Desmethyl macrolides: Synthesis and evaluation of 4,10-didesmethyl telithromycin

Article abstract of DOI:10.1021/ml200254h

Novel sources of antibiotics are required to keep pace with the inevitable onset of bacterial resistance. Continuing with our macrolide desmethylation strategy as a source of new antibiotics, we report the total synthesis, molecular modeling, and biological evaluation of 4,10-didesmethyl telithromycin (4), a novel desmethyl analogue of the third-generation drug telithromycin (2). Telithromycin is an FDA-approved ketolide antibiotic derived from erythromycin (1). We found 4,10-didesmethyl telithromycin (4) to be four times more active than previously prepared 4,8,10-tridesmethyl congener (3) in MIC assays. While less potent than telithromycin (2), the inclusion of the C-8 methyl group has improved biological activity, suggesting that it plays an important role in antibiotic function.

Full text of DOI:10.1021/ml200254h

Letter
pubs.acs.org/acsmedchemlett
Desmethyl Macrolides: Synthesis and Evaluation of 4,10-Didesmethyl
Telithromycin
Venkata Velvadapu,† Ian Glassford,† Miseon Lee,† Tapas Paul,† 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: Novel sources of antibiotics are required to keep pace with the inevitable onset of bacterial resistance. Continuing
with our macrolide desmethylation strategy as a source of new antibiotics, we report the total synthesis, molecular modeling, and
biological evaluation of 4,10-didesmethyl telithromycin (4), a novel desmethyl analogue of the third-generation drug
telithromycin (2). Telithromycin is an FDA-approved ketolide antibiotic derived from erythromycin (1). We found 4,10-
didesmethyl telithromycin (4) to be four times more active than previously prepared 4,8,10-tridesmethyl congener (3) in MIC
assays. While less potent than telithromycin (2), the inclusion of the C-8 methyl group has improved biological activity,
suggesting that it plays an important role in antibiotic function.
KEYWORDS: total synthesis, ketolide antibiotics, antibiotic resistance, telithromycin, molecular modeling, desmethyl analogues
ribosome by reversibly binding in the peptidyl transferase
center, thus blocking protein synthesis.5 TELI (2) is a third
generation semisynthetic drug used clinically since 2004 and is
derived from the flagship macrolide antibiotic erythromycin
(1).6
All macrolide antibiotics based on the erythromycin scaffold
are semisynthetic (i.e., prepared from erythromycin). Our
approach distinguishes itself from others in that total synthesis
is employed to access each analogue, which allows significant
flexibility and provides ample opportunity to explore the
chemical space of this important class of safe and effective
broad-spectrum antibiotics.7,8
Antibiotic resistance mechanisms fall into three major
categories: (1) drug modification, (2) drug efflux, and (3)
target (i.e., ribosomal) modification arising from either
ribonucleotide N-methylation of residues critical for binding
(e.g., A2058) or single point mutations (e.g., A2058G).9
he rapid development of bacterial resistance to antibiotic
Tdrugs, which is a natural consequence of their use and
abuse, has resulted in a global health crisis. To exacerbate the
problem, many pharmaceutical companies have terminated
their antimicrobial research programs due to economic
pressures. Thus, new sources of antibiotics are critical.1 To
address this need, we recently launched a structure-based drug
design program wherein desmethyl analogues (i.e., CH3 → H)
of the third-generation macrolide antibiotic telithromycin
(TELI) (2) are made via synthesis (Figure 1).2,3 We have
reported the total synthesis, molecular modeling, and biological
evaluation of 4,8,10-tridesmethyl TELI (3) against both wild-
type and macrolide-resistant bacteria, which was found to be
active against various bacterial strains (vide infra). Herein, we
report the total synthesis, molecular modeling, and biological
evaluation of 4,10-didesmethyl TELI (4), our second desmethyl
analogue of 2. Importantly, we have installed the (R)-C-8
methyl group in a chemo- and stereoselective manner by means
of substrate-controlled asymmetric synthesis,4 enabling us to
test the consequences of a single methyl group on bioactivity.
All macrolide antibiotics target the 50S subunit of the bacterial
Received: October 25, 2011
Accepted: January 15, 2012
Published: January 15, 2012
© 2012 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
methyls at C-8 and C-10 was to (1) simplify chemical synthesis
and (2) understand their roles in antibiotic function.
