Dimeric and trimeric derivatives of the azinomycin B chromophore show enhanced DNA binding

Article abstract of DOI:10.1039/c7ob00944e

To explore the utility of the azinomycin B chromophore as a platform for the development of major-groove binding small molecules, we have prepared a series of 3-methoxy-5-methylnaphthalene derivatives containing diamine, triamine, and carbohydrate linker moieties. All bis- and tris-azinomycin derivatives are intercalators that display submicromolar binding affinities for calf-thymus DNA, as revealed by viscometry measurements and fluorescent intercalator displacement (FID) assays, respectively. Although the tightest binding ligand 1d (K_a = 2.42 × 10⁷ M^-1) has similar affinities for sequence diverse polynucleotides, competition binding studies with methylated phage DNA and known major and minor groove binding small molecules suggest that the tether moiety linking the naphthalene chromophores may occupy the major groove of DNA.

Full text of DOI:10.1039/c7ob00944e

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DOI:
Dimeric and trimeric derivatives of the azinomycin B
chromophore show enhanced DNA binding
10.1039/x0xx00000x
Milena Balazy, Alejandra Fausto, Christina Voskanian, Bianca Chavez, Harmanpreet Panesar,
and Thomas G. Minehan*
Received 00th ,
Accepted 00th
DOI: 10.1039/x0xx00000x
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naphthoate and naphthamide analogues of the azinomycin
chromophore again provided evidence supporting an
intercalative mode of binding.3c Given the synthetic
accessibility of simple napthalene derivatives,4 we envisioned
that the azinomycin chromophore would be an ideal template
for the development of sequence-specific major-groove binding
small molecules. As a first step toward this goal, we have
To explore the utility of the azinomycin B chromophore as a
platform for the development of major-groove binding small
molecules, we have prepared a series of 3-methoxy-5-
methylnaphthalene derivatives containing diamine, triamine,
and carbohydrate linker moieties. All bis- and tris-
azinomycin derivatives are intercalators that display
submicromolar binding affinities for calf-thymus DNA, as
revealed by viscometry measurements and fluorescent
intercalator displacement (FID) assays, respectively.
Although the tightest binding ligand 1d (Ka=2.42 x 107 M-1)
has similar affinities for sequence diverse polynucleotides,
competition binding studies with methylated phage DNA and
known major and minor groove binding small molecules
suggest that the tether moiety linking the naphthalene
chromophores may occupy the major groove of DNA.
prepared
a
series of 3-methoxy-5-methyl naphthalene
derivatives and evaluated their affinity for duplex DNA by
ultraviolet and fluorescence spectroscopies.
OH
O
O
O
H
N
MeO
O
O
N
H
O
AcO
N
H3C
H
HO
Azinomycin B
CH3
There are relatively few naturally occurring compounds that
associate with the major groove of DNA. The vast majority of
nucleic acid-binding natural products prefer to occupy the
narrower minor groove, where hydrophobic and van der Waals
interactions with the walls and floor of the groove are
maximized.1 The notable exceptions to this trend are the
pluramycins, aflatoxins, azinomycin, leinamycin, and
neocarzinostatin i-gb.2 Intercalation of a planar delocalized-π
system into the backbone of DNA is a consistent binding mode
among all of these natural products, and with the exception of
the aflatoxins, all of these substances also possess polar major-
groove binding moieties. After a detailed study of the DNA
binding interaction of azinomycin B, Gates suggested that the
3-methoxy-5-methyl naphthalene chromophore is a uniquely
effective small, uncharged intercalator that accurately positions
appended groups in the major groove of DNA.3a Coleman’s
subsequent studies on non-covalently binding Azinomycin
derivatives indicated that intercalation did not occur for these
compounds.3b However, Searcy’s later investigation of similar
MeO
N
N
H
H
MeO
N
N
H
OMe
3
n
H3
C
3
5
1a-c n=1,2,3
1d
H3
C
CH3
H
N
MeO
O
MeO
N
H
NH
OMe
H
N
HO
OH
CH3
OH
3b
H3C
H3C
2a
Figure 1. Designed ligands bearing the azinomycin chromophore.
