, molecular modeling, and biological
evaluation of 4,8-didesmethyl telithromycin (5), a novel
desmethyl analogue of the third-generation ketolide antibiotic
telithromycin (2), which is an FDA-approved semisynthetic derivative of erythromycin (1). We found 5 to be eight times more
active than previously prepared 4,8,10-tridesmethyl congener (3) and two times more active than 4,10-didesmethyl regioisomer
(4) in MIC assays. While less potent than telithromycin (2) and paralleling the observations made in the previous study of 4,10-
didesmethyl analogue (4), the inclusion of a single methyl group improves biological activity, thus supporting its role in antibiotic
activity.
KEYWORDS: total synthesis, ketolide antibiotics, antibiotic resistance, telithromycin, molecular modeling, desmethyl analogues
acteria have evolved various resistance mechanisms to
1
Bundermine antibiotic efficacy. The therapeutic window
between the introduction of a novel antibiotic and the onset of
resistance to that drug can be frustratingly short, which
complicates matters from a drug discovery point of view.
Moreover, there has been a marked decline in active
antimicrobial research programs in the pharmaceutical sector,
resulting in a serious public health problem.2 To address this,
we initiated a structure-based drug design program wherein
desmethyl analogues (i.e., CH3 → H) of the third-generation
macrolide antibiotic telithromycin (TEL, 2)3 are prepared by
total synthesis (Figure 1). To date, we have reported the total
synthesis, molecular modeling, and biological evaluation of
4,8,10-tridesmethyl TEL (3)4,5 and 4,10-didesmethyl TEL (4)6
against both wild-type and macrolide-resistant bacteria, which
were found to be active (vide infra). Herein, we extend our
approach to 4,8-didesmethyl congener (4,8-didesmethyl TEL,
5), our third desmethyl analogue of 2.
All macrolide antibiotics target the 50S subunit of the
bacterial ribosome by reversibly binding in the peptidyl
transferase center, thus blocking protein synthesis.7 Compound
Figure 1. Structures of 1, 2, and de novo analogues 3−5.
2 is a third-generation semisynthetic drug used clinically since
2004 and is derived from the flagship macrolide antibiotic
erythromycin (1).3 All macrolide antibiotics based on the
erythromycin scaffold are semisynthetic (i.e., prepared from
erythromycin). Our approach is unique in that total synthesis is
leveraged to access each analogue, which allows synthetic
Received: August 8, 2012
Accepted: October 4, 2012
Published: October 4, 2012
© 2012 American Chemical Society
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flexibility to prepare macrolides with deep-seated changes for
both drug discovery and chemical biology (i.e., molecular
probes of fundamental processes).8−10
generation catalyst (Scheme 1).15 Application of this powerful
method toward the synthesis of 9, however, was ineffective in
a
Mechanisms of antibiotic resistance are divided into three
categories: (1) drug modification, (2) drug efflux, and (3)
ribosomal (i.e., target) modification arising from either
ribonucleotide N-methylation of residues critical for binding
(e.g., A2058) by erm enzymes or single point mutations (e.g.,
A2058G).1,11 Our desmethylation strategy was inspired by
Steitz's elegant structural studies of macrolide drugs (e.g., 1 and
2) cocrystallized with 50S ribosomal subunits of the archaeon
Haloarcula marismortui (Hm).12
Scheme 1. RCM Approaches to Macroketolactones 8 and 9
Unlike eubacteria that possess adenine at 2058, all archaea
possess a guanine (Escherichia coli numbering) and do not
efficiently bind macrolides 1 and 2. However, a point mutation
of guanine to adenine at position 2058 of 23S rRNA (i.e.,
G2058A) rendered mutants susceptible to the antibiotics,
allowing the structure of 2 bound to the HmA2058 mutant at
2.6 Å resolution to be obtained (Figure 2A). Thus, Steitz
a
Reagents and conditions: (a) G-II (20 mol %), CH2Cl2, 45 °C. (b)
G-I, G-II, or HG-II (20 mol %), CH2Cl2, 45 °C.
our hands despite the choice of catalyst (e.g., Grubbs' first-
generation catalyst and Hoveyda−Grubbs second-generation
catalyst).16 In fact, we were unable to isolate any product and
attribute this exclusively to the steric congestion about
trisubstituted enone, which is absent in congeners 8a and 8b.
