Relationship between structure of conjugated oxime esters and their ability to cleave DNA

Article abstract of DOI:10.1021/bc400060h

The size and geometry of polycycles are critical to intercalation into DNA. This work involves the establishment of a new compound library that includes 35 O-benzoyl oxime esters with intercalators of five types. These conjugated compounds were synthesized by the condensation of substituted benzoyl chlorides (XC₆H₄COCl; X = H, Me, CN, F, and NO₂) or naphthoyl chlorides with oximes of fluoren-9-one, 9,10-anthraquinone, xanthen-9-one, thioxanthen-9-one, and 9H-thioxanthen-9-one 10,10-dioxide to give the corresponding esters in 80-99% yields. All of these compounds could cleave DNA when photolyzed by UV light. Of these conjugates, 9,10-anthraquinone-O-9-(4- fluorobenzoyl)oxime with a binding constant of 4.49 × 10⁴ M^-1 cleaved DNA most efficiently. Examination of the structure-activity relationship supports a conclusion that two factors affect DNA-cleaving potency. These are (1) the planarity of the intercalating moiety, and (2) the size and substituents of the benzoyl ring. The DNA-cleaving ability followed the order 9,10-anthraquinone > fluoren-9-one ≥ xanthen-9-one ～ thioxanthen-9-one > 9H-thioxanthen-9-one 10,10-dioxide. The benzoyl-containing oxime ester conjugates were more active than the corresponding naphthoyl-containing conjugates. The potency that was associated with the different substituents on the benzoyl ring followed the order F > CN ≥ NO₂ > Me ～ H.

Full text of DOI:10.1021/bc400060h

Communication
pubs.acs.org/bc
Relationship Between Structure of Conjugated Oxime Esters and
Their Ability to Cleave DNA
Jih Ru Hwu,*,†,‡ Shwu-Chen Tsay,‡,§ Shih Chin Hong,† Ming-Hua Hsu,† Chih-Fen Liu,§
and Shang-Shing P. Chou*,§
†Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan
‡Department of Chemistry, National Central University, Jhongli 32001, Taiwan
§Department of Chemistry, Fu Jen Catholic University, Taipei 24205, Taiwan
S
* Supporting Information
ABSTRACT: The size and geometry of polycycles are critical to intercalation
into DNA. This work involves the establishment of a new compound library
that includes 35 O-benzoyl oxime esters with intercalators of five types. These
conjugated compounds were synthesized by the condensation of substituted
benzoyl chlorides (XC6H4COCl; X = H, Me, CN, F, and NO2) or naphthoyl
chlorides with oximes of fluoren-9-one, 9,10-anthraquinone, xanthen-9-one,
thioxanthen-9-one, and 9H-thioxanthen-9-one 10,10-dioxide to give the
corresponding esters in 80−99% yields. All of these compounds could cleave
DNA when photolyzed by UV light. Of these conjugates, 9,10-anthraquinone-
O-9-(4-fluorobenzoyl)oxime with a binding constant of 4.49 × 104 M−1 cleaved
DNA most efficiently. Examination of the structure−activity relationship
supports a conclusion that two factors affect DNA-cleaving potency. These are
(1) the planarity of the intercalating moiety, and (2) the size and substituents
of the benzoyl ring. The DNA-cleaving ability followed the order 9,10-anthraquinone > fluoren-9-one ≥ xanthen-9-one ∼
thioxanthen-9-one > 9H-thioxanthen-9-one 10,10-dioxide. The benzoyl-containing oxime ester conjugates were more active than
the corresponding naphthoyl-containing conjugates. The potency that was associated with the different substituents on the
benzoyl ring followed the order F > CN ≥ NO2 > Me ∼ H.
benzoyloxy radicals can be formed through the homolytic
fission of an O-benzoyl oxime by photolysis.11−13 The weak N−
O bond14 in oxime esters causes conjugates in this class to have
high reactivity.