DNA binding ligands possessing positively charged
residues have a high affinity for duplex nucleic acids due to
electrostatically favourable interactions with the negatively
charged phosphate backbone and electronegative atoms in the
major and minor grooves.5 Thus the primary series of
naphthalene derivatives (Figure 1, compounds 1 - 3) targeted
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J. Name., 2012, 00, 1-3 | 1

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for synthesis contain basic nitrogen atoms in the tethers linking
Compound 3b was derived from C-allyl pyranoside 6,
the chromophores. Furthermore, dimerization of intercalating which was prepared in turn according to the protocol of
moeities has been shown to result in high-affinity DNA-binding Trauner12 by TMSOTf-promoted ring opening of 1,6-anhydro-
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ligands such as ditercalinium6 and naphthalene diimides.7 It
was envisioned that ligands 1a-1d, containing 2-, 3-, 4- and 5-
atom tethers between the azinomycin chromophore units, would
allow us to explore optimal distances between the aromatic
moieties to achieve bis-intercalation.
2,3,4-tri-O-benzyl-β-D-glucose in theDOpI:r1e0s.1e0n3c9e/C7OoBf00a9l4l4yEl
trimethylsilane. Oxidative cleavage (cat. OsO4, NMO,
acetone/H2O; KIO4, dioxane/H2O) of the olefin and reduction
(NaBH4, MeOH, 2h, rt) provided an intermediate diol that was
then treated with excess TsCl (Et3N, DMAP, CH2Cl2, 2h, rt).
The crude bis-tosylate was immediately combined with NaN3
(6 equiv) in DMF (50 °C, 48 h) to provide bisazide 8 in 60%
overall yield from 6. Stirring 8, PPh3 (2 equiv) and
napthaldehyde 5 (2 equiv) in benzene (1M, 80 °C, 2h),
followed immediately by evaporation, dissolving in methanol,
and treatment with NaBH4 (4 equiv, 2h, rt) provided the
intermediate bisamine 9 in 87% yield from 8. Boc protection (3
equiv Boc2O, Et3N, DMAP, rt, 12 h) of the secondary amines,
followed by catalytic hydrogenation (H2, cat Pd(OH)2, EtOH,
rt, 12 h) and acidification (1:1 TFA/CH2Cl2, 30 min, rt) then
gave rise to ligand 3b in 52% yield from 9.
Waring8 and McGee9 have previously demonstrated that the
presence of
a carbohydrate moiety on an intercalating
chromophore contributes positively and significantly to the
binding association with DNA. It is also likely that
carbohydrate moieties directed into the major groove would be
able to participate in non-covalent interactions with functional
groups on the edges of the AT and GC base pairs.10 Ligand 3b
was therefore designed as an initial candidate for assessing
high-affinity binding in the major groove of DNA.
Ethyl 3-methoxy-5-methylnaphthalene-1-carboxylate, read-
ily available from 1-(2-methylphenyl)-2-propanone by
Shibuya’s protocol,11 was our starting material for the synthesis
of azinomycin chromophore derivatives. LiAlH4 reduction of
the ester gave the corresponding alcohol, which was oxidized
with PCC to give the corresponding aldehyde 5 in 91% overall
yield. Compounds 1a-1c were prepared in 62-86% yields by
O
O
O
SiMe3
HO
BnO
OBn
BnO
OBn
CH3CN, TMSOTf
66%
OBn
OBn
combining
2 equivalents of naphthaldehye 5 with one
6
equivalent of ethylene diamine, propylene diamine, or butylene
diamine, respectively, in CH2Cl2 (Et3N, MgSO4, rt, 12h)
followed by addition of CH3OH and NaBH4 (5 equiv) and
stirring for 2 hours. Similarly, compound 1d was prepared in
52% yield by combining 3 equivalents of naphthaldehyde 5
with one equivalent of tris(2-aminoethyl)amine in methanol (rt,
18 h), followed by addition of NaBH4 (6 equiv) and stirring at
rt for 2 hours. Combining instead N-Boc-N-methylenediamine
with one equivalent of 5 in methanol (rt, 18 h), followed by
addition of NaBH4 (6 equiv, rt, 2 h) gave an intermediate
carbamate, which was then treated with 1:1 TFA:DCM for 30
minutes and concentrated in vacuo to afford 2a in 68% yield
after purification.
