Cancer has been the second common cause of human hydroxide reacted with 4 resulted in the intermediate 5 in
death in the developed world.1-2 Natural products have long 30% yield. Then benzylation of 5 was conducted by reaction
been a source of antitumor drugs and new natural products with benzyl bromide in the presence of potassium carbonate
are reasonable to be expected as promising leads for to afford intermediate 6. Compound 7 was obtained by
antitumor drug discovery.1,3-4 Among natural products, acidified 6 in the presence of hydrochloric acid. Followed by
flavonoid is a group of polyphenolic compounds present in introduced a two or three or four-carbon linker to 8-OH to
plants and they show diverse biological activities such as form compound 8, which then reacted with various amines to
anti-inflammatory, neuroprotection and antitumor activity.4-5 give key intermediates 9. Debenzylation of 9a-9v give rise to
Epidemiological studies have been shown that the flavones the target compounds 10a-10x.
derived from Scutellaria possessed cytostatic and cytotoxic
The synthetic routes for compounds 19a-19g were
activities against many human cancer cell lines with little to
outlined in Scheme 3. Benzylation of 11 was conducted by
no toxicity to normal cells.5-6 As one of the representative
reaction with benzyl bromide in K2CO3 to afford intermediate
flavonoid, the natural product wogonin (5,7-dihydroxy-8-
12. Oxidation of 12 using 65% HNO3 provided the quinone
methoxyflavone, 1) and its derivatives have been recently
13, which was reduced by sodium thiosulfate to the phenol
reported to possess inhibitory activities against cancer.7
14. Methylation of 14 with dimethylsulfate obtained
Great efforts have been devoted to explore the mechanism of
intermediate 15, which then debenzylation to give compound
its antitumor activity and many results suggested that 1
16. Followed by Friedel-Crafts acylation with cinnamoyl
possessed potent antitumor activities both in vitro and in
chloride derivatives using BF3-Et2O as catalyst provided the
vivo.7-9 However, little is known about their structure-activity
intermediate 1a and 17a-17g. Subsequently, 1a and 17a-17g
relationship (SAR), by far.
were cyclized to the corresponding flavones (1b and 18a-
Recently, our laboratory has been committed to develop 18g) mediated by iodine at 120 oC. Finally, the target
derivatives of wogonin as cytotoxic drugs, and forty-nine compounds
1 and 19a-19g were obtained through
wogonin derivatives have been designed and synthesized. In demethylation of intermediate 1b and 18a-18g. All of the
1
this work, we mainly reported part of our work which target compounds were confirmed by H NMR, IR and HRMS
focused on investigating the substitutions at 7-, 8-position (ESI) spectra, and representative structure 10o was also
and B ring (Fig. 1), and compounds investigated on other confirmed by 13C NMR spectrum.
position would be reported in our further research. The
Cytotoxicity studies were performed on the derivatives of
cytotoxic activities of all these compounds were also
wogonin with cell survival being determined by the MTT
evaluated. For a detailed understanding of SAR of these
assay against the human liver carcinoma cell lines HepG2,
compounds and thus guiding our ongoing research to further
human non-small cell lung cancer (NSCLC) cell lines A549,
develop potent cytotoxic wogonin derivatives, we also
and human gastric carcinoma cell lines BCG-833. 5-Fu, a
carried the quantitative structure-activity relationship
standard cytotoxic drug, was selected as the positive control
(QSAR) studies. QSAR is one of the main research fields in
to compare the potency of cytotoxicity of the tested
drug design and the aim of it is to develop some quantitative
compounds under the same experimental condition. In
models to predict activity of a compound which can help to
addition, wogonin was also selected as the control. These
reduce the research time of new drugs.10-13 Many biological
compounds were treated over a range of concentrations from
activity correlates greatly with the structures and
0.1 to 100 μM for 48 h and the results of cytotoxic activity in
conformations of the compounds. QSAR model used
vitro were expressed as the IC50 which represents the
molecular descriptors to represent the characteristics of one
concentration of a drug that is required for 50% inhibition.
molecule and highly correlated to the activity.13
All of the derivatives were evaluated for their activity
towards HepG2 cell lines and some of them were tested
against the other cell lines (Table 1).
As shown in Table 1, part of these compounds showed
moderate to potent cytotoxicity against all the three cell
lines. Some of these compounds, such as compounds 3a-3h,
3j-3k, 3m, 3o with substitution at 7-position, even showed
more potent against all the three cell lines compared with the
control 5-Fu and wogonin. Especially, compound 3h was
Fig.
1 The structure of wogonin (1) and the designed wogonin
found to be the most potent, with IC50 values of 1.07 μM
(HepG2), 1.74 μM (A549) and 0.98 μM (BCG-823), over ten-
fold more potent than the control 5-Fu and wogonin.
However, compounds 10a-10x and 19a-19g with
substitutions at 8-position or B-ring were generally less
potent than the control. Through the observed cytotoxic
efficacy of the synthesized wogonin derivatives, a general
SAR rule could be attained, the activity was enhanced when
the 7-position of wogonin was occupied by aliphatic amines
rather than the case when 8-position or B-ring was
substituted, as shown in all of the tested derivatives. In order
to further explore the observed pharmacological properties
and determining the main controlling factors governing the
activities, QSAR study was carried.
derivatives.
The synthesis of wogonin derivatives was described in
Scheme 1-3. First, 7-OH substituted derivatives (3a-3r) was
outlined in Scheme 1. Starting from wogonin (1), a three or
four-carbon linker was introduced to 7-OH to form the
intermediate 2, which was subsequently reacted with several
structurally diverse amines to provide compounds 3a-3o.
Compounds 3p-3r were obtained directly from 1 with
corresponding chloroheterocycle by reflux in acetonitrile.
Scheme 2 described the synthesis of 8-OH substituted
derivatives (10a-10v). These compounds were synthesized
in six steps from chrysin (4). Tetramethylammonium