Structural Optimization of Indole Derivatives Acting at Colchicine Binding Site as Potential Anticancer Agents

Article abstract of DOI:10.1021/acsmedchemlett.5b00208

A new series of indole analogues based on our earlier lead compound, 2-(1H-indol-5-yl)-4-(3,4,5-trimethoxyphenyl)-1H-imidazo[4,5-c]pyridine (42), was prepared as tubulin inhibitors in an effort to find a molecule with improved cytotoxic potency and metabo

Full text of DOI:10.1021/acsmedchemlett.5b00208

Letter
pubs.acs.org/acsmedchemlett
Structural Optimization of Indole Derivatives Acting at Colchicine
Binding Site as Potential Anticancer Agents
Dong-Jin Hwang,† Jin Wang,† Wei Li,* and Duane D. Miller*
Department of Pharmaceutical Sciences, University of Tennessee, Health Science Center, Memphis, Tennessee 38163, United States
S
* Supporting Information
ABSTRACT: A new series of indole analogues based on our earlier lead compound, 2-(1H-indol-5-yl)-4-(3,4,5-
trimethoxyphenyl)-1H-imidazo[4,5-c]pyridine (42), was prepared as tubulin inhibitors in an effort to find a molecule with
improved cytotoxic potency and metabolic stability. A series of indolyl-imidazopyridines (IIP) were synthesized and exhibited
potent tubulin polymerization inhibitory activity with potent IC50 values ranging from 3 to 175 nM against a panel of human
melanoma and prostate cancer cell lines. Among these compounds, the 6-indolyl compound 43 showed improved cytotoxic
potency (average IC50 of 9.75 nM vs 55.75 nM) and metabolic stability in human liver microsomes (half-life time was 56.3 min
vs. 45.4 min) as compared to previously reported 42. It was also shown to be effective against P-glycoprotein (P-gp) mediated
multiple drug resistance (MDR) and taxol resistance.
KEYWORDS: Colchicine-binding site, tubulin polymerization inhibitor, prostate cancer, melanoma, antiproliferative activity,
structure−activity relationship (SAR), multiple drug resistance, liver microsomal stability
transporter mediated drug resistance while complying with
icrotubules are tubular polymers of tubulin that have
Mbeen crucial chemotherapeutic targets in a variety of Lipinski’s Rule of Five.6 Recently, colchicine scaffolds in in vitro
cancers.1 Interfering with tubulin dynamics in tumor cells is a
studies showed strong cancer inhibition and also overcame
resistant phenotypes of carcinoma.7,8 A number of potent
validated approach in developing antimitotic drugs to treat
cancers.2 Using potent cytotoxic drugs that inhibit microtubules
tubulin inhibitors targeting the colchicine binding site have
been reported, including combretastatin A-4 (CA-4),9
has been useful in inducing cancer cells to undergo apoptosis
BRP0L075,10 phenstatin,11 ARAP,12 and SD40013 as shown
in Figure S1 of the Supporting Information. Following our
discovery of (3-(1H-indol-2-yl)phenyl)(1H-indol-2-yl)-
methanone14 as an antitubulin agent, our group showed several
diaryl-ketone chemotypes as tubulin inhibitors that bind to the
colchicine domain, including phenyl ring as linker (I-387),15
phenylaminothiazoles (PAT),4 arylbenzoylimidazoles (ABI),16
reverse ABIs (RABI),17 and 4-substituted methoxybenozyl aryl
thiazoles (SMART).18 Unsubstituted examples of these chemo-
types are shown in Figure S1. Among them, the SMART, ABI,
and PAT analogues have shown very strong in vivo efficacy in
human melanoma and prostate cancer xenograft models.18
through various mechanisms.3 Most of the small molecule
antitubulin agents bind to one of the three best characterized
binding sites on α,β-tubulin subunits. For example, the taxane,
vinca alkaloids, and colchicine binding sites bind to paclitaxel,
vinblastine, or colchicine, respectively. Antitubulin agents are
also classified according to whether they prevent microtubule
degradation (e.g., taxanes, epothilones) or induce microtubule-
destabilization (e.g., vinca alkaloids, colchicine).4
While a number of tubulin inhibitors binding to the taxane or
vinca alkaloid sites exhibit high potency and have been
approved by the FDA for the treatment of various cancers,
the emergence of resistant phenotypes still leads to diminished
efficacy in tumors expressing drug efflux transporters.1,5
Compared to the taxane or vinca alkaloid binding sites,
targeting the colchicine binding site may provide a better
opportunity for structural optimization to overcome such ABC-
Received: May 22, 2015
Accepted: August 6, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.5b00208
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Figure 1. Hybrid indolyl-imidazopyridine general structure 4 (IIP) derived from a combination of isoquinoline (2) and imidazo-benzene (3)
templates.