1. OsO4, NMO
2. KIO4, dioxane/H2O
O
N3
N3
6
3. NaBH4, MeOH
4. TsCl, Et3N, DMAP
NaN3, DMF, 50 °C
60%
BnO
OBn
OBn
8
1. 2 eq 6, 2 eq PPh3, benzene
80 °C, 2 h
2. NaBH4, MeOH
O
N3
N3
BnO
OBn
CH3
OBn
8
H
N
MeO
O
MeO
CHO
MeO
CO2Et
N
H
OMe
1. LiAlH4, THF
RO
OR
2. PCC, KOAc,
CH2Cl2
OR
H3C
H3C
H3C
5 91%
1. Boc2O, THF, DMAP
2. H2, Pd(OH)2
3. TFA, DCM, 30 min
9 R=Bn 87%
3b R=H 52%
MeO
CHO
1. Et3N, MgSO4,
DCM;
Scheme 2. Synthesis of ligand 3a.
1a n=1, 62%
1b n=2, 86%
1c n=3, 70%
NH2
H2N
n
2. NaBH4, MeOH
Table 1. Estimation of CT-DNA association constants and stoichiometry for
ligands 1a-d, 2a and 3b by ethidium displacement assays.
H3C
5 (2 equiv)
Ligand
1a
1b
1c
1d
Kapp (x106 M-1)a
7.19±0.92
3.15±0.60
5.00±0.46
24.2±1.5
b
rbd
4.2
6.2
7.0
MeO
CHO
1. MeOH, rt, 12 h;
2. NaBH4, MeOH
N
1d 52%
2a 68%
+
H2N
9.1
3
2a
3b
0.47±0.03
6.47±0.65
4.0
10.0
H3C
5 (3 equiv)
Boc
N
1. MeOH, rt, 12 h;
[a]
K
values obtained by the competitive ethidium displacement method (10
[b]
app
mM Tris-EDTA, pH=5.48), where Kapp=Ke x Ce/C50 and Ke=2.1 x 106M-1.13
rbd (ratio of CT DNA (bp):ligand) values were determined from the
breakpoint of the curve in a plot of Δ fluorescence vs. CT DNA:ligand ratio,
with the data obtained from the competitive ethidium displacement method.14
+
5 (1 equiv)
2. NaBH4, MeOH
3. TFA, DCM, 30 min.
H2N
CH3
Scheme 1. Synthesis of ligands 1a-d and 2a.
2 | J. Name., 2012, 00, 1-3
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of our ligands, we investigated the displacement of ethidium
To compare the strengths of binding of compounds 1a-1d, bromide from CT DNA by 1d in the presence of either the
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2a, and 3b to calf thymus (CT) DNA, the competitive ethidium
minor groove binding agent netropsin (NP, 30 µM) or the major
groove binding agent methyl green (DMOGI: ,10.310039µ/CM7O).B10809T4h4Ee
addition of netropsin resulted in an increase in the C50 value
(concentration of 1d required to achieve a 50% decrease in the
fluorescence of ethidium) from 0.85 µM to 1.5 µM, corres-
ponding to a 1.7-fold drop in the binding affinity of 1d for CT
DNA (Figure 2). The addition of methyl green instead resulted
in a more pronounced increase in the C50 value from 0.85 µM
to 2.0 µM, corresponding to an approximately 2.4-fold drop in
the binding affinity of 1d for CT DNA. These data suggest that
the tethering moiety of 1d may occupy either the major or
minor grooves of DNA. Subsequent experiments (see below)
provided additional evidence supporting major groove
occupancy by 1d.
