Structural factors affecting cytotoxic activity of (E)-1-(Benzo[d ][1,3]oxathiol-6-yl)-3-phenylprop-2-en-1-one derivatives

Article abstract of DOI:10.1111/cbdd.12296

Derivatives of (E)-1-(5-alkoxybenzo[d][1,3]oxathiol-6-yl)-3-phenylprop-2- en-1-one demonstrated exceptionally high in vitro cytotoxic activity, with IC₅₀ values of the most active derivatives in the nanomolar range. To identify structural fragm

Full text of DOI:10.1111/cbdd.12296

Chem Biol Drug Des 2014; 84: 86–91
Research Article
Structural Factors Affecting Cytotoxic Activity of
(E)-1-(Benzo[d ][1,3]oxathiol-6-yl)-3-phenylprop-2-
en-1-one Derivatives
Marek T. Konieczny1,*, Anita Bułakowska2,
potential antitumor drugs, in vitro cytotoxic activity of most
Justyna Polak2, Danuta Pirska2, Wojciech
of the new derivatives is in the low micromolar range.
Meanwhile, some of the obtained by us oxathiole-fused
chalcones 1 (Figure 1) (14) exhibited activity at low nanom-
olar level, comparable only with activity of 3,4,5-trimethoxy
derivatives of chalcone (11).
2
ꢀ2
Konieczny , Patrycja Gryn , Andrzej
Skladanowski3, Michał Sabisz3, Krzysztof
Lemke4, Anna Pieczykolan4, Marlena Gałazka4,
z
Katarzyna Wiciejowska4 and Joanna Wietrzyk5
1Department of Chemical Technology of Drugs, Medical
University of Gdansk, 80-416 Gdansk, Poland
2Department of Organic Chemistry, Medical University of
Gdansk, 80-416 Gdansk, Poland
Cytotoxic chalcones are generally believed to act as inhibitors
of microtubule polymerization, interacting with tubulin at col-
chicine-binding site (11, 15). For this reason, and based on
preliminary studies of mechanism (16), it seems that oxathi-
ole-fused chalcones 1 act similarly. However, taking into
account the diversity of chalcones activity and mechanisms of
action (e.g., 1, 13), other possibilities could not be ruled out.
3Department of Pharmaceutical Technology and
Biochemistry, Gdansk University of Technology, 80-233
Gdansk, Poland
4Drug Discovery Department, Adamed Ltd., 05-152
Czosnow, Poland
5Department of Experimental Oncology, Institute of
Immunology and Experimental Therapy, 53-114 Wroclaw,
Poland
The outstanding cytotoxic activity of chalcones
1
prompted us to carry out detailed studies on structural
factors essential for the high cytotoxicity.
*Corresponding author: Marek T. Konieczny,
markon@gumed.edu.pl
As a part of these studies, dioxolone derivatives 2, ring-
opened chalcones 3 and OR-group-deprived oxathiole
derivative 4 (Figure 1) were prepared to establish signif-
icance of (i) the presence of sulfur atom, (ii) the presence
of the heterocyclic ring, (iii) the presence of the OR substi-
tuent, (iv) structure of substituents OR and X. The informa-
tion should be useful in optimization of activity and
pharmacological properties of the compounds.
Derivatives of (E)-1-(5-alkoxybenzo[d][1,3]oxathiol-6-yl)-
3-phenylprop-2-en-1-one (1) demonstrated exception-
ally high in vitro cytotoxic activity, with IC50 values of
the most active derivatives in the nanomolar range. To
identify structural fragments necessary for the activity,
several analogs deprived of selected fragments were
prepared, and their cytotoxic activity was tested. It
was found that the activity depends on combined
effects of (i) the heterocyclic ring, (ii) the alkoxy group
at position 5 of the benzoxathiole ring, and (iii) the
substituents in the phenyl ring B. Replacement of the
sulfur atom by oxygen does not influence the activity.
None of the listed structural fragments alone assured
high cytotoxic activity.
Methods and Materials
Chemistry
Melting points were determined using a Stuart SMP3
instrument (Bibby Scientific Ltd., Staffordshire, UK) and
were uncorrected. Infrared spectra were obtained from
Key words: benzoxathiole, chalcone, cytotoxic activity, SAR,
structure optimization
Received 7 August 2013, revised 14 November 2013 and
accepted for publication 19 January 2014
Chalcones are widely explored as potential lead com-
pounds for new therapeutic agents (1–13). Every year,
hundreds of new chalcone derivatives are prepared and
tested in pursuit of analogs with better pharmacological
properties. Concerning compounds being prepared as
Figure 1: Structures of the studied compounds.
