摘要
许多类黄酮化合物都具有抗肿瘤活性,如芹菜苷元,黄芩素,金雀异黄素,flavopiridol等,且它们对正常细胞没有或很少有毒性。这个特性激起了人们对合成和改造类黄酮的兴趣,并且取得了很多成果。其中,类黄酮的C环改造尤其引人注意,很多报道显示C-3和C-4被杂原子或杂环取代能增强其母体化合物的抗肿瘤活性。因此,我们希望能够通过对黄酮的C环改造寻找高活性的化合物。又因为最近很多报道称噻二唑环具有广泛的生物活性,如抗增殖,抗菌等,引起人们广泛的关注。根据拼合原理,我们设计在黄酮的C环引入噻二唑环,合成了1-芳基-4-芳基苯并二氢吡喃[4,3-d]-Δ~(1,9b)-1,2,3-噻二唑啉和4-芳基-4H-苯并吡喃[4,3-d]-1,2,3-噻二唑类衍生物,并对所合成的噻二唑啉类化合物进行了初步抗肿瘤活性体外筛选。
我们按照所设计的合成路线,采用Mohamed的方法合成1-芳基-4-芳基苯并二氢吡喃[4,3-d]-Δ~(1,9b)-1,2,3-噻二唑啉类化合物。先由黄烷酮与苯肼反应制得黄烷酮-4-苯腙,后者先在SOCl_2中回流环合,再与无水醇反应,得到目标产物。在合成过程中发现,所生成的产物C3a-,C4-位都被烷氧基取代(此烷氧基来自于相应的醇),E环H-2″被氯原子取代,此外,一些产物A环和B环的质子也被氯原子取代,取代的数目和位置取决于原料上的取代基。利用此法合成此类新化合物25个。
4-芳基4H-苯并吡喃[4,3-d]-1,2,3-噻二唑类化合物按Hurd-Mori法合成。由黄烷酮和氨基脲盐酸盐反应得到黄烷酮-4-缩氨基脲类化合物,后者与SOCl_2环合后经无水乙醇处理得到目标分子。我们考查了母环上取代基对反应的影响,发现当原料C5-或C7-位存在甲氧基时,产物C4-位上能引入氯原子,当原料A环为5,7-二甲氧基取代时,产物6-位也能引入氯原子。按此法合成了此类化合物共11个,其中新化合物9个。
所有上述产物都经过~1HNMR,IR确证,部分产物还经MS确证,其中,代表化合物6a的结构经X-单晶衍射确立,并经过~(13)CNMR,~1H-~1H COSY,HMQC,MS(ESI),IR共同确证。
Flavonoids, such as apigenin, baicalein, genistein, flavopiridol, quercetin genistein and flavopiridol have antitumor activity. These compounds are cytotoxic to cancer cells but have no or insignificant activity in normal cells. These beneficial properties prompted synthesis of flavonoid derivatives.For many years, 1,2,3-thiadiazole derivatives were reported for their bioactivity including antitumor and antibacterial. It was thought the combination of the flavonoid with the 1,2,3-thiadiazole may be benefit to the biological activity. Thus, the title compounds were synthesized with the hope that they might be having antitumor activity.1-aryl-4-aryl-chromano[4,3-d]-Δ~(1,9b)-1,2,3-thiadiazolines were synthesized with flavanone-4-arylhydrazone in SOCl_2 then the reaction mixture was treated with alcohol. In all the products, position 3a- and 4- were substituted by alkyloxy- and position 2"- was substituted by Cl. Some of products were substituted by chlorine on A ring and B ring, the number and position of which depending on the substituent of material. By this method, 25 compounds were prepared.4-aryl-chromene [4, 3-d]-1,2,3-thiadiazoles were prepared with flavanone-4-semicarbazone in SOCl_2 and then in EtOH. The result showed that position 4- of some products was substituted by Cl. The conceivable mechanism was proposed to explain their formation. 11 compounds were prepared by the same method.All the structures were confirmed by ~1HNMR and IR, and some of them also confirmed by MS. The structure of 6a was determined by single crystal X-ray crystallography, and also confirmed by ~(13)CNMR, ~1H-~1H COSY, HMQC.All the thiadiazolines prepared in this study were tested for their cytotoxicity against HL-60. At the concentration of 5mg/L, most of the compounds showed some activity in inhibition proliferation. The cytotoxic data showed that 9 compounds displayed strong activity against HL-60 (IC_(50) < 1μM). Among them, compound 7b,
showed the most potent activity (IC5o=O.14uM).The low solubility of all the compounds, especially the 4-aryl-chromene [4,3-d]-l,2,3-thiadiazoles, blocked their pharmacological study.
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