displacement technique was employed to obtain apparent
13
association constants (Kapp
)
and binding ratios (rbd).14 From
this analysis (Table 1) the tightest binding synthetic ligand was
the trisazinomycin derivative 1d (Kapp=2.42±1.5 x 107 M-1),
which has an apparent association constant more than 50-fold
greater than that obtained for monoazinomycin derivative 2a
(Kapp=4.7±0.3 x 105 M-1). In addition, the bisazinomycin
derivative 1a (Kapp=7.2±0.9 x 106 M-1) has a 15-fold higher
binding constant for CT DNA than 2a, and since both ligands
have two positively charged protonated nitrogen atoms at
pH=5.48 and bind approximate the same number of base pairs
(rbd=~4.0), these results are suggestive of a bis-interacalative
mechanism of association for the bis- and trisazino derivatives
with DNA (vide infra). Interestingly, ligand 3b (Kapp=6.5±0.7 x
106 M-1) showed no significantly enhanced binding relative to
1a-1c, perhaps indicating that any stabilization due hydrogen-
bond interactions between the glucosyl moiety linking the
azinomycin chromophores and the DNA bases is offset either
by steric crowding or entropic restriction of bond rotation in the
intercalated complex.
The binding of 1d to different DNA polynucleotides was also
explored using the ethidium displacement assay (Table 2). The
Kapp values for the association of 1d with polydG•polydC,
polydA•polydT, and poly (dA•dT)2 were in the range of 18 – 20
x 106 M-1, indicating similar affinities for these binding sites.
The higher value obtained for calf thymus DNA, however,
likely indicates that 1d prefers to bind heterogeneous sequences
of natural B-form DNA. Since lambda phage DNA20 is
methylated in the major groove (N6-methyl adenine, C5-methyl
cytosine), the three-fold lower binding constant observed for
the association of 1d with phage DNA vs. calf thymus DNA
suggests that the aliphatic tethering moiety may occupy the
major groove of DNA. In contrast, it was found that the minor
groove binder netropsin binds to lambda phage DNA with a
slightly higher apparent affinity than to calf thymus DNA
(3.79±0.26 x 105 M-1 and 2.11±0.79 x 105 M-1, respectively; see
ESI).
To investigate the importance of electrostatic interactions5
in the binding of the azinomycin chromophore derivatives to
DNA, we evaluated the association of both 1a and 1d with CT
DNA under high- and low-salt conditions using the ethidium
displacement assay (See ESI). Increasing NaCl concentrations
in the buffer (10 µM CT DNA in 10 mM Tris-EDTA, pH=5.48
)
from 0.01-1.0 M results in an approximately four-fold drop in
1d’s DNA binding affinity; a similar lowering of DNA affinity
was observed for 1a between the concentrations of 0 mM and
100 mM NaCl. These data suggest that the positively charged
protonated nitrogen atoms may be involved both in polar
hydrogen bonding interactions in the grooves of DNA and in
ionic interactions with the phosphate backbone.
Table 2. Evaluation of the binding of 1d to different DNA
polynucleotides by ethidium displacement assay
.
Titration of CTDNA•ethidium with 1d
-9
-8
-7
-6
-5
-4
DNA
polydG•polydC
Calf thymus
Kapp (x106 M-1)
18.4±0.6
1.2
1
1.2
1
24.2±1.5
poly(dA•dT)2
polydA•polydT
Lambda phage
17.7±1.5
20.0±2.5
8.02±0.7
0.8
0.6
0.4
0.2
0
0.8
0.6
0.4
0.2
0
1.75
1.5
1.25
1
no competitor, C(50)=0.85 μM
30 μM NP, C(50)= 1.5 μM
30 μM MG, C(50)= 2.0 μM
-0.2
-0.2
-9
-8
-7
-6
-5
-4
0.75
0.5
0.25
0
log([1d])
Figure 2. Binding isotherms for the titration of CT DNA (10 µM) and
ethidium (10 µM) with 1d (10 mM Tris-EDTA, pH=5.48) in the
absence of competitor (black circles) or in the presence of netropsin
(red squares) or methyl green (green diamonds). Black circles: no
competitor, Ka = 2.47 ± 1.5 x 107 M-1; red squares: 30 µM netropsin,
Ka=1.40 ± 1.2 x 107 M-1; green diamonds: 30 µM methyl green,
Ka=1.05 ± 0.9 x 107 M-1.
200
300
400
Figure 3. UV spectra of 1d (25.0 µM in 10 mM Tris-EDTA, pH=5.48)
in the presence of varying concentrations of CT-DNA: 0, 0.25, 0.5, 1.0,
2.0, 4.0, 5.0, 10.0, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 100 µM
.