INTRODUCTION
■
Intercalating moieties are commonly incorporated into DNA-
cleaving agents to improve their activity.1 Schuster, Williams,
and co-workers2 used anthraquinone derivatives as intercalators
for DNA scission. Fluoren-9-one and thioxanthen-9-one also
serve as DNA intercalators, as indicated by Kearns and co-
workers.3 Cushman and co-workers4 found that the electro-
static attraction between intercalating indeno[1,2-c]-
isoquinolines and the base pairs of the “DNA−topoisomerase
I cleavage complex” plays a role in stabilization. More
importantly, some organic intercalators are valuable drugs, as
Some oxime esters have recently been reported to exhibit
DNA-cleaving ability in a process that is triggered by UV
light.15−17 These esters perform single-strand scission because
of the iminyl and carboxyl radical species. Meanwhile, an oxime
moiety is incorporated into aromatic nuclei as a chromophore
that absorbs UV light. We planned to study systematically the
intercalating capacity of the polycyclic moieties including
fluoren-9-one, 9,10-anthraquinone, xanthen-9-one, thioxanth-
en-9-one, and 9H-thioxanthen-9-one 10,10-dioxide when
conjugated with a benzoyl or a naphthoyl group. These
intercalators have similar ring sizes but different degrees of
planarity. Our goal is to understand the relationship between
their structure and their activity, as doing so will support the
design of new agents cleaving DNA efficiently.
reported by Brana et al.5 Such drugs have been used to treat
̃
ovarian cancer, breast cancer, and acute leukemias. In 2004,
Dervan and co-workers6 synthesized a polyamide−acridine
conjugate as a combination of a groove binder and an
intercalator for sequence-specific DNA bis-intercalation.
Arylhydrazones can nick DNA when UV light is used as a
trigger.7 In these photochemical reactions, iminyl and aminyl
radicals are generated to cleave DNA. Zard and co-workers8
described elegant methods for producing iminyl radicals by
reacting O-benzoyl oximes with tributylstannane and 2,2′-
azobisisobutyronitrile or with nickel powder and acetic acid.9
Intramolecular capture of such species can efficiently lead to the
formation of heterocycles and alkaloids.10 Iminyl and
This paper describes the synthesis of 35 oxime ester
conjugates that bore various intercalating moieties and aroyl
Received: January 31, 2013
Revised: August 6, 2013
Published: October 24, 2013
© 2013 American Chemical Society
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Scheme 1. Synthesis of Conjugated Oxime Esters 4 with Various Intercalating Moieties and Aroyl Groups
groups with different substituents. Their DNA-cleaving ability
was analyzed. It depended on the intercalating moiety on one
side of the conjugates, as well as the electronic and the steric
effects of the substituents on the other side. The relationship
between their structure and activity is revealedthe intercalat-
ing polycyclic moieties and the substituents in the benzoyl
nucleus are ordered in terms of their effect on DNA scission.
Their values of absorption maximum (λmax) and molar
absorptivity (ε) of UV spectra were summarized in Table 1.
DNA Cleavage by Conjugated Oxime Esters Upon UV
Irradiation. To a sodium phosphate buffer solution (Na2HPO4
and NaH2PO4; 0.10 M, pH = 6.0) that contained supercoiled
circular ϕX174 RFI DNA (form I, 50 μM/base pair) was added
an oxime ester (5−9) at a concentration of 500 μM. The
solution under aerobic conditions was irradiated with UV light
(312 nm, 16 W) at room temperature for 2.0 h. The results of
gel electrophoresis revealed that relaxed circular DNA (form II)
was generated in all of these experiments. The ratios of (form
II)/(form I) for 5−9 ranged from 0.37 to 44 (Table 2).
Moreover, our results shown in Figure 1 indicate that
anthraquinone oxime ester 6c also performed double strand
cleavage of DNA.
Measurements of the doses of conjugates 6c−e (0−50 μM)
presented in Figure 2 show that the cleavage of DNA depended
on their concentrations. These three oxime ester conjugates
that bore a 9,10-anthraquinone moiety nicked DNA with (form
II)/(form I) = 1.0 at concentrations even as low as 12, 26, and
2.5 μM, respectively. This figure illustrates a two-phase process
for DNA scission by oxime esters: a fast one at low oxime ester
concentration and a slower one at concentration above 2.5 μM.
