抗癌性胺基吲哚啉磺胺類及苯乙烯磺胺類化合物之化學結構與活性關係研究

針對本實驗室於2006年發表的7-aroyl-aminoindoline-1-benzene- sulfonamides結構性衍生物所表現的強效抗癌活性，其IC50 數值的範圍大多在9.6至297 nM間. 我們設計以1-aroylindoline-7-benzenesulfonamides為骨架，合成出以7-(4-methoxybenzenesulfonylamino)indoline以及7-(4-sulfamoylbenzenesulfonylamino)indoline為結構的衍生物，化合物1-7 以及8-12。藉由SAR間的關係發現到其抗KB活性測試結果並未如我們先前所預期的良好，這之中僅有化合物6表現中度抗癌活性。另一方面，針對以7-aminoindoline 1-benzenesulfomamide為基本骨架，我們試圖將此類型結構的衍生物完整化並藉以探討其結構與抗癌活性間的關係，合成出以烷羰基（13-16, 18）、苯基（19-23）或烷基（17, 24-28）作取代的一系列化合物。細胞活性測試結果也顯示出在第七位上的胺基上接有烷羰基取代的化合物15, 16, 17及接有苯基的化合物23表現強效的抗癌細胞活性；其餘此一系列的化合物13, 14 , 18-22, 24-28所顯示的抗KB細胞活性則是介於在微弱到中度之間。此外，利用生物等效性的觀念，我們在原來吲哚琳的醯胺基轉換成為具有碳-碳雙鍵，設計並且合成出以styrene為骨架的磺胺類抗癌化合物 29-31, 32a, 32b, 33。藉由抗癌生物活性檢測數據，化合物29, 32a, 33，均表現相當理想的抗KB細胞活性，其IC50 數值各別為195, 114, 46 nM，而這樣的結果也激勵著我們並且指引我們在未來繼續朝向此類衍生物做研究以及發展。

關鍵字

胺基吲哚啉磺胺類化合物；抗癌；苯乙烯磺胺類化合物

並列摘要

The 7-aroyl-aminoindoline-1-benzenesulfonamides developed in our labactory demonstrated excellent anticancer activity, with IC50 values ranging from 9.6~297 nM. For the continuation of structure activity relationship studies on this series, we prepared two classes of indolines, namely 7-(4-methoxy- benzenesulfonylamino)indolines 1-7 and 7-(4-sulfamoylbenzenesulfonyl- amino)indolines 8-12. Data of antiproliferative activity against KB cell line showed that, except for compound 6, most of these series compounds didn’t exhibit substantial cytotoxicity. The second part of the study was focus on modification of 7-amino- indoline-1-benzenesulfonamide core. The alkylcarbonyl derivatives (13-16, 18), the benzyl derivatives (19-23) and the alkyl derivatives (17, 24-28) were synthesized and evaluated for antiproliferative activity. Results indicated that compound 15, 16, 17 and 23 exhibited potent cytotoxicities with IC50 value ranging from 31~91 nM. The others including compounds 13, 14, 17-22, 24-28 displayed weak to moderate cytotoxicity. Utilizing the bioisosterism concept, we designed and prepared a novel series of styrene benzenesulfonamide analogues 29-31, 32a, 32a and 33. Compound 29, 32a and 33 displayed cytotoxicity with IC50 values of 195,114 and 46 nM against KB cell line, respectively, which inspired us to further investigate and synthesize this series of compounds in the future.

並列關鍵字

Antitumor ； Aminoindolinesulfonamides ； Styrenesulfonamides ； KB cell

參考文獻

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抗癌性胺基吲哚啉磺胺類及苯乙烯磺胺類化合物之化學結構與活性關係研究

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