However, the ketone represented a metabolically labile site in
human liver microsomes (HLM) studies and thus new
approaches were sought to improve antimitotic effects and
reduce untoward effects.19 In an effort to improve potency and
metabolic stability, we explored general structure 4. As shown
in Figure 1, 4 was designed as a fusion of metabolically stable
nonketone templates 215 and 3.19 The building-blocks for
analogues of 4 are indoles and pyrido-imidazoles connected
with (3,4,5-trimethoxyphenyl)-(TMP-) template. The imida-
zole ring is a widely used template in many drugs.20 Also the
indole group has been investigated in many antitubulin
agents,21 such as 3-formyl-2-phenylindoles, heterocombretasta-
tins, diarylindoles, 2-aroylindoles, D-24851, 2-aryl-3-aroylin-
doles, 3-aroyl- and 1-aroylindoles, and arylthioindoles.21 We
herein report the evaluation of two classes of nonketone
antitubulin agents that contain indole and imidazole moieties.
Isoquinolines (class I) and imidazopyridines (class II), as
shown in Schemes 1 and 2, are bioisosteric chemotypes
explored herein as new classes of tubulin inhibitors binding to
the colchicine site.
Scheme 2. Synthesis of Class II (2,4-Disubstituted 1H-
Imidazo[4,5-c]pyridines) Antitubulin Agents
a
a
Reagents and conditions: (a) n-BuLi, DMF, −78 °C; (b) PhSO2Cl,
KOH, TBAHS, DCM, 16 h, room temperature; (c) p-toluenesulfonic
acid, 1,4-dioxane, reflux; (d) 8, Pd(PPh3)4, aqueous Na2CO3, THF/
MeOH/H2O, 100 °C, MW; (e) aqueous NaOH, EtOH, reflux.
The structure−activity relationship (SAR) was optimized
with regard to site of indole attachment to the core motif in an
effort to develop new therapeutic candidates for future in vivo
studies. 6-Indolyl (43) demonstrated high potency and
metabolic stability in vitro. In class I of Scheme 1, five
isoquinolines analogues (2, 10−13) with TMP-, 5-indolyl-, or
4-fluorophenyl-groups in A- and/or C-rings were prepared and
tested for their cytotoxicity against prostate cancer and human
melanoma cell lines,22 and their metabolic stability is discussed.
The majority of the isoquinolines derivatives and intermediates
were prepared by Suzuki-cross coupling of commercially
available aryl halides (5, 9) with boric acids (6−8) using
Pd(PPh3)4 as a catalyst. Compounds 7 and 8 were synthesized
using 2 equiv of boric acid (7 and 8, respectively).
Scheme 1. Synthesis of Class I (1,7-Disubstituted
Isoquinolines) Antitubulin Agents
a
Scheme 2 shows the synthesis of class II agents, indole-based
2,4-disubstituted 1H-imidazo[4,5-c]pyridines 39−44. Each of
the six substitutable positions of the indolyl moiety was
synthesized using different indolylaldehydes 14−19 as shown in
Scheme 2. The protected aldehydes (20−25) were prepared by
known procedures.23 Condensation of the N-protected
a
Reagents and conditions: (a) 1 equiv of each boric acid 6−8,
Pd(PPh3)4, K2CO3, DMF, H2O, reflux; (b) 2 equiv of boric acid 7 or
8, Pd(PPh3)4, K2CO3, DMF, H2O, reflux.