At this stage, we revisited an alternate macrocyclization
strategy also successfully employed in the synthesis of 8a,
namely, the intramolecular Nozaki−Hiyama−Kishi (NHK)
reaction (Scheme 2).17,18 This was realized by preparing vinyl
Figure 2. (A) TEL and A2058 interactions in H. marismortui with
select distances in Angstroms (Steitz et al.; PDB ID 1YIJ). (B) Steric
consequences of A2058G mutation. Image produced with VMD.13
a
Scheme 2. Intramolecular NHK Routes to 8a and 9
showed that A2058G mutations in bacteria confer resistance by
(1) loss of hydrogen bonding to the C-2′ hydroxyl of
desosamine and (2) a steric clash of the exocyclic C-2 amino
group of guanine 2058 with C-4 methyl of the macrolide drug
(Figure 2B). We in turn hypothesized that replacing the C-4
methyl group with hydrogen (i.e., desmethylation) should
relieve the steric clash component as other residues within the
ribosome (e.g., 2059) can also form hydrogen bonds with
desosamine's hydroxyl in addition to electrostatic interactions
between the protonated dimethylamino group of desosamine
and the neighboring phosphate residues.1,11 Our rationale
behind removing methyls at C-8 and C-10 was to (1) simplify
chemical synthesis and (2) understand their roles in antibiotic
function.
To test our desmethylation hypothesis and study the effects
of specific methyl residues on the macrolactone ring, we
embarked on a total synthesis of 5. With 5 in hand, biological
evaluation against a host of wild-type and resistant bacterial
strains would follow (i.e., minimum inhibitory concentrations
or MICs).14 Molecular modeling would assist in the
interpretation of the results.
a
Reagents and conditions: (a) CrCl2, cat. NiCl2, DMSO. (b) Dess−
Martin periodinane (DMP), pyridine, CH2Cl2, 82%.
iodide 10a bearing a pendant ω-aldehyde moiety. Treatment of
10a with stoichiometric CrCl2 and catalytic NiCl2 in degassed
dimethyl sulfoxide (DMSO) at ambient temperature for 12 h
furnished a 1:1 mixture of diastereomeric allylic alcohols.
Dess−Martin oxidation of the alcohols furnished macro-
ketolactone 8a in 41% overall yield.5 To access 9 bearing a
methyl group at C10, we prepared substrate 10b and subjected
it to the same conditions. Unfortunately, we obtained a
maximum of 20% yield after oxidation.
As the synthesis of target 5 from 9 required installation of
(1) the C5 desosamine sugar and (2) the biaryl side chain, we
concluded that this approach was not viable. It was critical that
we improve the overall synthetic efficiency by maximizing
convergence. To this end, we recruited Martin's brilliant abiotic
strategy toward the erythromycins wherein macrocyclization
was performed on a substrate bearing carbohydrate residues D-
desosamine and L-cladinose.19 This order of events is in direct
Our experience with the total syntheses of 4,8,10-
tridesmethyl analogue 3 and 4,10-didesmethyl analogue 4
informed the synthesis of target 4,8-didesmethyl analogue 5.4−6
Specifically, we found that the ring-closing metathesis (RCM)
strategy was ideal for preparing 14-membered macroketolac-
tones 8a and 8b in 60% isolated yields with Grubbs' second-
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a
Scheme 3. Synthesis of 5
a
Reagents and conditions: (a) CBr4, PPh3, CH2Cl2, 67%. (b) n-BuLi, MeI, THF then 1 N HCl, MeOH, 64% over two steps. (c) Pd2(dba)3, Bu3SnH,
THF, 48%. (d) I2, CH2Cl2, 82%. (e) TBSOTf, 2,6-lutidne, CH2Cl2, 0 °C. (f) n-BuLi, BnOH, THF, −78 °C to rt, 7 h, 63% over two steps. (g) CSA,
MeOH, 0 °C, 1 h, 85%. (h) TBSCl, imidazole, DMF. (i) AgOTf, 18, 4 Å MS, toluene/CH2Cl2, 72% over two steps. (j) 10% Pd/C, H2, EtOH/
EtOAc (1:1). (k) C6H2Cl3COCl, NEt3, THF, 3 h, 14, DMAP, PhMe, 16 h, 72% over two steps. (l) HF·Pyr, THF/Pyr. (m) DMP, CH2Cl2, 73% over
two steps. (n) CrCl2/NiCl2 (100/1), DMSO. (o) DMP, CH2Cl2, 18% over two steps. (p) NaH, CDI, DMF/THF(10/1), −15 to 0 °C, 30 min. (q)
23, CH3CN, H2O, 72 h, 45% over two steps, dr = 6:1 at C-10. (r) TAS-F, H2O, DMF, 16 h. (s) NCS, Me2S, Et3N, CH2Cl2, −20 to 0 °C, 55%. (t)
MeOH, rt, 65%.
contrast to the biosynthetic sequenece wherein modular
polyketide synthases first assemble the 14-membered ring by
macrolactonization and then install the requisite sugars and
perform site- and stereospecific C−H oxidations.20
C5 hydroxyl with Woodward's desosamine donor 1824,25 under
the agency of AgOTf furnished 19 in 72% over two steps.