86
ª 2014 John Wiley & Sons A/S. doi: 10.1111/cbdd.12296

SAR of Cytotoxic Oxathiole-Fused Chalcones
KBr pellets on a Thermo Mattson Satellite instrument
(Mattson Technology, Inc., Fremont, CA, USA). The 1H
NMR spectra were recorded on 200 MHz (Varian Gemini)
or 500 MHz (Varian Unity Plus) spectrometers. Elemental
analyses were performed using a Carlo-Erba 1108 instru-
ment (CE Instruments Ltd., Hindley Green, Wigan, UK),
and results were within 0.4% of theoretical values. TLC
was carried out on Merck 0.2 mm silica gel 60 F254 alu-
minum plates. The described reactions are unoptimized.
100 lg/mL streptomycin. Cultures were grown in stan-
dard conditions: 37 °C, 5% CO2, 95% humidity.
Cell viability assays
Cells were seeded in 96-well plates in a total volume of
150 lL medium per well, 1 day prior to start of the
experiment. Then, 50 lL of medium containing different
concentrations of tested compounds (seven concentra-
tions, each in triplicates) was added to cells. Fifty
microliters of medium with 0.25% DMSO was added to
the control cells. Next, cells were incubated with tested
compounds for the following 72 h. After incubation,
20 lL of MTT working solution in PBS (5 mg/mL) was
added and incubated for 3 h in 37 °C in 5% CO2.
Finally, medium with MTT solution was removed, and
formazan crystals were dissolved by adding 100 lL of
DMSO. After mixing, absorbance was measured at
570 nm wavelength (690 nm reference filter). MTT
reduction occurs only in living cells. Data analysis
consisted of determining the IC50 concentration of the
compound (in lM), at which the 50% reduction in the
number of cells occurs in the population treated,
compared with the control cells. Results were analyzed
Methods of synthesis and analytical data of the described
compounds are presented in the Appendix S1.
Determination of cytotoxic activity
A549 (human lung carcinoma, NSCLC), HCT116 (human
colorectal carcinoma) and HeLa (human cervix adeno-
carcinoma) cell lines were obtained from the American
Type Culture Collection (ATCC, Manassas, VA, USA).
A549 cells were maintained in RPMI 1640 medium,
HCT116 in McCoy’s 5A medium, and HeLa cells were
maintained in Minimum Essential Medium (all media from
Life Technologies). The media were supplemented with
10% fetal bovine serum and 100 units/mL penicillin and
Table 1: In vitro cytotoxicity of the prepared chalcones of general structure 1
Cytotoxicity, IC50 [lM] Æ SD*
Cmpd no (cmpd code),
yield
Substituent R
Substituent X
A549
HCT116
HeLa
24 (AMG-173), 60%
25 (AMG-190), 70%
26 (AMG-303), 76%
27 (AMG-301), 84%
28 (AMG-305), 47%
29 (AMG-377), 41%
30 (AMG-379), 60%
31 (AMG-378), 30%
32 (AMG-310), 22%
33 (AMG-300), 55%
34 (AMG-299), 76%
35 (AMG-296), 45%
36 (AMG-336), 14%
37 (AMG-349), 65%
38 (AMG-350), 58%