B
DOI: 10.1021/acsmedchemlett.5b00208
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Table 1. Antiproliferative Activities of Isoquinoline Analogues (Class I) and 1H-Imidazo[4,5-c]pyridine Analogues (Class II) in
Parental and MDR (LLC6R1) or Paclitaxel Resistant (TxR) Cancer Cell Lines
a
b
ND: Not determined. 2-(1H-Indol-7-yl)-4-(3,4,5-trimethoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine, which is dihydro-imidazole on B-
ring.
indolylaldehydes (2023 and 21−2524) with pyridodiamine 26
was accomplished using TsOH in 1,4-dioxane, or catalytic
amount of c-H2SO4 in toluene/DMF solution using a Dean−
Stark trap, to give the desired imidazopyridines 27−32. The
Suzuki cross-coupling reaction was performed between this
series of protected bromides 27−32 and 3,4,5-trimethoxyphe-
nylboric acid (8) to obtain compounds 33−38.
internal strain as compared to the relatively bulky TMP C-ring
of 2. Perhaps rotation of bond connecting the C- and D-rings in
class I compounds is not tolerated within the colchicine binding
pocket.
N-Protected class II compounds with TMP as the C-ring (35
or 38) showed moderate activity (average ∼400 nM), but
compound 29, which had a bromide substituent instead of the
C-ring, was inactive (>30 μM). This indicated again that TMP
on the C-ring position was critical for antiproliferative activity.
Generally, all the tested compounds with A-ring indole
substituents (39−44) showed strong antiproliferative activity
against melanoma and prostate cancer cell lines, including taxol
resistant PC-3/TxR and DU145/TxR cells, and overcame the
P-gp mediated MDR in M14/LCC6R1 cells. In this series, 2-
indolyl 39 was less cytotoxic with IC50 values at around a few
hundred nanomolar. 3- and 7-Indolyl compounds 40 and 44
presented comparable potency (average IC50 values in the low
nanomolar range) to the previously reported 5-indolyl
compound 42 (average 55.75 nM). The dihydro-imidazole
44a, which was made as a side product, showed 10−20-fold
lower potency in melanoma and prostate cell lines than
imidazole analogue 44, indicating that the imidazole ring is an
important moiety for inducing apoptosis. This suggests that the
planar central ring of 44 is more complementary to the
colchicine binding site, which apparently does not tolerate the
nonplanar arrangement of the A- and C-rings caused by the
dihydro-imidazole of 44a. The most active A-ring indolyl
compounds were the 4- and 6-indolyl 41 and 43, which
demonstrated IC50 values as low as 3 nM in human melanoma
A375 cells. Mechanistic and molecular modeling studies
suggested that selected compounds 41, 42, and 43 maintained
their mode of action as tubulin polymerization inhibitors as
shown in Figure S2 of the Supporting Information. To
The deprotection of the phenysulfonyl group (SO2Ph) was
performed using aqueous NaOH to generate the desired IIP
products 39−44. Interestingly, we also found and purified 2-
(1H-indol-7-yl)-4-(3,4,5-trimethoxyphenyl)-2,3-dihydro-1H-
imidazo[4,5-c]pyridine (44a) when modifying the conditions
by heating ethanol to reflux in conditions c (Scheme 2), rather
than using 1,4-dioxane. Compound 44a could only be
separated at the final step and was tested in our assay system
in order to compare it to compound 44. The in vitro cytotoxic/
antiproliferative activity of the synthesized class I and II
compounds against a panel of human melanoma and prostate
cancer cell lines was characterized using the MTS assay (Tables
1). Compounds in class II were further tested in P-gp
overexpressing multidrug resistant (MDR) and taxol resistant
cancer cell lines. The results for class I showed that compounds
with 5-indolyl A-rings (2, 12, and 13, 26−929 nM) had higher
growth inhibition potency than compounds with TMP or 4-
fluorophenyl A-rings (10 and 11, 10 to >30 μM ranges).
