Scaffolds for microtubule inhibition through extensive modification of the epothilone template

Article abstract of DOI:10.1002/anie.200501760

(Chemical Equation Presented) The microtubule-stabilizing agent 1 was obtained through extensive modification (colored circles) of the structure of natural epothilone. Despite these structural differences, the biological potency of 1 is comparable with th

Full text of DOI:10.1002/anie.200501760

Angewandte
Chemie
Epothilones
DOI: 10.1002/anie.200501760
Scaffolds for Microtubule Inhibition through
Extensive Modification of the Epothilone
Template**
FrØdØric Cachoux, Thomas Isarno, Markus Wartmann,
and Karl-Heinz Altmann*
Cellular microtubules are important targets for the develop-
ment of anticancer drugs, and a variety of microtubule-
interacting agents are currently in clinical use for the treat-
ment of human cancer.[1] Agents interfering with microtubule
functionality may either stabilize or destabilize microtu-
bules;[2] the most prominent examples of microtubule stabil-
izers are the clinical anticancer drugs taxol (paclitaxel) and
docetaxel (taxotere).[3] While taxol and related compounds
had long been the only structures known to stabilize micro-
tubules and promote tubulin polymerization, a variety of
other natural products have been recognized over the last ten
years to exert their antiproliferative activity through a
mechanism of action similar to that of taxol. These com-
pounds include, for example, epothilones A and B (Epo A
and B), discodermolide, laulimalide, and peloruside.[4]
Natural products have been the most productive source of
potent microtubule stabilizers by far,[4] and the systematic
screening of natural-product-based libraries (or perhaps
libraries based on natural-product-like compounds) is likely
to reveal additional templates for microtubule stabilization in
the future.[5] Alternatively, such templates may be developed
from existing microtubule stabilizers through extensive
structural modification (and perhaps simplification), pro-
vided such modifications do not produce an unacceptable loss
in the desired biological activity.
[*] Dr. F. Cachoux,[+] Dr. T. Isarno,[++] Prof. Dr. K.-H. Altmann
ETH Zürich
Department of Chemistry and Applied Biosciences
Institute of Pharmaceutical Sciences
ETH Hönggerberg, HCI H 405
Wolfgang-Pauli-Strasse 10, 8093 Zürich (Switzerland)
Fax: (+41)44-633-1360
E-mail: karl-heinz.altmann@pharma.ethz.ch
Dr. M. Wartmann
Oncology DA
Novartis Institute for Biomedical Research
Basel (Switzerland)
[+] Current address:
Prestwick Chemical, Illkirch (France)
[
++] Current address:
Carbogen AG, Aarau (Switzerland)
[**] This research was supported by Novartis Pharma AG (postdoctoral
fellowships to F.C. and T.I.). We also thank Dr. Peter Ertl, Novartis
Institute for Biomedical Research, Basel, for calculating the
Tanimoto coefficients.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Of the various newly discovered microtubule-stabilizing
agents mentioned above, the most extensively studied is
Epo B,[6] for which numerous synthetic and semisynthetic
variants have been prepared and subjected to biological
profiling.[7] These efforts have produced an extensive data-
base on structure–activity relationships (SAR) for epothi-
lones and, most significantly, they have also led to the
discovery of at least five analogues that are currently under-
going clinical evaluation in humans (in addition to Epo B).[7a]
While the structures of these analogues are not significantly
different from the original natural product lead, their
biochemical and pharmacological properties appear to be
distinct from that of Epo B, thus indicating that structural
analogues closely related to Epo B may embody significant
improvements in preclinical profile. Perhaps the most impres-
sive examples are the 9,10-didehydro derivatives of Epo D,[8]
which were recently described by the Danishefsky laboratory
(and one of which has recently started phaseI clinical trials).[9]
Notwithstanding these findings, it is still important to
explore more extensive structural modifications of the
epothilone scaffold that may lead to analogues with only
limited or even no obvious structural resemblance to the
starting natural product. Such analogues (if sufficiently
potent) could be considered new templates for microtubule
inhibition (in the same way a newly discovered natural
product would be; vide supra). Here we provide a preliminary
account of our synthetic and SAR work on a series of new
epothilone analogues, which illustrates how iterative changes
of the epothilone scaffold can lead to greatly modified
(“hypermodified”) structures that are still associated with
potent tubulin-polymerizing and antiproliferative activity.