39 (AMG-338), 75%
40 (AMG-295), 89%
41 (AMG-334), 85%
42 (AMG-322), 67%
43 (AMG-333), 62%
44 (AMG-337), 91%
45 (AMG-308), 49%
46 (AMG-353), 60%
Doxorubicin
CH3
CH3
CH3
CH3
CH3
CH2CH3
CH2CH3
CH2CH3
–
3.79 Æ 0.21
0.369 Æ 0.029
0.050 Æ 0.008
0.269 Æ 0.069
0.309 Æ 0.113
0.009 Æ 0.001
0.012 Æ 0.003
2.84 Æ 0.608
7.00 Æ 0.245
0.091 Æ 0.015
0.093 Æ 0.007
6.69 Æ 1.62
1.85 Æ 0.30
0.168 Æ 0.009
0.037 Æ 0.007
0.454 Æ 0.120
0.401 Æ 0.011
0.006 Æ 0.002
0.014 Æ 0.002
1.40 Æ 0.141
4.68 Æ 0.360
0.037 Æ 0.019
0.048 Æ 0.016
3.34 Æ 0.08
1.85 Æ 0.456
0.061 Æ 0.008
0.012 Æ 0.002
0.078 Æ 0.015
0.103 Æ 0.004
0.001 Æ 0.000
0.006 Æ 0.002
2.95 Æ 0.771
3.11 Æ 0.030
0.027 Æ 0.008
0.035 Æ 0.010
3.02 Æ 0.74
4-OCH3
3-OH-4-OCH3
3-F-4-OCH3
2,4,6-triOCH3
3-OH-4-OCH3
3-F-4-OCH3
3,4,5-triOCH3
–
4-OCH3
3-F-4-OCH3
–
3-OH-4-OCH3
3-OPO3Na2-4-OCH3
3-OCH2CH2OH-4-OCH3
3-OTHP-4- OCH3
3-F-4-OCH3
2,4,6-triOCH3
3-F-4-OCH3
2,4,6-triOCH3
3,4,5-triOCH3
3-F-4-OCH3
3-F-4-OCH3
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH2CH2CH3
CH2CH2CH3
CH2CH2CH3
CH2CH2CH3
CH2CH2CH3
CH2CH2CH3
CH2CH2CH3
CH2CH2CH2CH3
CH2CH2CH2CH3
CH2CH2CH2CH3
CH2CH2CH2NHBoc
CH2CH2CH2NH2
0.022 Æ 0.005
0.121 Æ 0.026
2.58 Æ 0.064
2.31 Æ 0.244
0.142 Æ 0.032
5.43 Æ 2.38
0.010 Æ 0.003
0.097 Æ 0.001
1.76 Æ 0.537
3.54 Æ 0.872
0.046 Æ 0.008
2.05 Æ 0.423
0.161 Æ 0.023
2.43 Æ 0.628
3.52 Æ 0.330
1.10 Æ 0.080
1.04 Æ 0.200
0.069 Æ 0.027
0.004 Æ 0.002
0.004 Æ 0.001
0.004 Æ 0.001
0.009 Æ 0.001
1.72 Æ 0.049
1.78 Æ 0.145
0.044 Æ 0.002
2.12 Æ 0.215
0.130 Æ 0.028
1.80 Æ 0.527
15.0 Æ 4.495
0.970 Æ 0.156
1.20 Æ 0.090
0.154 Æ 0.017
0.003 Æ 0.000
0.008 Æ 0.004
0.331 Æ 0.069
3.37 Æ 1.92
12.0 Æ 4.810
3.52 Æ 0.940
1.20 Æ 0.280
0.124 Æ 0.006
0.008 Æ 0.003
0.006 Æ 0.002
Combretastatin A4
Paclitaxel
*SD – standard deviation.
Chem Biol Drug Des 2014; 84: 86–91
87

Konieczny et al.
Table 2: In vitro cytotoxicity of the prepared chalcones of general structure 2
Cytotoxicity, IC50 [lM] Æ SD*
Cmpd no (cmpd code),
Yield
Substituent X
A549
HCT116
HeLa
47 (AMG-263), 33%
48 (AMG-260), 76%
49 (AMG-261), 92%
50 (AMG-249), 80%
51 (AMG-250), 68%
52 (AMG-251), 81%
–
4-Br
2-Cl
4-OCH3
3-F-4-OCH3
3,4,5-triOCH3
6.00 Æ 0.08
4.98 Æ 0.25
8.75 Æ 1.24
0.199 Æ 0.003
0.213 Æ 0.001
6.30 Æ 0.01
2.95 Æ 0.13
2.72 Æ 0.06
2.55 Æ 0.30
0.063 Æ 0.004
0.066 Æ 0.004
3.06 Æ 0.33
4.10 Æ 0.37
4.03 Æ 0.88
6.27 Æ 0.64
0.043 Æ 0.005
0.049 Æ 0.004
4.40 Æ 0.25
*SD – standard deviation.
Table 3: In vitro cytotoxicity of compounds 4, 53, and 54
[d][1,3]oxathiol-2-one (5) (17) by alkaline ring opening and
recyclization with methylene bromide (Scheme 2).
Other 6-acetyl-5-alkoxybenzo[d][1,3]oxathioles (9-13) were
prepared from 6-acetyl-5-hydroxybenzo[d][1,3]oxathiol-
2-one (7) (17) by its transformation into oxathiole 8, fol-
lowed by alkylation with a suitable halide (Scheme 3).