To evaluate the groove occupancy of the aliphatic tethering
moiety connecting the intercalating naphthalene chromophores
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Monitoring the UV absorbance of 1d at 228 nm upon titration
with CT-DNA revealed a distinct hypochromic shift along with
a slight redshift to 236 nm, observations again suggestive of an
intercalative mode of binding (Figure 3).15, 16 To confirm this,
we performed viscometry studies for all synthetic ligands.17
Increasing concentrations of 1d (Figure 4) in the presence of
CT-DNA resulted in an increase in solution viscosity
comparable to that obtained with reference compound ethidium
bromide, indicative of the helix lengthening and rigidification
that occurs upon ligand intercalation. Similar results were
obtained for ligands 1a-1c, 2a, and 3b (see ESI). By
comparison, the non-intercalative minor groove binder
netropsin showed a relatively minimal increase in solution
viscosity under the same conditions.
0.00 µM 1d + 80 µM CTDNA
0.15 µM 1d + 80 µM CTDNA
0.30 µM 1d + 80 µM CTDNA
!
View Article Online
DOI: 10.1039/C7OB00944E
0.45 µM 1d + 80 µM CTDNA
1.10 µM 1d + 80 µM CTDNA
2.00 µM 1d + 80 µM CTDNA
!
)
g
e
( m d
C D
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
3
2.5
2
3
!
Wavelength (nm)
2.5
2
Figure 5. The 220-310 nm region of the CD spectrum of solutions of CT
DNA (80 µM) in the absence (black line) and presence of various
concentrations of 1d: blue line, 0.15 µM 1d; light green line, 0.30 µM 1d;
orange line, 0.45 µM 1d; red line, 1.1 µM 1d; dark green line 2.00 µM 1d.
1.5
1
1.5
1
Conclusions
1d
We have prepared a series of dimeric (1a-1c, 3b) and trimeric (1d)
derivatives of the azinomycin chomophore that show sub-
micromolar binding affinities for duplex DNA. Viscometry data
indicate that each of these ligands intercalate the backbone of DNA.
Although the tightest binding derivative, 1d, was shown to have low
sequence selectivity, competitive binding studies with methyl green
and lambda phage DNA indicate that association of this ligand with
DNA may take place via the major groove. Since the CD and
viscometry data for the interaction of 1d with CT-DNA are very
similar to that for ethidium bromide,22 a bis-intercalation model for
the association of 1d with DNA is proposed, with the tethering
moiety occupying the major groove.
ethidium bromide
netropsin
0.5
0.5
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
1/R
Figure 4. Effect of increasing amounts of 1d (●), ethidium bromide ( )
and netropsin on the relative viscosity of CT-DNA. R=
[DNA(bp)]/[ligand]; 1d (●): [CT-DNA] = 300 µM, [1d]: 1, 2, 4, 10, 18,
and 26 µM; ethidium bromide ( ): [CT-DNA] = 300 µM, [ethidium
(♦)
bromide]= 4, 26, 70, 113, 160, and 200 µM; netropsin (
ꢀ): [CT-DNA]
= 300 µM, [netropsin]= 4, 26, 70, 113, 160, and 200 µM.
CD spectra of CT DNA recorded in the 220-310 nm region
in the presence of increasing concentrations of 1d revealed an
initial increase in the intensities of both the helicity band at 240
nm and base-stacking band at 280 nm at low 1d:DNA ratios,
followed by a decrease in both bands at higher ligand
concentrations (Figure 5). These observations, which mirror
data previously recorded for the titration of CT DNA with
ethidium bromide,21 are indicative of an intercalative mode of
DNA binding.
Molecular docking studies of ligand 1d23 with 5’-ATGCAT-3’
(PDB 1x95) were performed using Autodock vina.24 The energy-
minimized bis-intercalation complex shows the chromophore
tethering moiety occupying the major groove of DNA, with the
ligand amino groups engaging in hydrogen bonding contacts with
the edges of the sandwiched GC base pairs (Figure 6).