One of the strategic starting points for our development of
hypermodified potent epothilone analogues was the removal
of the hydroxy group in the 3-position of the epothilone
scaffold. Rather surprisingly, the consequences of this simple
modification have not been investigated explicitly to date,
although other modifications at the 3-position have been
described. Thus, formal dehydration at C2and C3 (leading to
3-deoxy-2,3-didehydro derivatives) is well tolerated,[10] which
is in agreement with an anti-periplanar conformation of the
edly, macrolactonization was accompanied by partial epime-
rization at C15 (!), which later necessitated purification of 12
by preparative HPLC.
The data summarized in Table 1 indicate that 1 exhibits
potent tubulin-polymerizing and antiproliferative activity,
such that its cellular activity against the human epidermoid
cancer cell line KB-31 is only ca. 25 times lower than that of
Table 1: Tubulin-polymerizing and antiproliferative activity of 3-deoxy-
epothilone analogues.
Cmpd.[a] % Tubulin
polymerization[b]
IC50(KB-31)[c] [nm] IC50(KB-8511)[c] [nm]
Epo A
Epo B
Epo C[a]
62.6 (n.d.)
2.15ꢁ0.07
0.29ꢁ0.05
24.9[d]
1.91ꢁ0.07
0.22ꢁ0.05
9.9[d]
1.44ꢁ0.78
805ꢁ144
4.0ꢁ1.6
37.6ꢁ1.4
1.89[e]
95.8 (73.7)
n.d.
Epo D[a] 81.0 (n.d.)
2.70ꢁ1.31
3.68ꢁ0.68
7.4ꢁ2.2
taxol
1
2
53.7 (n.d.)
92.2 (68.0)
91.9 (67.5)
n.d.
7.4ꢁ0.7
3
0.58[e]
4
82.0 (71.9)
78.7 (68.7)
86.4 (66.5)
n.d.
3.16ꢁ0.55
7.60ꢁ2.44
12
16
17
18
114ꢁ7
74ꢁ3
ꢀ
C2 C3 bond in the proposed bioactive conformation of
58.7ꢁ3.6
4.99ꢁ2.15
39.9ꢁ1.8[f]
58.6ꢁ7.1
5.75ꢁ3.24
47.3ꢁ4.8[f]
Epo A.[11] Activity is also largely retained upon replacement
of the (3S)-hydroxy group by a (3S)-cyano group,[10a] while
inversion of configuration at C3 leads to a profound loss in
biological potency (for both Epo A and Epo B[7d] as well as
for the corresponding 3-deoxy-3-cyano analogues[10a]). Given
the absence of biological information about simple 3-deoxy
analogues of epothilones (with a single bond between C2and
C3), we have prepared 3-deoxy-Epo B (1) and assessed the
biological activity of this compound. Scheme 1 summarizes
our synthesis of 1, which follows strategic principles similar to
those we previously employed for the preparation of other
types of epothilone analogues.[12]
92.2 (65.5)
[a] All compounds tested were pure stereoisomers (HPLC, NMR).
Epo C=12,13-deoxyepothilone A. [b] Induction of polymerization of
pure bovine brain tubulin (Cytoskeleton; catalog no. TL238) by 5 mm
(2 mm) of test compound relative to the effect of 25 mm of Epo B, which
gave maximal polymerization (100%). Tubulin polymerization was
determined using a modified version of the centrifugation assay
described in ref. [18]. n.d.=not determined. [c] IC50 values for growth
inhibition of the human epidermoid carcinoma cell lines KB-31 and KB-
8511, respectively. KB-8511 is a P-glycoprotein 170 (P-gp170)-over-
expressing multidrug-resistant subline of the KB-31 parental line. Cells
were exposed to compounds for 72 h. Cell numbers were estimated by
quantification of protein content of fixed cells by staining with methylene
blue.[19a] For further experimental details see ref. [19b]. Values represent
the means of at least three independent experiments (ꢁ standard
deviation). [d] Single determination. [e] Average values for two determi-
nations. Individuals values are 0.54/0.62 (KB-31) and 1.61/2.16 (KB-
8511). [f] The corresponding values for trans-Epo C are 96.2 nm and
36.8 nm, respectively.