To test the consequences of adding another methyl vis-a-vis
̀
our simplest analogue 3 while probing the effects of removing
the C-4 and C-10 methyl groups of TELI (2), we launched a
total synthesis of 4 to realize biological evaluation (i.e.,
minimum inhibitory concentrations, or MICs).12
The installation of the requisite (R)-C-8 methyl group
commenced with enoate 5, which was utilized in the synthesis
of tridesmethyl analogue 3 (Scheme 1).2,3 Sharpless dihydrox-
Scheme 1. Installation of (R)-C-8 Methyl Group and
a
Stereochemical Confirmation
Figure 1. Structures of erythromycin (1), TELI (2), and novel
analogues 4,8,10-tridesmethyl TELI (3) and 4,10-didesmethyl TELI
(4).
Inspiration for our desmethylation strategy is derived from
Steitz's elegant structural studies of macrolide drugs (e.g., 1 and
2) cocrystallized with 50S ribosomal subunits of the archaeon
Haloarcula marismortui (Hm).10
Unlike eubacteria that possess adenine at 2058, all archea
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 TELI (2) bound to the HmA2058
mutant at 2.6 Å resolution to be obtained (Figure 2A). Thus,
a
Reagents and conditions: (a) AD mix-β, 85%, er >20:1. (b) TESCl,
imidazole. (c) LDA, MeI. (d) LDA, Me3CCO2H (dr = 6:1), 54% over
three steps or LDA, Ph3CCO2H (dr = 14:1, 82% over three steps). (e)
TBAF, THF. (f) DCC, (R)-MTPA, DMAP, 60% over two steps.
ylation (AD mix-β) of 5 furnished γ-lactone 6 by in situ
lactonization of the newly formed C-6 hydroxyl in 85% yield
(er > 20:1).13,14 Protection of the C-5 alcohol as its triethylsilyl
(TES) ether was accomplished with TESCl and imidazole.
Treatment of 7 with lithium diisopropylamide (LDA) at −78
°C and alkylation with MeI afforded a (S)-C-8 methyl
intermediate. Inversion at C-8 to obtain the (R) configuration
was accomplished by (1) re-enolization with LDA and (2)
quenching with trimethylacetic acid (dr = 6:1, 54% overall yield
from 6).
Alternatively, quenching the enolate with a bulklier acid
source (e.g., triphenylacetic acid) greatly improved the
selectivity of epimerization (dr = 14:1, 82% overall from 6).
Confirmation of the stereochemical course of the experiment
was obtained by preparing Mosher ester 9 and subsequent
single crystal X-ray analysis, which was realized by removing the
TES ether on the C-5 hydroxyl with tetrabutylammonium
fluoride (TBAF) and esterification with (R)-α-methoxy-α-
(trifluoro-methyl)phenylacetic acid (MTPA).13,14
Subsequent steps in the synthesis of 4,10-didesmethyl TELI
(4) were guided by the previously reported synthesis of
tridesmethyl congener 3 (Scheme 2).2,3 Thus, lactone 8 was
reduced with LiAlH4 and the primary alcohol chemoselectively
protected as its tert-butyldimethylsilyl (TBS) ether to afford 10
(78% yield over two steps). Methylation of the tertiary C-6
alcohol was accomplished with MeOTf and 2,6-di-tert-butyl-4-
methylpyridine (DTBMP) to furnish 11 in 75% yield. The use
Figure 2. (A) TELI and A2058 interactions in H. marismortui with
select distances in Angstroms (Steitz et al. PDB = 1YIJ). (B) Steric
consequences of A2058G mutation.
Steitz 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.11 The rationale behind removing
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a
Scheme 2. Synthesis of 4,10-Didesmethyl TELI (4)
a
Reagents and conditions: (a) LiAlH4, THF. (b) TBSCl, imidazole, 78% over two steps. (c) MeOTf, DTBMP, 75%. (d) H2, Pd/C, 80%. (e)
(COCl)2, DMSO, Et3N. (f) Bu2BOTf, Et3N, dr > 20:1, 76% over two steps. (g) TBSOTf, 2,6-lutidine. (h) LiOOH, THF, H2O, 88% over two steps.