RESULTS
■
Synthesis of Conjugated Oxime Esters. First, the
oximation of various ketones 1 with hydroxyamine hydro-
chloride in ethanol was carried out according to the methods
shown in Scheme 1. Second, the corresponding oximes 2 were
condensed with 1.3−1.5 equiv of benzoyl chlorides 3 to
generate the desired conjugated oxime esters 4. The
intercalating moieties in the final targets 4 came from the
starting materials 1, which were fluoren-9-one, 9,10-anthraqui-
none, xanthen-9-one, thioxanthen-9-one, and 9H-thioxanthen-
9-one 10,10-dioxide. At the para position of benzoyl chlorides
was a substituent of Me, CN, F, or NO2. As well as benzoyl
chlorides 3, 1- and 2-naphthoyl chlorides were used for the
oximation. Accordingly, conjugated compounds 5−9 with
purity >98.0% were generated in high yields (80−99%).
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Table 1. Values of Absorption Maximum (λmax) and Molar
Absorptivity (ε) of UV Spectra for Conjugated Oxime Esters
Table 2. Ratios of (Form II)/(Form I) in DNA Cleavage
Obtained by Use of Conjugated Oxime Esters 5−9 with
a,b
Various Intercalating Moieties and Aroyl Groups
compound
UV (CH2Cl2) λmax (ε)
intercalating moiety
5a
5b
5c
5d
5e
5f
304 (ε 9,600), 259 (ε 48,000), 251 (ε 35,000), 225 (ε 19,385)
304 (ε 13,543), 259 (ε 60,547), 250 (ε 47,109), 221 (ε 25,469)
310 (ε 11,097), 259 (ε 49,321), 250 (ε 42,037), 217 (ε 21,296)
310 (ε 14,159), 259 (ε 54,458), 250 (ε 42,320), 221 (ε 23,631)
304 (ε 17,104), 259 (ε 68,476), 219 (ε 27,429), 214 (ε 26,000)
314 (ε 12,595), 259 (ε 53,971), 251 (ε 43,197), 224 (ε 55,235)
314 (ε 12,782), 259 (ε 54,774), 251 (ε 43,840), 224 (ε 56,057)
310 (ε 7,315), 279 (ε 20,444), 252 (ε 29,259), 218 (ε 26,444)
310 (ε 9,131), 280 (ε 20,325), 252 (ε 29,351), 218 (ε 20,994)
310 (ε 19,243), 259 (ε 79,109), 250 (ε 67,426), 217 (ε 34,158)
310 (ε 10,351), 279 (ε 21,839), 253 (ε 33,124), 231 (ε 26,228)
310 (ε 12,759), 278 (ε 18,416), 253 (ε 28,614), 218 (ε 18,911)
321 (ε 12,161), 283 (ε 11,390), 221 (ε 51,358)
304 (ε 10,504), 282 (ε 15,228), 236 (ε 60,020)
340 (ε 12,240), 221 (ε 45,217)
9,10-
thioxanthen-9-
one 10,10-
dioxide
fluoren-
9-one
(cf. 5)
anthra-
quinone
(cf. 6)
xanthen- thioxanthen-
9-one
(cf. 7)
9-one
(cf. 8)
aroyl group
(cf. 9)
C6H5CO
(cf. a)
1.8
5.7
2.1
2.7
0.42
5g
6a
6b
6c
6d
6e
6f
p-Me-
C6H4CO
(cf. b)
2.1
5.2
2.5
1.6
0.37
p-CN-
C6H4CO
(cf. c)
24
31
1.4
1.4
1.9
p-F-C6H4CO
(cf. d)
6.1
1.3
44
11
4.9
1.8
1.9
1.2
2.1
1.0
p-NO2−
C6H4CO
(cf. e)
6g
7a
7b
7c
7d
7e
7f
340 (ε 12,265), 222 (ε 42,904)
1-C10H7CO
(cf. f)
0.82
0.92
1.2
1.0
1.3
1.1
0.85
0.78
1.1
343 (ε 7,815), 238 (ε 21,346), 220 (ε 24,674), 212 (ε 14,182)
340 (ε 10,109), 221 (ε 37,470)
2-C10H7CO
(cf. g)
0.92
347 (ε 10,987), 239 (ε 16,760), 220 (ε 33,582)
341 (ε 13,583), 222 (ε 65,585), 211 (ε 22,909)
340 (ε 14,604), 235 (ε 56,126), 222 (ε 61,634)
357 (ε 4,192), 233 (ε 26,420), 216 (ε 17,761)
a
Cleavage of supercoiled circular ϕX174 RFI DNA (form I; 50 μM/
base pair, molecular weight 3.50 × 106, 5386 base pairs in length) to
form relaxed circular DNA (form II) under aerobic conditions and
photolysis under 312 nm UV light at room temperature for 2.0 h.