Macrocyclization of the 14-membered ring via the intra-
molecular NHK reaction commenced with hydrogenation of
the benzyl ester in 19 to afford an intermediary acid.17,18
Chemoselective coupling of this acid with diol 14 proceeded
smoothly at the secondary alcohol, affording ester 20 in 72%
yield over two steps. Removal of the primary C9-OTBS group
with HF·pyridine (Pyr) in tetrahydrofuran (THF)/Pyr and
oxidation to the aldehyde with Dess−Martin periodinane
(DMP) furnished NHK substrate 21 (73% over two steps).
Treatment of 21 with CrCl2 and NiCl2 (100:1) in degassed
DMSO at rt and DMP-mediated oxidation of the diastereo-
meric mixture of C9 alcohols gave macroketolactone 22 in 18%
yield over two steps.
The endgame for the synthesis of 5 required (1) installation
of the biaryl side chain pioneered by Baker and co-workers at
Abbott and (2) oxidation of the C3-hydroxyl to the ketone.26
To this end, 22 was treated with NaH and carbonyldiimidazole
(CDI) in a mixture of N,N-dimethylformamide (DMF)/THF
(10:1) to form an intermediary imidazolyl carbamate. The
addition of known biaryl butylamine 2327 triggered a one-pot
amidation/intramolecular aza-Michael reaction that furnished
The synthesis began with the preparation of requisite vinyl
iodide 14 from known aldehyde 11 (Scheme 3).21 Corey−
Fuchs alkynylation, subsequent trapping with methyl iodide,
and removal of the acetonide afforded 12 in 43% yield over
three steps. Palladium-catalyzed hydrostannylation gave 13 in
48% yield, which was smoothly converted to vinyl iodide 14 by
treatment with I2 in 82% yield.22 The C1−C9 aldol fragment
15a, which was employed in the synthesis of tridesmethyl
congener 3,4,5 was protected as its tert-butyldimethylsilyl (TBS)
ether 15b with TBSOTf and 2,6-lutidine. Removal of the Evans
auxiliary was accomplished with lithium benzyloxide, furnishing
ester 16 in 63% over two steps.23
The site- and stereoselective installation of the D-desosamine
residue required protecting group manipulation. To this end,
both the secondary C5-OTES and the primary C9-OTBS
ethers were removed with camphorsulfonic acid (CSA) in 85%
yield. Chemoselective reprotection of the primary C9 hydroxyl
was effected with TBSCl and imidazole. Glycosylation of the
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oxazolidinone 24 in 45% overall yield as an inseparable 6:1
mixture of diastereomers at C-10 with the major isomer being
the desired C10-(R) isomer. Two lines of evidence support our
assignment. First, in the C10-(R) series, Baker observed a
characteristic singlet for H-11, which results from its coplanar
disposition to vicinal H-10. In the C10-(S) series, H-11 appears
as a doublet (J = 1 Hz).26 Second, our direct comparison with
the 1H NMR spectra of 5 and 2 is consistent with Baker's data,
wherein the H-11 signal of 2 appears as a singlet.3
To facilitate interpretation of the MICs, we employed the
conformationally sampled pharmacophore (CSP) approach
using Hamiltonian Replica Exchange Molecular Dynamics
(HREX MD), from which conformational properties of 2−5
were obtained.32 Probability distributions of distances between
select functional groups on 2 (black), 3 (blue), 4 (purple), and
5 (red) are shown in Figure 3A−D. The distributions for both
Removal of the C3-OTBS ether was accomplished with
tris(dimethylamino)sulfonium difluorotrimethylsilicate (TAS-
F) in DMF/H2O (10:1) at rt for 16 h.28 Corey−Kim oxidation
furnished the C3 ketone 25 in 55% yield over two steps, which
was separated from the minor C10-(S) diastereomer at this
step.29 Stirring 25 in MeOH overnight at rt delivered 5 in 65%
yield.
With desired analogue 5 in hand, we turned our attention to
biological evaluation of antibacterial activity against both
Escherichia coli and Staphylococcus aureus.14 Compound 2, in
addition to 3 and 4, were used as comparators (Table 1).4−6
Figure 3. CSP probability distributions for 2 (black), 3 (blue), 4
(purple), and 5 (red). The vertical line corresponds to the
crystallographic distances from PDB ID 1YIJ. Atom pairs represented
in A−D are shown in the inset figure.