Cytotoxicity, IC50 [lM] Æ SD*
Cmpd no (cmpd
code), Yield
A549
HCT116
HeLa
6-Acetyl-5-methoxybenzo[d][1,3]dioxole (15), required as
substrate for chalcones 2, was prepared by alkylation of
phenol 14 (Scheme 4) (18,19).
4 (AMG-470), 87%
53 (AMG-180), 67%
22.8 (0.97)
4.51 (0.18)
16.8 (5.68)
2.68 (0.84)
–
4.07
(0.69)
>10
54 (AMG-181), 64%
>10
>10
2,5-dimethoxy-4-(methylthio)acetophenone (17) required
as substrate for chalcones 3, was prepared by alkaline
hydrolysis of oxathiolone 5 to 5-hydroxy-2-methoxy-4-
mercaptoacetophenone (16), and followed by methylation
with methyl iodide (Scheme 5).
*SD – standard deviation.
using GraphPad Prism 5.0 (GraphPad Software, Inc., La
Jolla, CA, USA).
6-acetylbenzo[d][1,3]oxathiole (23) required as substrate
for synthesis of chalcone 4, was prepared starting from
Results are presented in Tables 1, 2 and 3.
Results
Chemistry
Chalcones 1-4 were prepared by condensation of suitable
acetophenones with benzaldehydes in alkaline alcoholic
solution (Scheme 1).
Scheme 2: Synthesis of 6-acetyl-5-methoxybenzo[d][1,3] oxath-
iole (6).
The starting 6-acetyl-5-methoxybenzo[d][1,3]oxathiole (6)
was obtained in one step from 6-acetyl-5-methoxybenzo
Scheme 1: The synthetic route employed to access the described
chalcones.
Scheme 3: Synthesis of 6-acetyl-5-alkoxybenzo[d][1,3]oxathioles
(9-13).
88
Chem Biol Drug Des 2014; 84: 86–91

SAR of Cytotoxic Oxathiole-Fused Chalcones
most active compounds (29, 30, 36) in the nanomolar
range (9, 12 and 22 nM, respectively) (all IC50 values used
in this discussion were measured in A549 cells).
Cytotoxic activity of compounds deprived of oxathiole ring
is given in Tables 2 and 3.
Scheme 4: Synthesis of 6-acetyl-5-methoxybenzo[d][1,3]dioxole
(15).
Discussion
The importance of the heterocyclic ring was verified by
comparison of activities of 4-OCH3 derivative of oxathiole 25
(0.369 lM) (Table 1) with activity of ring-opened compound
54 (>10 lM) (Table 3). The last derivative was found to be
about 40 times less active than its cyclic analog, which
indicated a crucial role of the heterocyclic ring. However,
differences in cytotoxicity of analogs, ring B-unsubstituted
pair of compounds oxathiole 24 (3.79 lM) and ring-opened
derivative 53 (4.51 lM), were negligible. The result sug-
gested that cytotoxic effects of the compounds resulted
from a combined influence of the both factors, and the
heterocyclic ring had to be accompanied by suitable
substituents X.
Scheme 5: Synthesis of 2,5-dimethoxy-4-(methylthio)acetoph-
enone (17).
Replacement of sulfur by oxygen in the heterocyclic ring
did not affect the activity, as indicated by comparison of
values of IC50 of oxathiole–chalcones 25 (0.369 lM) and
27 (0.269 lM) with activities of related dioxole derivatives
50 (0.199 lM) and 51 (0.213 lM).
The presence of ring A 5-OR substituent and structure of
the R group were very important. Activity of ring B 3-F-4-
OCH3-substituted compound 4 (22.8 lM) (Table 3) deprived
of the 5-OR substituent was significantly lower than activity
of related 5-OCH3 (27) (0.264 lM), 5-OC2H5 (30) (0.012 lM),
5-OCH(CH3)2 (34) (0.093 lM), 5-OCH2CH2CH3 (40)
(0.142 lM) and 5-OCH2CH2CH2CH3 (42) (0.331 lM) analogs
(Table 1). As can be seen, the best activity was found for
5-OC2H5 compound, whereas both 5-shorter and 5-longer
alkoxy chain analogs were significantly less active. Similar
result was obtained for ring B 3-OH-4-OCH3-substituted
compounds: The 5-OC2H5 derivative (29) (0.009 lM) was
more active than related 5-OCH3 (26) (0.050 lM) and
OCH2CH2CH3 (36) (0.022 lM) analogs.