7g
8a
8b
8c
8d
8e
8f
b
357 (ε 4,159), 234 (ε 22,826)
Analyzed by gel electrophoresis with 1.0% agarose gel and ethidium
360 (ε 2,181), 246 (ε 32,933)
bromide staining.
357 (ε 5,025), 233 (ε 27,771), 212 (ε 19,179)
360 (ε 3,534), 257 (ε 15,714), 233 (ε 13,835)
356 (ε 3,614), 224 (ε 40,079), 207 (ε 19,382)
8g
9a
9b
9c
9d
9e
9f
357 (ε 15,506), 238 (ε 57,950)
304 (ε 6,768), 264 (ε 16,694), 229 (ε 32,149), 208 (ε 20,579)
304 (ε 12,652), 269 (ε 20,603), 231 (ε 35,427), 203 (ε 23,744)
304 (ε 7,184), 264 (ε 16,746), 235 (ε 27,937), 218 (ε 22,302)
304 (ε 14,376), 268 (ε 18,198), 230 (ε 34,142), 220 (ε 30,676)
304 (ε 12,399), 268 (ε 23,100), 232 (ε 26,500), 217 (ε 27,100)
320 (ε 8,788), 222 (ε 57,279)
Figure 1. Dose measurement of oxime ester 6c for its DNA cleaving
ability in sodium phosphate buffer (pH 6.0, 0.10 M) upon irradiation
with 312 nm UV light at 25 °C for 2.0 h; Lane 1, DNA with 6c, 500
μM, in the dark; Lanes 2−6, 25, 50, 100, 250, 500 μM, individually.
9g
304 (ε 10,220), 234 (ε 69,510)
At low dose with a low compound base pair ratio, 6e was more
potent than 6c. The outcome of the two-phase process
indicates that two different binding modes may exist, including
intercalation and groove binding.
Measurement of Binding Constants for Conjugated
Oxime Esters with an Intercalating Moiety. For the
measurement of the apparent equilibrium binding constants
(Kapp), the oxime esters were used to inhibit the binding of
ethidium bromide to calf thymus DNA.18 The solubility,
however, was poor in phosphate buffers for most oxime esters
except the anthraquinone derivatives. The Kapp values of
anthraquinone oxime ester conjugates 6c−e were obtained as
3.31 × 104, 4.49 × 104, and 3.64 × 104, respectively (Figure 3).
exhibited a significant potency of 24. Therefore, 9,10-
anthraquinone and fluoren-9-one have been proven to be
better DNA intercalators than xanthen-9-one, thioxanthen-9-
one, and 9H-thioxanthen-9-one 10,10-dioxide.3,5 These results
emerge clearly from the columns in Figure 4. Overall, potencies
followed the order 9,10-anthraquinone > fluoren-9-one ≥ xanthen-
9-one ∼ thioxanthen-9-one > 9H-thioxanthen-9-one 10,10-dioxide.
This order matches the order of planarity of these polycyclic
moieties.
The aroyl group on the other terminal of oxime ester
conjugates influenced their DNA-cleaving capacity. In these
conjugates, almost all of the phenyl-containing compounds
were more potent than the naphthyl-containing compounds
(Figure 4 and Table 2). None of the columns that are
associated with the conjugates containing a naphthyl group (1-
or 2-C10H7) had a (form II)/(form I) ratio of over 1.5.
Accordingly, the size of the aroyl groups also affected the
capacity of DNA scission. In the series of anthraquinone−
benzoyloxime conjugates, the effectiveness of the substituents on
the benzoyl nuclei in DNA scission followed the order F > CN >
NO2 > Me ∼ H. The substituents are therefore concluded to
contribute substantially to DAN cleavage.
