發(fā)布時間：2018-05-28 19:50

  本文選題：甾體雜環(huán) + 甾體螺吲哚��； 參考：《鄭州大學》2017年碩士論文

【摘要】：作為藥物研發(fā)的熱門領域,甾體因其獨特的結構和多取代位點從而被更多的藥物學家所關注,擴大甾體化合物的結構多樣性以及探究其豐富的生物學活性越來越成為重中之重。結構改造后的甾體化合物也不局限于原有的激素類活性,抗菌、抗腫瘤等更多潛在的藥效正在被發(fā)現(xiàn)利用。其中,甾體雜環(huán)化是甾體化學修飾的熱點,利用化學方法在甾體骨架結構中引入雜環(huán)結構可豐富甾體類化合物的種類,增加其結構新穎性、復雜性和多樣性,同時亦賦予其新的生物學活性,為甾體新藥研發(fā)打下了基礎。故本論文設計合成基于甾體的雜環(huán)化衍生物,并對合成的系列衍生物進行抗腫瘤、抗菌活性評價,主要包括以下幾個方面:(1)利用廉價易得的的DHEA二腈基烯、靛紅、丙二腈、乙酸銨一鍋四組分法經(jīng)關鍵的索普-齊格勒反應,自身環(huán)合異構化高效制備了DHEA螺吲哚環(huán)己二烯衍生物Ⅱ-8a-m�；衔铫�-8a和Ⅱ-8b對G+金黃色葡萄球菌和耐藥的MRSA菌均有良好的抑菌活性,最優(yōu)可達到MIC50=2μM;化合物對PC-3、Hela和EC-109細胞都具有良好的抑制作用,尤其是Ⅱ-8a、Ⅱ-8b表現(xiàn)出相當強的抑制效果,對PC-3活性是5-FU的4倍,Hela更是達到了8倍,且合成的所有化合物對GES-1的IC50128μM,顯示出極好的選擇性;此外,化合物Ⅱ-8a可呈濃度依賴性的方式促進PC-3細胞的線粒體膜電位降低和誘導PC-3細胞凋亡,尤其是早期凋亡細胞且具有濃度依賴性特征。(2)以DHEA為原料,與乙酰乙酸乙酯通過酯交換得到化合物Ⅱ-11,然后化合物Ⅱ-11與芳香醛和脲(或硫脲)在甲磺酸催化下以一鍋多組分的Biginelli反應構建去氫表雄酮嘧啶類衍生物Ⅱ-14a-r�；衔铫�-14a-r對肺癌A549的抑制活性是最好的,其中Ⅱ-14k的抑制程度可達到陽性對照5-FU的活性3倍(IC50=4.0μM,5-FU的IC50=12.0μM),Ⅱ-14l也是5-FU的兩倍強度,甲基、異丙基、異丁基烷基取代苯基的嘧啶衍生物也表現(xiàn)出強于5-FU的優(yōu)秀抑制活性。(3)以DHEA與芳香醛發(fā)生Claisen-Schmidt縮合而成的α,β 不飽和酮結構,堿性條件下與活潑1,4-二硫-2,5-二醇發(fā)生分子內Sulfa-Michael反應和Aldol反應,一步高效地構建了一系列具有一個C-C鍵、一個C-S鍵和一個全碳季碳手性中心的去氫表雄酮D環(huán)螺噻吩類衍生物Ⅱ-19a-f。此系列化合物對EC-109、PC-3、Hela和F10B16都有較強的抑制活性,尤其PC-3和Hela的抑制效果都優(yōu)于5-FU,其中化合物Ⅱ-19a的IC50=1.8μM,是陽性對照5-FU的8.5倍(IC50=15.4μM);化合物Ⅱ-19a可以顯著地濃度性依賴誘導PC-3細胞凋亡,尤其是晚期凋亡;進一步的線粒體研究結果表明其隨濃度遞增促進PC-3細胞的線粒體膜電位下降。
[Abstract]:As a hot field of drug research and development, steroids have attracted more and more attention from pharmacologists because of their unique structure and polysubstitution sites. It has become more and more important to expand the structural diversity of steroids and explore their rich biological activities. The steroids after structural modification are not limited to the original hormone activity, antibacterial, anti-tumor and more potential drug effects are being found. Among them, heterocyclization of steroids is a hot spot in chemical modification of steroids. The introduction of heterocyclic structures into steroid skeleton structures can enrich the species of steroids and increase their structural novelty, complexity and diversity. At the same time, it is endowed with new biological activity, which lays the foundation for the research and development of new steroidal drugs. In this paper, the heterocyclic derivatives based on steroids were designed and synthesized, and the antitumor and antibacterial activities of the synthesized derivatives were evaluated, including the following aspects: 1) using cheap and easily available DHEA dinitrile, indigo red, malonitrile, DHEA spiroindole cyclohexadiene derivatives 鈪，

本文編號：1947963