Table 1. MIC Values in μg/mL for 3−5 and 2
didesmethyl analogues overlap well with that of TEL, which is
consistent with both analogues binding to the ribosome and
exhibiting antimicrobial activity. Reduced MIC values for
a
b
Previous experiment carried out in EtOH. Current experiment
̀
analogues 3−5 vis-a-vis 2 are presumably due to increased
carried out in DMSO.
conformational flexibility. This is indicated by their broader
distributions as compared to TEL in the CSP analysis (Figure
3A−C). The presence of an additional methyl in didesmethyl 5
versus tridesmethyl 3 reduces conformational flexibility,
indicating that 5 is sampling more of the bioactive
conformation, thereby contributing to the improved MIC
values. Altogether, these results indicate a model where removal
of the methyl groups leads to increased conformational
flexibility and therefore lower biological activity. Other factors
such as solubility (i.e., membrane permeability) and desolvation
effects, which are not addressed with CSP, could also explain
the decreased activity of the desmethyl congeners as compared
to 2.
In conclusion, 5 was prepared via total synthesis using an
intramolecular NHK approach in 36 steps (26 steps in the
longest linear sequence) from commercially available starting
materials.33 The efficiency of Martin's abiotic erythromycin
synthetic strategy (i.e., cyclizing the 14-membered macro-
lactone ring with a pendant glycone) is evident when
comparing the step count of the 4,10-didesmethyl congener
4, which was prepared by a stepwise RCM/glycosylation
approach in 44 steps overall (32 steps in the longest linear
sequence).19 The biological evaluation of 5 in MIC assays
revealed inhibition in the growth of two bacterial strains,
including an A2058G mutant. Significantly, the addition of an
extra methyl group at C-10 resulted in an 8-fold increase in
activity as compared to tridesmethyl analogue, providing
evidence for the critical role of the methyl groups about the
macrolactone scaffold in determining antibiotic activity. We are
actively pursuing the synthesis and evaluation of other
desmethyl TEL analogues, the results of which will be reported
in due course.
The data reveal that none of the macrolides 2−5 inhibited E.
coli A2058G (entry 1) or S. aureus ermA mutants (entry 5). By
contrast, all macrolides inhibited both E. coli wild-type (entry 2)
and E. coli A2058G mutant strains (entry 3). The inhibitory
activity was directly proportional to the number of methyl
groups; in other words, tridesmethyl analogue 3 was less potent
than either didesmethyl congener, which was less potent than 2.
This trend was recognized in the evaluation of 4.6 Curiously,
the new 4,8-didesmethyl analogue 5 was 8-fold more potent
than 4,8,10-tridesmethyl analogue 3 and 8-fold less potent than
2 against wild-type E. coli. Additionally, 5 was 2-fold more
potent than regioisomeric 4,10-didesmethyl analogue 4 (entry
2). However, when compared to the E. coli A2058G mutant
strain (entry 3), the potency of both didesmethyl analogues was
inverted. Specifically, 4 was 16-fold less potent than 2 yet 2-fold
more potent than 4,8-didesmethyl congener 5. Finally, it is
interesting to note that the only macrolide capable of inhibiting
the S. aureus A2058T mutant (entry 4) was the simplest
tridesmethyl analogue 3. Altogether, these data reveal that
replacing methyl groups on the macrolide ring with hydrogens
modulates inhibitory activity and that this activity is strain
dependent. X-ray crystallographic data of 2 bound to the
ribosomes of H. marismortuii,12 D. radiodurans,30 and E. coli31
reveal that while the macrolactone ring binds with an identical
conformation to all ribosomes,11 the biaryl side chain binds in
three unique conformations depending on the species! This fact
has broad implications for antimicrobial drug discovery,
mandating more chemical space be explored to customize
antibiotic chemotherapy for each targeted pathogen.
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ASSOCIATED CONTENT
■
S
* Supporting Information
General experimental protocols, computational methods, full
structural assignment of 22, and characterization of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: randrade@temple.edu.
Funding
This work was supported by the NIH (AI080968 and
GM070855) and the University of Maryland Computer-Aided
Drug Design Center.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank Dr. Alexander Mankin (University of Illinois at
Chicago) for helpful suggestions. We also thank Dr. Richard
Pederson (Materia, Inc.) for catalyst support.
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ABBREVIATIONS
■
dba, dibenzylideneacetone; TBS, tert-butyldimethylsilyl; RCM,
ring-closing metathesis; NHK, Nozaki−Hiyama−Kishi; MIC,
minimum inhibitory concentration; CSA, camphorsulfonic
acid; CSP, conformationally sampled pharmacophore;
DMSO, dimethyl sulfoxide; DMAP, N,N-dimethylamino
pyridine; DMP, Dess−Martin periodinane; DMF, N,N-
dimethylformamide; Tf, trifluoromethanesulfonyl; TEL, teli-
thromycin; HREX MD, Hamiltonian Replica Exchange
Dynamics; NCS, N-chlorosuccinimide; CDI, carbonyldiimida-
zole; Hm, Haloarcula marismortui; THF, tetrahydrofuran; TAS-
F, tris(dimethylamino)sulfonium difluorotrimethylsilicate; Pyr,
pyridine
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Supporting Information for details.
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