DISCUSSION
■
Intercalation occurs when ligands (such as polycycles and
arenes) with a suitable size fit well in between base pairs in
DNA.19−21 The planarity of the nuclei generally influences the
ability of the molecules to intercalate with DNA.22−24 The
results in Table 2 reveal that anthraquinone−benzoyloxime
conjugates 6c−e exhibited higher potencies with values of 11−
44 than most others, as determined by the ratio of (form II)/
(form I). Conjugate 5c with the fluoren-9-one nucleus also
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Figure 2. Measured doses of conjugated oxime esters 6c−e and their ability to cleave DNA in a sodium phosphate buffer (pH 6.0, 0.10 M) under
irradiation with 312 nm UV light.
Figure 3. Apparent equilibrium binding constants of conjugated oxime ester 6c−e determined by inhibition of ethidium bromide binding to calf
thymus DNA in a phosphate buffer (pH = 6.0, 0.10 M).
All of the new compounds exhibited favorable solubility in
DMSO and acetone. The solubility of the conjugates other than
anthraquinone derivatives in methanol or ethanol was poor.
When solutions of either DMSO or acetone were added to
buffers, the salting-out effect25 was evident. Given the issue of
solubility, the oxime esters of anthraquinone are considered to
be the best candidate DNA cleavers. The apparent equilibrium
binding constants of anthraquinone derivatives 6c−e were on
the order of 104 M−1 in a phosphate buffer at pH 6.0.
Among the 35 oxime ester conjugates in the new compound
library,26 para-fluoro-O-benzoyl oxime (6d), bearing an
anthraquinone moiety, bound DNA (Kapp = 4.49 × 104 M−1)
efficiently and had the greatest DNA-cleaving capacity. Hence,
an electron-withdrawing group in O-benzoyl oximes with
minimal steric congestion is an ideal candidate for increasing
their potency in DNA cleavage.
CONCLUSIONS
■
O-Benzoyl oxime ester conjugates 5−9 with five polycyclic and
aromatic intercalators were synthesized. When irradiated under
UV light, all of these conjugates nicked DNA. Of these oxime
esters, 9,10-anthraquinone O-9-(4-fluorobenzoyl)oxime (6d)
was the most potent cleaver. Investigations of the relationship
between their structures and activities reveal the involvement
and functions of the two adjacent moieties in the conjugated
molecules. The nuclei are crucial to intercalation and the
attachment of an electron-withdrawing group to the benzoyl
nucleus increases the potency of oxime ester conjugates.
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Figure 4. Differences in DNA-cleaving capacity are evident from the column representation of conjugated oxime ester conjugates 5−9, which bore
different intercalating moieties and aroyl groups.
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Ramos, A. (2001) Intercalators as anticancer drugs. Curr. Pharm. Des.
7, 1745−1780.
̃
ASSOCIATED CONTENT
* Supporting Information
■
S
1H NMR, 13C NMR, IR, UV, HRMS, and elemental analysis
data for oxime esters and their UV spectra as well as
experimental details about the synthetic procedures, DNA
cleaving procedure, and measurements of apparent equilibrium
binding constants. This material is available free of charge via
the Internet at http://pubs.acs.org.
(6) Fechter, E. J., Olenyuk, B., and Dervan, P. B. (2004) Design of a
sequence-specific DNA bisintercalator. Angew. Chem., Int. Ed. 43,
3591−3594.
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Tsay, S.-C. (2004) Aminyl and iminyl radicals from arylhydrazones in
the photo-induced DNA ceavage. Bioorg. Med. Chem. 12, 2509−2515.
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M., and Zard, S. Z. (1995) Iminyl, amidyl, and carbamyl radicals from
O-benzoyl oximes and O-benzoyl hydroxamic acid derivatives.
Tetrahedron 51, 6517−6528.
AUTHOR INFORMATION
Corresponding Author
*Tel.: +886-35-725813. fax: +886-35-721594. E-mail address:
jrhwu@mx.nthu.edu.tw.
Notes
■
(9) Boivin, J., Schiano, A.-M., Zard, S. Z., and Zhang, H. (1999) A
new method for the generation and capture of iminyl radicals.
Tetrahedron Lett. 40, 4531−4534.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors are grateful to the National Science Council (NSC
100-2923-I-008-001, NSC 97-2113-M-030-001-MY3, and
NSC101-2120-M-006-008), Ministry of Education of the
R.O.C., Taiwan (grants nos. 102N2018E1 and 102N2011E1),
and National Central University (102G918) for their financial
support. Mr. Ted Knoy is appreciated for his editorial
assistance.
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