Key steps are the aldol reaction between ketone 5 and
aldehyde 6 (which proceeded with ca. 2.5:1 selectivity in favor
of the desired aldol product 7 and was not optimized), the B-
alkyl Suzuki coupling of 9 with vinyl iodide 10, Yamaguchi
ꢀ
macrolactonization, and finally epoxidation of the C12 C13
double bond in the deprotected macrolactone 12. Unexpect-
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Scheme 1. a) LDA, ꢀ788C, 2 h, 58% (d.r. 2.5:1); b) TBSOTf, 2,6-lutidine, ꢀ108C, 1 h, 82%; c) H2/Pd-C, MeOH, 1 h, 97%; d) o-NO2PhSeCN, Bu3P,
NaHCO3, H2O2, RT, 2 h, 69%; e) 9-BBN, THF, RT, 2 h, then added to mixture of Cs2CO3 (2 equiv), [PdCl2(dppf)2] (0.2 equiv), Ph3As (0.2 equiv.),
vinyl iodide 10, DMF, ꢀ108C!RT, 16 h, 55%; f) LiOH (6 equiv), iPrOH/H2O 4:1, 608C, 3 h, 98%; g) 2,4,6-Cl3C6H2C(O)Cl, Et3N, THF, 08C,
15 min, then diluted with toluene and added to a solution of DMAPin toluene, RT, 1 h, 80% (2:1 mixture of epimers); h) HF·pyridine, THF, RT,
6 h, 90% (2:1 mixture of isomers; pure 12 obtained through purification by preparative HPLC); i) MeReO3, H2O2/pyridine/H2O, RT, 90 min, 72%
(9:1 mixture of epoxide isomers; pure 1 obtained through purification by preparative HPLC). 9-BBN=9-borabicyclo[3.3.1]nonane, Bn=benzyl,
DMAP=4-dimethylaminopyridine, dppf=1,1’-bis(diphenylphosphanyl)ferrocene, LDA=lithium diisopropylamide, TBSOTf=tert-butyldimethylsilyl
triflate, TES=triethylsilyl.
Epo B. The cellular potency of 1 is comparable with that of
taxol, Epo A, and also 3-deoxy-2,3-didehydro-Epo B (data
not shown), but in contrast to taxol the compound retains
activity also against multidrug-resistant KB-8511 cells. The
reduction in antiproliferative activity is somewhat larger at
the level of deoxy compound 12, which is roughly 40 times less
potent than Epo D (12/13-deoxyEpo B).[8]
In the next step we asked whether at least some of the
activity loss incurred by the removal of the 3-hydroxy group in
Epo B could be recovered through additional and compensa-
tory structural modifications. Based on our previous studies
on potency-enhancing side-chain modifications,[12b] we
designed compounds 2 and 3, whose synthesis is summarized
in Scheme 2. Starting from olefin 9, Pd0-catalyzed B-alkyl
Again, macrolactonization produced two isomers (which
we presume to be epimers at C15), but in both cases the major
isomer was obtained in pure form at the stage of the 12/13-
deoxy compound (i.e. after removal of the TBS group from
O–C7). Epoxidation of 16 and 17 with H2O2/pyridine in
[14]
CH2Cl2 and catalytic MeReO3 gave the desired analogues
of Epo A and B, compounds 2 and 3, respectively, but
profound differences in epoxidation selectivity were observed
between the two substrates. Thus, epoxidation of 16 pro-
ceeded with only 2:1 selectivity (in favor of the desired
epoxide isomer); in addition, the epoxidation products were
difficult to separate and 2 could be obtained in only 16% yield
after purification by preparative TLC. In contrast, epoxida-
tion of 17 gave the desired isomer with > 10:1 selectivity
(85% yield for the mixture of isomers), and pure 3 was
obtained in 54% yield after purification by preparative
HPLC.
As can be seen in Table 1, the presence of the benzimi-
dazole side chain in 3 leads to a significant potency increase
over 1 against the drug-sensitive KB-31 cell line, while a
smaller difference is observed for the multidrug-resistant KB-
8511 line. In fact, compound 3 shows a small (three- to
fourfold) but clearly detectable activity differential between
the sensitive and the resistant cell line, indicating that it may
be a weak substrate for the P-gp efflux pump. We have
previously observed a similar decrease in activity against KB-
8511 cells for the corresponding benzimidazole-based ana-
Suzuki coupling with cis-vinyl iodides 13 (free OH group) and
14[13] was followed by ester saponification, selective removal
of the TES protecting group from O–C15 (only in the
synthesis of 3), Yamaguchi macrolactonization, and depro-
tection of O–C7 to produce 12/13-deoxy intermediates 16 and
17, respectively (Scheme 2).