Compound 13 was the most potent class I compound bearing a
5-indolyl A-ring with a 4-fluorophenyl C-ring. Compound 13
had potent activity against prostate cell lines in the range of 26
to 47 nM, which was better than that observed with the TMP
analogue 2. Class I, with the six-membered B-ring, has
increased intramolecular repulsion more than class II. This
may be due to the increased steric overlap between the A- and
C-rings. Therefore, 4-fluorophenyl of 13 (class I) may have less
C
DOI: 10.1021/acsmedchemlett.5b00208
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Figure 2. (A) Compounds 41 and 43 effectively inhibited the tubulin polymerization in vitro. The microtubule polymerization was monitored by
measuring the absorbance at 340 nm in the absence or presence of drugs (N = 3). A representative experiment is shown. Vehicle control (sky blue);
paclitaxel (5 μM) (black); colchicine (5 μM) (brown); 41 (5 μM) (blue), 41 (10 μM) (red); 43 (5 μM) (green), 43 (10 μM) (purple). (B)
Compounds 41 and 43 arrested human melanoma A375 and human prostate cancer PC-3 cells in G2/M phase in vitro (N = 3).
experimentally determine whether the new analogues maintain
their mode of action, we tested the two most potent
compounds, 41 and 43, in a microtubule polymerization
assay in vitro (at 5 or 10 μM). Vehicle, taxol (5 μM), and
colchicine (5 μM) were used as control groups and assayed
under the same conditions (Figure 2A). Both 41 and 43
effectively inhibited the tubulin polymerization in a dose-
dependent manner. Compound 43 at lower concentration (5
μM) was a more effective inhibitor than 41 at 10 μM. Human
melanoma A375 cells and human prostate cancer PC-3 cells
were treated with 41 or 43 for 24 h and analyzed through flow
cytometry to determine their cell cycle distributions. As shown
in the Figure 2B, while the general distributions of A375 cells
were not significantly affected by either 41 or 43 at a low
concentration of 10 nM, at a higher concentration of 50 nM, 41
and 43 effectively blocked A375 cells at the G2/M phase. The
(IIP compounds) 41, 42, and 43 showed favorable metabolic
stability in both HLM and MLM. Among them, 43 having an
A-ring 6-indolyl substituent and showing the highest anticancer
potency, also exhibited the best stability (t1/2 = 56.3 min in
HLM and 27.7 min in MLM). This suggests that the
adjustment from 5-indolyl 42 to 6-indolyl 43 has improved
both antitumor efficacy and metabolic stability.
In summary, our previous discovery of the 5-indolyl 42
demonstrated that the indolyl-imidazo[4,5-c]pyridine class II
chemotype with TMP B-ring could potently bind the colchicine
site and additionally provide a metabolic stability benefit.
Herein we performed an “indole-walk” study to optimize the
best configuration for biological activity on the 4-(3,4,5-
trimethoxyphenyl)-1H-imidazo[4,5-c]pyridin-2-yl (IIP tem-
plate). All six new indolyl derivatives were investigated for
their in vitro cytotoxicities in cancer cell lines and stability to
metabolism in liver microsomes. We also tested isoquinoline
motifs (class I) to compare the structure−activity relationships
of cytotoxicity and metabolic stability across nonketone classes
I and II. The results showed the pyridine D-ring motif of IIP
provided some benefits toward metabolic stability in HLM.