(i) Cl3PhCOCl, Et3N, DMAP, 16, 78%. (j) TBAF, AcOH, 20%. (k) DMP, NaHCO3. (l) Vinyl MgBr, THF. (m) DMP, 50% over three steps. (n) 20
mol % Grubbs' second generation catalyst, 60%. (o) NaBH4, CeCl3·7H2O, dr = 5:2. (p) TESOTf, 2,6-lutidine. (q) p-TsOH, 30% over three steps. (r)
TESCl, imidazole. (s) Compound 21, AgOTf, DTBMP, 50% over two steps. (t) HF·Et3N, Et3N, CH3CN. (u) DMP, CH2Cl2, 60% over two steps.
(v) NaH, CDI, THF/DMF. (w) Compound 23, 45% over two steps. (x) TAS-F, DMF/H2O, 75%. (y) NCS, Me2S, Et3N, 70%. (z) MeOH, 80%.
of Proton Sponge, previously employed in the synthesis of 3,
gave an inferior 35% yield. Hydrogenolysis of benzyl ether 11
(80% yield) afforded an intermediary alcohol that was oxidized
to aldehyde 12 with the Swern method.
At this stage, the Evans aldol reaction with propionimide 13
was employed to set the configurations at both C-2 and C-3
positions.15 In the event, the aldol adduct was isolated in 78%
yield (dr > 20:1). Protection of the C-3 hydroxyl with TBSOTf
to access 14 and removal of the auxiliary furnished acid 15 in
88% yield (two steps). Chemoselective Yamaguchi esterifica-
tion of 15 with known diol 16 delivered ester 17 in 78%
yield.2,3
To prepare the 14-membered macrolactone ring, we
recruited the ring-closing metathesis (RCM) strategy pre-
viously employed in the simpler congener 3.2,3 To this end, we
removed the primary TBS ether in 17 with TBAF buffered with
AcOH (20% yield, unoptimized).16 The resulting alcohol was
oxidized to the aldehyde with the Dess−Martin periodinane
(DMP);17 moreover, the addition of vinyl MgBr and
subsequent DMP oxidation afforded vinyl ketone 18 in 50%
overall yield. Treatment of dienone 18 with 20 mol % Grubbs'
second-generation catalyst effected the desired RCM, affording
macroketolactone 19 in 60% yield.18
Stereo- and regioselective installation of desosamine at the C-
5 hydroxyl paralleled the approach taken for 3. Specifically, the
C-9 ketone in 19 was reduced under Luche conditions to avoid
ketalization with the C-5 hydroxyl with a dr of 5:2, and the C-
12 hydroxyl was protected as its TES ether to prevent
glycosylation with desosamine donor 21.2,3 Silylation of both
C-9 and C-12 hydroxyls with TESOTf and subsequent
treatment with p-toluenesulfonic acid (p-TsOH) selectively
deprotected the C-5 and the C-9 silyl ethers while leaving the
tertiary C-12 hydroxyl TES-protected (30% yield over three
steps).
Site-selective silylation of the secondary, allylic C-9 alcohol in
the presence of the secondary C-5 alcohol with TESCl and
imidazole furnished 20, which was subjected to glycosylation
with known desosamine donor 21 (50% yield over two steps)
under the agency of AgOTf and DTBMP.19,20 When removing
both C-9 and C-12 silyl ethers, we found that HF·3Et3N gave
better selectivity as compared to TBAF. DMP oxidation
afforded glycosylated macroketolactone 22 in 60% yield over
two steps.
Installation of the C-11/C-12 carbamate was accomplished
by employing methods originally developed by Baker at Abbott
and later adapted by Hoechst Marion Roussel to prepare 2.21,6
Thus, treatment of 22 with NaH and carbonyldiimidazole
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ACS Medicinal Chemistry Letters
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(CDI) and subsequent addition of butylamine 23 effected a
tandem carbamoylation/intramolecular aza-Michael sequence
to stereoselectively afford oxazolidinone 24 in 45% overall
yield.22 Removal of the C-3 TBS ether with tris-
(dimethylamino)sulfonium difluorotrimethylsilicate (TAS-F)
proceeded in 75% yield.23 Corey-Kim oxidation afforded the
C-3 ketone (70% yield), and methanolysis of the methyl
carbonate on the C-2′ position of desosamine delivered target
molecule 4,10-didesmethyl TELI (4) in 80% yield.24
With 4 in hand, we initiated biological evaluation by testing
its activity against several bacterial strains of E. coli and
Staphylococcus aureus.12 TELI (2) and 4,8,10-tridesmethyl TELI
(3) were used as comparators (Table 1).2,3
Figure 3. CSP probability distributions for TELI (2, black); 4,8,10-
tridesmethyl TELI (3, blue); and 4,10-didesmethyl TELI (4, red). The
vertical line corresponds to the crystallographic distances from PDB
1YIJ. Atom pairs represented in A−D are shown in the inset figure.