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tural premises were realized in compound 4, which was
obtained from 9 by B-alkyl Suzuki coupling with vinyl iodide
15,[13] elaboration of the coupling product into deoxy ana-
logue 18, and final epoxidation (Scheme 3).
Scheme 2. a) 9-BBN (0.8 equiv), THF, RT, 100 min, then added to a
mixture of Cs2CO3 (1.5 equiv), [PdCl2(dppf)2] (0.2 equiv), Ph3As
(0.2 equiv), vinyl iodide 13, DMF, 08C!RT, 75 min, 65%; b) LiOH
(6 equiv), iPrOH/H2O 4:1, 608C, 45 min, 87%; c) 2,4,6-Cl3C6H2C(O)Cl,
Et3N, THF, 08C!RT, 30 min, then diluted with toluene and added to a
solution of DMAPin toluene, RT, 2 h, 85% (4:1 mixture of epimers);
d) HF·pyridine, CH3CN, RT, 3 h, 68% (single isomer); e) MeReO3,
H2O2, pyridine, CH2Cl2, RT, 5 h, 16% (preparative TLC); f) 9-BBN,
THF, RT, 2 h, then added to a mixture of Cs2CO3 (2 equiv), [PdCl2-
(dppf)2] (0.2 equiv), Ph3As (0.2 equiv), vinyl iodide 14 (1 equiv), DMF,
08C!RT, 2 h, 77%; g) LiOH (6 equiv), iPrOH/H2O 4:1, 608C, 3 h,
90%; h) TBAF, THF, RT, 24 h, 75%; i) 2,4,6-Cl3C6H2C(O)Cl, Et3N, THF,
08C, 15 min, then diluted with toluene and added to a solution of
DMAPin toluene, RT, 1 h, 85% (10:1 mixture of epimers); j) HF·pyr-
idine, CH3CN, RT, 3 h, 54% (single isomer; 87% for mixture of
epimers); k) MeReO3, H2O2/pyridine/H2O, RT, 30 min, 64% (10:1
mixture of epoxide isomers). TBAF=tetrabutylammonium fluoride.
Scheme 3. a) 9-BBN (0.8 equiv), THF, RT, 2 h, then added to a mixture
of Cs2CO3 (1.5 equiv), [PdCl2(dppf)2] (0.1 equiv), Ph3As (0.2 equiv),
vinyl iodide 15 (1 equiv), DMF, ꢀ108C!RT, 16 h, 58%; b) LiOH
(6 equiv), THF/H2O 7:1, RT, 24 h, 76%; c) 2,4,6-Cl3C6H2C(O)Cl, Et3N,
THF, 08C, 15 min, then diluted with toluene and added to a solution
of DMAPin toluene, RT, 1 h, 71%; d) HF·pyridine, THF, RT, 6 h, 94%;
e) Oxone, ketone 19 (0.8 equiv), Bu4N(HSO4) (cat.), K2CO3, MeCN/
DME/0.05m Na2B4O7 ꢀ10H2O in 4ꢀ10ꢀ4 m Na2EDTA 1:1:1.3, 08C, 3 h,
65% (86% based on recovered starting material; single isomer).
DME=dimethoxyethane.
For the epoxidation of 18 to give 4, the fructose-derived
epoxidation catalyst 19 was employed,[17] and pure 4 was
obtained in 65% yield after simple flash chromatography.
This outcome represents a major advance over the epoxida-
tion of trans-deoxyEpo A under similar conditions, which
proceeded less efficiently (similar selectivity, but lower
conversion); in addition, isolation of pure (12S,13S)-trans-
Epo A required purification by preparative HPLC and
provided the isolated target compound in only 13% yield.[12a]
Quite remarkably, compound 4 exhibits potent biological
activity in spite of major structural differences to the native
epothilone scaffold (Table 1). Thus, the tubulin-polymerizing
and antiproliferative activity of 4 is virtually identical to that
of Epo A and taxol. As for 2 and 3, the growth inhibitory
activity of 4 is slightly lower against the multidrug-resistant
KB-8511 cell line than against the taxol-sensitive KB-31 line.
However, given the high levels of P-gp expression by the KB-
8511 line, this small difference in cellular potency would seem
unlikely to be pharmacologically relevant in a clinical setting.
