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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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