Table 1. MIC Values in μg/mL for 4,8,10-Tridesmethyl
Analogue (3), 4,10-Didesmethyl Analogue (4), and TELI (2)
steps in the longest linear sequence) from commercially
available starting materials. The novel analogue was evaluated
for biological activity and found to inhibit the growth of two
bacterial strains, including an A2058G mutant. Significantly, the
addition of an extra methyl group at C-8 resulted in a 4-fold
increase in activity as compared to tridesmethyl congener,
suggesting that it plays an important role in antibiotic function.
We are currently working toward the synthesis of other
desmethyl TELI analogues. Those results will be reported in
due course.
a
b
Previous experiment carried out in EtOH. Current experiment
carried out in DMSO.
Although both resistant strains (entries 1 and 5) were not
susceptible to any of the macrolides, both E. coli wild-type and
A2058G mutant (entries 2 and 3) were inhibited by
tridesmethyl analogue 3, didesmethyl analogue 4, and TELI
(2). In these strains, the didesmethyl congener was 4-fold more
potent than tridesmethyl variant. As compared to TELI (2), the
novel analogue was 16-fold less potent. While the current
evaluation was carried out in DMSO and not EtOH, the MIC
values for TELI (2) were found to be identical in both, thus
ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental protocols, computational methods, C-8
epimerization studies, crystallographic details of 9, 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.
̀
suggesting the potency of didesmethyl analogue 4 vis-a-vis 3 is
not derived from solvent change. Thus, these data illustrate the
consequences of deleting methyl groups from the erythronolide
scaffold. Interestingly, 4 did not inhibit the growth of the
UCN14 strain that carries an A2058T mutation as compared to
3.
AUTHOR INFORMATION
Corresponding Author
*E-mail: randrade@temple.edu.
Funding
■
To facilitate interpretation of the MICs, we employed the
conformationally sampled pharmacophore (CSP) approach
using Hamiltonian Replica Exchange Dynamics (HREX MD),
from which conformational properties of 2, 3, and 4 were
obtained.25 Probability distributions of distances between select
points on TELI (2, black), 4,8,10-tridesmethyl (3, blue), and
4,10-didesmethyl (4, red) TELI are shown in Figure 3A−D.
The distributions for both desmethyl analogues overlap well
with that of TELI, consistent with both analogues binding to
the ribosome. The additional conformational flexibility of 3 and
4 as seen in panels A−C of Figure 3 are suggested to contribute
to the decrease in their MICs vs 2. Consistent with the
additional methyl in didesmethyl 4 vs tridesmethyl 3, 4 has
decreased conformational flexibility, which is supported by the
improved MIC values. Altogether, these results indicate a
model where removal of the methyl groups lead to increased
conformational flexibility, which has a negative impact on the
biological activity, a consideration that must be taken into
account when removing the C-4 methyl group to avoid
resistance associated with the A2058G mutation.
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.
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.
ABBREVIATIONS
■
TBS, tert-butyldimethylsilyl; TES, triethylsilyl; LDA, lithium
diisopropylamide; DTBMP, 2,6-di-tert-butyl-4-methylpyridine;
RCM, ring-closing metathesis; MIC, minimum inhibitory
concentration; CSP, conformationally sampled pharmaco-
phore; DMP, Dess−Martin periodinane; Tf, trifluoromethane-
sulfonyl; TBAF, tetrabutylammonium fluoride; HREX MD,
Hamiltonian Replica Exchange Dynamics; TELI, telithromycin;
CDI, carbonyldiimidazole; TAS-F, tris(dimethylamino)-
sulfonium difluorotrimethylsilicate
In conclusion, 4,10-didesmethyl TELI (4) was prepared via
total synthesis using a RCM approach in 44 steps overall (32
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ACS Medicinal Chemistry Letters
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