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新蟲(chóng) (初入文壇)

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金幣: 445.8
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在線(xiàn): 4.7小時(shí)
蟲(chóng)號(hào): 2053868
注冊(cè): 2012-10-11
專(zhuān)業(yè): 人工晶體

[求助] 求求求

oretinoids and a class of new retinoic acid conjugates.20-23
Among the isoxazole heteroretinoids some compounds
were found to be endowed with significant differentiat-
ing and antiproliferative activities; moreover, some new
retinoic acid conjugates proved of interest for their
antitumor activity and low toxicity.22
In an effort to learn more about the general structure-
activity relationships of vitamin A and to better eluci-
date those structural features that are important to get
selectivity toward the different retinoid receptor sub-
families (RARR, -β, and -γ) and with the aim of synthe-
sizing compounds endowed with apoptotic activity, we
decided to prepare novel heteroretinoids containing an
isoxazole heterocycle in their skeleton. The new com-
pounds were designed by combining features of potent
retinoids 3-5 with features of some heteroretinoids
(compounds 6 and 7 as examples) prepared during our
previous studies.20-23 Briefly, we designed compounds
bearing a tetramethyltetrahydronaphthyl group coupled
directly (or via an alkenyl portion) to an isoxazole
residue.
Here, we describe our results from the synthesis and
the biological activity of some new isoxazole-containing
heteroretinoids. All new heteroretinoids 13b, 14b, 17,
18b, 19b, and 24 were tested for their differentiating,
cytotoxic, and apoptotic activities. The newly synthe-
sized compounds were evaluated also in vitro in tran-
scriptional activation and competition binding assays
for RARs and RXRs. In particular, we describe for the
first time a novel heteroretinoid (14b) containing an
isoxazole moiety able to induce apoptosis in HL-60 cells
after only 24 h of treatment. We have compared the
activity of 14b with that of three well-characterized
retinoids: 13-cis-retinoic acid, 9-cis-retinoic acid, and
all-trans-retinoic acid (ATRA).
Chemistry
For the construction of the two heteroretinoids 13b
and 14b (Scheme 1) our approach started from the
chloro oxime 8a easily prepared from commercially
available glycine methyl ester as described in the
literature.24,25 The nitrile oxide generated from 8a by
treatment with triethylamine was reacted through a [3
+ 2] cycloaddition reaction into the alkyne 9b, to afford
in a regioselective manner and good yield the corre-
sponding isoxazole derivative 10b. Removal of the
protective pyranyl group by use of Amberlite H-15 in
methanol at 50 °C led to the primary alcohol 10a in very
high yield. The latter derivative has been previously
obtained through the [3 + 2] cycloaddition of the nitrile
oxide generated from the chloro oxime 8a into the
alkyne 9a bearing the free alcoholic function.25 However,
in our hands this reaction afforded only a moderate yield
of the desired isoxazole. The oxidation of the primary
alcohol of 10a to the aldehyde 11 was easily performed
by pyridinium chlorocromate (PCC) in methylene chlo-
ride solution in 85% yield. Finally, the Wittig reaction
between the aldehyde 11 and the phosphonium salt 12,
which was in turn prepared as described in the litera-
ture,26 afforded in moderate yield a 9/1 mixture of the
two isomers 13a and 14a. The stereochemistry E or Z
for the latter derivatives was assessed by means of their
1HNMR spectra. The signal for the vinylic proton of the
Z-isomer appeared at higher field than that of the
E-isomer. Moreover, the vinylic proton of the Z-isomer
appears as a doublet with a higher coupling constant.
These data agree with those reported for a trisubstituted
double bond bearing a methyl group and two aryl
functions as substituents; moreover they are consistent
with those of other arotinoids previously described in
the literature.26-28 Our data are also corroborated by
NOESY and COSY-2D experiments. Finally, the hy-
drolysis of the ester function by use of lithium hydroxide
afforded in good yields the desired 13b and 14b.
The preparation of the isoxazole derivatives 17, 18b,
and 19b was initially attempted by the cycloaddition of
the nitrile oxide generated from the chloro oxime 8b into
the alkyne 15 (Scheme 2). Surprisingly, the reaction

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