Scheme 6: Synthesis of 6-acetylbenzo[d][1,3]oxathiole (23).
4-hydroxy-3-methoxyacetophenone (18) (Scheme 6), by
reaction with dimethylthiocarbamoyl chloride, and followed
by Newman–Kwart rearrangement of the formed thiocar-
bamate 19 to thiophenol derivative 20 (20). Deprotection
of methoxy group to 3-hydroxyacetophenone 21 and sub-
sequent cyclization gave oxathiolone derivative 22, which
was transformed into the desired oxathiole 23 by ring-
opening ring-closure reaction with methylene bromide
under alkaline conditions.
Increase in polarity of the 5-OR group decreased the
cytotoxic activity in vitro, as evidenced by comparison of
activities of 5-OCH2CH2CH2CH3 (42) (0.331 lM) and
5-OCH2CH2CH2NH2 (46) (1.2 lM) derivatives. Similarly,
3-OH-4-OCH3 compound 36 (0.022 lM) was more active
than its polar phosphate prodrug 37 (0.121 lM). However,
although the polar compounds were less active in vitro,
their water solubility could result in much better pharmaco-
kinetic parameters.
Cytotoxicity in vitro
The cytotoxicity of the prepared compounds was evalu-
ated against three tumor cell lines using the MTT test.
Most of the compounds of general formula 1 (Table 1)
demonstrated significant activity, with IC50 values of the
The differences in in vitro activity of phosphate prodrug 37
and its precursor 36 are intriguing, as when tested toward
HCT116 cells, 37 is about 10-fold less cytotoxic than 36
Chem Biol Drug Des 2014; 84: 86–91
89

Konieczny et al.
(0.097 and 0.010 lM, respectively), whereas for HeLa cells
the activities are comparable (0.009 versus 0.004 lM). The
phosphate derivative is activated in the cytoplasm by intra-
cellular phosphatases, and possible differences in the
activity of these enzymes could be responsible for cellular
response to phosphate prodrugs of chalcones. However,
this is not a unique property of our compounds as similar
relation was described by Pettit et al. for combretastatin
A4 and its analogs (21). In addition, it was noted that
changing the counter-cation in the phosphates of
combretastatin A4 derivatives also influences their
cytotoxicity. Together, it follows that the activity of cellular
phosphatases is probably not a sole reason for the differ-
ent cytotoxicities of chalcones and their phosphate salts.
4. Lawrence N.J., McGown A.T. (2005) The chemistry
and biology of antimitotic chalcones and related enone
systems. Curr Pharm Design;11:1679–1693.
5. Nowakowska Z. (2007) A review of anti-infective and
anti-inflammatory chalcones. Eur J Med Chem;42:125–
137.
6. Katsori A.-M., Hadjipavlou-Litina D. (2009) Chalcones
in cancer: Understanding their role in terms of QSAR.
Curr Med Chem;16:1062–1081.
7. Batovska D.I., Todorova I.T. (2010) Trends in utilization
of the pharmacological potential of chalcones. Curr Clin
Pharmacol;5:1–29.
8. Katsori A.-M., Hadjipavlou-Litina D. (2011) Recent pro-
gress in therapeutic applications of chalcones. Expert
Opin Ther Patents;21:1575–1596.
9. Sahu N.K., Balbhadra S.S., Choudhary J., Kohli D.V.
(2012) Exploring Pharmacological significance of chal-
cone scaffold: A review. Curr Med Chem;19:209–
225.
10. Roman B.I., Heugebaert T.S.A., Bracke M.E., Stevens
C.V. (2013) Assessment of the antineoplastic potential
of chalcones in animal models. Curr Med Chem;
20:186–221.
11. Ducki S. (2009) Antimitotic chalcones and related
compounds as inhibitors of tubulin assembly. Anti-
Canc Agents Med Chem;9:336–347.
12. Brown T., Holt H. Jr, Lee M. (2006) Synthesis of
biologically active heterocyclic stilbene and chalcone
analogs of combretastatin. Top Heterocycl Chem;
2:1–51.
Conclusion
The studies identified structural requirements for very high
cytotoxic activity in vitro of oxathiole-fused chalcones 1.