Additionally, cytoxicity studies demonstrated compounds of
general structure 4 (i.e., class II or IIP compounds) were very
potent against the tested tumor cell lines. Among them, 6-
indolyl derivative (6-IIP, 43) showed the strongest inhibition
activities (IC50 at 3 nM on A375 and 8 nM on PC-3) and best
metabolic stability (56.3 min in HLM). We will evaluate the in
vivo efficacy of the IIP series, which will be further characterized
as potent novel anticancer agents. The IIP series can serve not
only as a valuable tool for preclinical research of the modulation
of tubulin polymerization dynamics but also as a promising
candidate series for clinical development.
vehicle control group only had 4.0
0.5% of A375 cells
distributed in G2/M phase, but 42.0 3.8% or 65.9 2.2% of
A375 cells were arrested in G2/M phase for 41 or 43 at 50 nM,
respectively. In PC-3 cells, even at the low concentration of 10
nM, 41 or 43 efficiently arrested cells in G2/M phases as
shown in Figure S3 of the Supporting Information. This dose-
dependent G2/M phase block for 41 and 43 confirms the
cytotoxic mechanism of action was conserved. The most potent
compounds of each class were selected to be further evaluated
for in vitro metabolic stability in human liver microsomes
(HLM) and mouse liver microsomes (MLM). As shown in
Table 2, Class I B-ring isoquinoline compounds (2 and 13)
showed significantly better metabolic stability in HLM (t1/2
=
38.9 and 30.7 min), than was observed in MLM (t1/2 = 2.1 and
2.0 min). The replacement of TMP (for 2) with 4-fluorophenyl
group on C-ring (for 13) increased the antiproliferative
potency but decreased the metabolic stability slightly. Class II
ASSOCIATED CONTENT
■
Table 2. Half-Lives in Human (HLM) and Mouse (MLM)
Liver Microsomes
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.5b00208.
t1/2 (min)
compd ID
class I
HLM
MLM
Synthetic procedures, the structures of known colchicine
inhibitors (Figure S1), molecular modeling (Figure S2),
quantification data for cell cycle analysis (Figure S3), and
the analytical spectra for 41, 42, and 43 and their
derivatives (Figure S4) (PDF)
2
38.9 3.4
30.7 2.6
33.1 4.8
45.4 3.0
56.3 2.3
2.1 1.1
2.0 0.8
10.5 1.8
16.1 4.4
27.7 6.1
13
41
42
43
class II
D
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ACS Medicinal Chemistry Letters
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AUTHOR INFORMATION
Corresponding Authors
*E-mail: dmiller@uthsc.edu. Tel: +1-901-448-6026.
*E-mail: wli@uthsc.edu. Tel: +1-901-448-7532.
■
(12) La Regina, G.; Bai, R.; Coluccia, A.; Famiglini, V.; Pelliccia, S.;
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Rensen, W. M.; Miele, A.; Nalli, M.; Alfonsi, R.; Di Marcotullio, L.;
Gulino, A.; Brancale, A.; Novellino, E.; Dondio, G.; Vultaggio, S.;
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Miller, D. D.; Dalton, J. T. A novel bis-indole destabilizes microtubules
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Author Contributions
†These authors contributed equally to this work. All authors
have given approval to the final version of the manuscript.
Funding
This research was supported by the Van Vleet Endowed
Professorship (to D.D.M.), NIH grants R01CA148706,
1S10OD010678-01, and RR-026377-01 (to W.L.), and
UTHSC Fellowship, Alma & Hal Reagan (to J.W.).
Notes
This content is solely the responsibility of the authors and does
not necessarily represent the official views of the National
Institutes of Health.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Dr. Michael L. Mohler at GTx, Inc., for his
proofreading and editorial assistance.
■
(17) Xiao, M.; Ahn, S.; Wang, J.; Chen, J.; Miller, D. D.; Dalton, J. T.;
Li, W. Discovery of 4-Aryl-2-benzoyl-imidazoles as tubulin polymer-
ization inhibitor with potent antiproliferative properties. J. Med. Chem.
2013, 56, 3318.
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