Figure 6. Model for bis-intercalation of ligand 1d in the major groove of
DNA sequence 5’-ATGCAT-3’, generated by Autodock Vina using DNA
(PDB 1x95) and 1d minimized by Spartan 14 for Macintosh.26
We are currently exploring the cell permeability and cytotoxicity of
these compounds (via MTT/MTS assays)25 and the results of these
studies will be reported in due course.
4 | J. Name., 2012, 00, 1-3
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12 D. Hager, C. Paulitz, J. Tiebes, P. Mayer, D. Trauner, J. Org.
Acknowledgements
Chem. 2013, 78, 10784.
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13 A. R. Morgan, J. S. Lee, D. E. Pulleyblank, N. L. Murray, D.
DOI: 10.1039/C7OB00944E
H. Evans, Nucleic Acids Res. 1979, 7, 547.
14 S. Kumar, L. Xue, D. P. Arya, J. Am. Chem. Soc. 2011, 133,
7361.
This paper is dedicated to Professor Yoshito Kishi on the occasion of
his 80th birthday. We thank the National Science Foundation (CHE-
1508070), the National Institutes of Health (SC3 GM 096899-01),
and the donors of the American Chemical Society Petroleum
Research fund (53693-URI) for their generous support of our
research program. BC thanks the NIH MARC program (GM008395
and AF thanks the NIH RISE program (GM063787) for support. We
would also like to thank Ryan Shaktah for the preparation of 5, Ligia
Zelaya for the binding data of 1d with CT DNA, and Joshua
Manlutac for establishing protocols for the DNA binding assays.
15 L. Perez-Flores, A. J. Ruiz-Chica, J. G. Delcros, F. Sanchez-
Jimenez, F. J, Ramirez, J. Mol. Struct. 2005, 744-747, 699.
16 Thermal denaturation studies of calf thymus (CT) DNA in the
presence and absence of 1d were complicated by overlap of
absorbances of drug and DNA in the 260-280 nm region of the
UV spectrum (Figure 2): W. D. Wilson, F. A. Tanious, M.
Fernandez-Saiz, C.T. Rigl, Methods in Mol. Biol. Drug-DNA
Interact. Protoc. 1997, 90, 219.
Department of Chemistry and Biochemistry, California State University,
Northridge, 18111 Nordhoff Street, Northridge, CA 91330, USA.
E-mail: thomas.minehan@csun.edu
17 P. C. Dedon In Curr. Protoc. Nucleic Acid. Chem. 2000, New
York: John Wiley and Sons, 8.1.1.
18 S. K. Kim, B. Norden, FEBS Letters 1993, 315, 61.
19 M. L. Kopka, D. S. Goodsell, G. W. Han, T. K. Chiu, J. W.
Lown, R. E. Dickerson Structure, 1997, 5, 1033.
20 From E. coli host strain W3110: A. M. Desimone and J. D.
Laney Mol. Cell. Biol. 2010, 30, 3342.
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/c000000x/
21 N. C. Garbett, P. A. Ragazzon, J. B. Chaires Nature Protocols,
2007, 2, 3166.
Notes and references
22 Waring, M. J. J. Mol. Biol.1962, 13, 269.
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2
3
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(a) H. Zang and K. S. Gates, Biochemistry 2000, 39, 14968. (b)
R. S. Coleman, R. J. Perez, C. H. Burk, A. Navarro, J. Am.
Chem. Soc. 2002, 124, 13008. (c) M. A. Casely-Hayford, K.
Pors, L. H. Patterson, C. Gerner, Neidle, S. M. Searcey.
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23 Minimized using Spartan 14 for Macintosh (Wavefunction,
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24 O. Trott, A. J. Olson J. Comput. Chem. 2010, 31, 455.
25 (a) T. Mossmann, J. Immunol. Methods, 1983, 65, 55; (b) A. H.
Cory, T. C. Owen, J. A. Barltrop and J. G. Cory, Cancer
Commun., 1991, 3, 207.
26 Additional binding modes for the association of 1d with 5’-
ATGCAT-3’ were apparent from the molecular docking studies,
and these included mono-intercalation from the major groove and
non-intercalative major groove binding (see ESI). Though the
DNA search space included both major and minor grooves, none
of the computed binding modes showed the ligand associating
with the minor groove of DNA.
4
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