The results revealed that the nanomolar level cytotoxic
activity depends on combination of three factors: (i) the
presence of the heterocyclic ring, (ii) the presence and
structure of 5-OR group in ring A, and (iii) substituents in
ring B of chalcones. Concerning the cytotoxic activity
in vitro, the oxathiole ring in combination with 2 -3 carbon
alkoxy group OR, and (3-OH-4-OCH3) or (3-F-4-OCH3)
substituents in ring B, seemed to be optimal.
Current Author Addresses
13. Boumendjel A., Ronot X., Boutonnat J. (2009)
Chalcones derivatives acting as cell cycle blockers:
Potential anticancer drugs? Curr Drug Target;10:
363–371.
14. Konieczny M., Skladanowski A., Lemke K., Pieczyko-
lan J. (2011) Novel Chalcone derivatives with Cytotoxic
Activity. PCT Int. Appl. WO 2011/009826 A2.
15. Ducki S., Rennison D., Woo M., Kendall A., Chabert
J.F.D., McGown A.T., Lawrence N.J. (2009) Combre-
tastatin-like chalcones as inhibitors of microtubule
polymerisation. Part 1: Synthesis and biological evalua-
tion of antivascular activity. Bioorg Med Chem;17:
7698–7710.
16. Serocki M., Sabisz M., Bulakowska A., Konieczny
M.T., Skladanowski A. (2013) Interaction of novel syn-
thetic chalcone derivatives with tubulin in vitro and in
tumor cells. 7th Polish-German Symposium on Phar-
maceutical Sciences, Gdansk, 24 - 25 May 2013.
Book of Abstracts, page 168, poster no V-7.
17. Konieczny M.T., Konieczny W., Wolniewicz S., Wierzba
K., Suda Y., Sowinski P. (2005) New Domino Reac-
tion. One Pot Synthesis of 4,7-Dihydroxythioaurone
Derivatives from Benzaldehydes and 4-Acetyl-2-oxo-
benz[1,3]oxathiole. Tetrahedron;61:8648–8655.
18. Fukui K., Nakayama M. (1964) Synthetic Studies of
Sesamol Derivatives. IV. Preparation and Reaction of
2-Hydroxy-4,5-methylenedioxyacetophenones. Bull Chem
Soc Japan;37:300–302.
Krzysztof Lemke’s current address is Research and Devel-
opment Department, Biovico Ltd. 81-340 Gdynia, Poland.
Michal Sabisz’s current address is Laboratory of Thera-
peutic Proteins and Peptides, Ecole Polytechnique Fede-
rale de Lausanne, CH - 1015 Lausanne, Switzerland.
Acknowledgments
The Authors wish to thank the Polish Ministry of Science
and Higher Education for grant no 0630/B/P01/2008/34
(for M. Konieczny), and ADAMED, Ltd. for grant ONCO–
3CLA/II–01/AMG (for M. Konieczny).
References
1. Dimmock J.R., Elias D.W., Beazely M.A., Kandepu
N.M. (1999) Bioactivities of chalcones. Curr Med Chem;
6:1125–1149.
2. Ni L., Meng C.Q., Sikorski J.A. (2004) Recent
advances in therapeutic chalcones. Expert Opin Ther
Patents;14:1669–1691.
3. Go M.L., Wu X., Liu X.L. (2005) Chalcones: An update
on cytotoxic and chemoprotective properties. Curr Med
Chem;12:483–499.
90
Chem Biol Drug Des 2014; 84: 86–91

SAR of Cytotoxic Oxathiole-Fused Chalcones
19. Royer R., Colin G., Demerseman P., Combrisson S.,
Cheutin A. (1969) Reactions induced by pyridine
hydrochloride. III. New method for benzoxazole synthe-
sis. Bull Soc Chim France;8:2785–2792.
agents. 548. Synthesis of iodo- and diiodocombstatin
phosphate prodrugs. J Nat Prod;75:385–393.
Supporting Information
20. Bourgery G.R., Lacour A.P., Moinet G.H., Pourrias
B.M., Ruch A.M.P. (1981) Substituted benzodioxan,
benzodioxole and benzodioxepin compounds. US
4248788 A.
Additional Supporting Information may be found in the
online version of this article:
21. Pettit G.R., Rosenberg H.J., Dixon R., Knight J.C.,
Hamel E., Chapuis J.C., Pettit R.K., Hogan F., Sumner
B., Ain K.B., Trickey-Platt B. (2012) Antineoplastic
Appendix S1. Synthesis and analytical data of the
described compounds.
Chem Biol Drug Des 2014; 84: 86–91
91