I n fact, this minor shortcoming might even be correctable
through the incorporation of other types of fused heteroar-
omatic side chains.[12b]
In summary, by employing an iterative approach for the
modification of a natural-product structural scaffold, we have
derived a new microtubule-stabilizing agent, which we con-
sider to represent a novel structural scaffold for microtubule
inhibition. As such, 4 and related compounds may offer the
same potential for pharmacological differentiation from the
original epothilone leads as various newly discovered natural-
product microtubule inhibitors with macrolactone structure,
such as laulimalide, peloruside, and dictyostatin.[4] This view is
supported by preliminary data from similarity analyses, which
indicate that 4 is as structurally dissimilar to Epo A or B as
laulimalide and peloruside are.[20] Future work will focus on
logue of Epo B.[12b] Moreover, we have repeatedly noted
reduced activity against multidrug-resistant cells for structur-
ally unrelated analogues, when they were more polar
(reduced clogP) than the corresponding parent epothilone.[15]
It is worth noting, however, that the activity of 3 against the
KB-31 line is comparable with that of Epo B. Likewise,
analogue 2 exhibits antiproliferative activity similar to that of
Epo A and taxol, indicating that the presence of the
dimethylbenzimidazole side chain can compensate for the
removal of the 3-hydroxy group also in the epothilone A
series. Similar conclusions can be derived from the data for
12/13-deoxy analogues 16 and 17, which are only two times
less potent antiproliferative agents than Epo C and D,
respectively (Table 1; data for Epo C not shown).[8]
While the structures of compounds 2 and 3 deviate from
those of Epo A and B, respectively, with regard to the core
macrocycle as well as the heterocycle-bearing side chain, they
are still characterized by a cis-configurated epoxide moiety at
positions 12/13, which is a major structural hallmark of the
natural products. However, we have previously shown that
(12S,13S)-trans Epo A (but not the corresponding (12R,13R)
isomer) is as potent as Epo A in terms of inducing tubulin
polymerization and inhibiting cancer cell growth.[12a,16] In light
of the potent biological activity of analogues 2 and 3, the
modification of (12S,13S)-trans-Epo A through removal of
the hydroxy group at C3 and concomitant replacement of the
natural side chain by a dimethylbenzimidazole moiety thus
emerged as a promising approach for the creation of hyper-
modified but still potent epothilone analogues. These struc-
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[15] M. Wartmann, K.-H. Altmann, A. Flörsheimer, unpublished
synthesis scale-up and the extensive biological profiling of 4
and related structures in vitro and in vivo, in order to establish
whether these compounds are in fact pharmacologically
distinct from Epo A and Epo B. At the same time we will
assess the effects of further structural modifications of 4 in the
C8–C11 region and at the 2-position of the benzimidazole
nucleus, which may or may not mirror the effects observed for
analogous modifications of Epo A and Epo B.
data.
[16] See also: a) K. C. Nicolaou, K. Namoto, A. Ritzen, T. Ulven, M.
Shoji, J. Li, G. DꢀAmico, D. Liotta, C. T. French, M. Wartmann,
K.-H. Altmann, P. Giannakakou, J. Am. Chem. Soc. 2001, 123,
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[17] Z.-X. Wang, Y. Tu, M. Frohn, J.-R. Zhang, Y. Shi, J. Am. Chem.
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[18] C. M. Lin, Y. Q. Jiang, A. G. Chaudhary, J. M. Rimoldi, D. G.
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Received: May 21, 2005
Published online: October 20, 2005
[19] a) T. Meyer, U. Regenass, D. Fabbro, E. Alteri, J. Rösel, M.
Mꢁller, G. Caravatti, A. Matter, Int. J. Cancer 1989, 43, 851 – 856;
b) K. C. Nicolaou, R. Scarpelli, B. Bollbuck, B. Werschkun,
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[20] Structural similarity was assessed on the basis of Tanimoto
coefficients (i.e., by a simple 2D fragment-based approach; see,
for example: X. Chen, C. H. Reynolds, J. Chem. Inf. Comput. Sci.
2002, 42, 1407 – 1014). Similarity analyses using other
approaches are currently underway, and the results of these
studies will be published elsewhere.
Keywords: antitumor agents · drug design · epothilones ·
microtubule stabilizers · natural products · total synthesis
.
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