本發(fā)明屬于藥物化學(xué)領(lǐng)域，具體涉及一類結(jié)構(gòu)新穎的對(duì)叔丁基單氧雜二同杯[4]芳烴類化合物以及該類化合物在藥物方面的應(yīng)用。
背景技術(shù)：
：杯芳烴是由酚類物質(zhì)與醛或酮通過縮合反應(yīng)得到的一類環(huán)狀低聚物，因分子形狀酷似希臘圣杯而得名為杯芳烴。它的歷史可追溯到1872年德國(guó)化學(xué)家a.baeyer(chemlife,2002,22(3):265-267)對(duì)苯酚與甲醛水溶液加熱反應(yīng)的研究，因合成方法步驟較多、收率低，所以未能引起人們的注意。二十世紀(jì)70年代末，c.d.gutsche(j.am.chem.soc.,1981,103(13):3782-3792)通過嚴(yán)格控制反應(yīng)條件成功地確立了杯[n]芳烴的高收率一步合成法，以此啟動(dòng)杯芳烴化學(xué)的迅猛發(fā)展，使杯芳烴成為繼冠醚、環(huán)糊精之后的第三代超分子主體化合物。杯芳烴與冠醚和環(huán)糊精相比具有以下特點(diǎn)：(l)空腔大小可人為調(diào)節(jié),它的空穴結(jié)構(gòu)大小調(diào)節(jié)具有較大的自由度,目前己合成了4-24個(gè)苯酚單元所構(gòu)成的不同空腔尺寸的杯芳烴；(2)構(gòu)象可變,通過改變化學(xué)反應(yīng)的條件及引入適宜的取代基可以固定所需的構(gòu)象；(3)易于化學(xué)改性與修飾,利用芳烴上不同基團(tuán)的活性及芳環(huán)不同部分的活性,通過置換、取代等化學(xué)反應(yīng)導(dǎo)入或衍生出具有特殊功能的官能團(tuán),來改善杯芳烴的自身缺陷并增強(qiáng)整體分子的選擇性；(4)多數(shù)杯芳烴便于合成且各項(xiàng)物理、化學(xué)性質(zhì)穩(wěn)定；(5)杯芳烴不但能與陰離子、陽離子還能與中性分子形成主一客體包結(jié)物,這是集冠醚、環(huán)糊精兩者之長(zhǎng)。下式1為對(duì)叔丁基杯[4]芳烴的立體結(jié)構(gòu)及分子模型，隨著對(duì)杯芳烴研究的深入發(fā)展的同時(shí)，在杯芳烴家族中還出現(xiàn)了一類由氧雜亞丙基(ch2och2)代替部分或全部橋亞甲基而形成的含更多氧的環(huán)狀低聚物。gutsche(royalsocietychem.,1989,16(2):387-398)將這類杯芳烴稱為氧雜杯芳烴(oxacalixarene)，由此打開了氧雜杯芳烴的序幕。下式2為氧雜杯芳烴的結(jié)構(gòu)，其中對(duì)叔丁基單氧雜二同杯[4]芳烴是氧雜杯芳烴家族中重要一員，與傳統(tǒng)對(duì)叔丁基杯[4]芳烴相比，二者的結(jié)構(gòu)和性能也有較大的區(qū)別。首先，由于比橋亞甲基多了兩個(gè)原子，對(duì)叔丁基單氧雜二同杯[4]芳烴的空腔比對(duì)叔丁基杯[4]芳烴的大；其次，由于對(duì)叔丁基單氧雜二同杯[4]芳烴橋連環(huán)上含有醚氧鍵的氧原子，從而使其空腔內(nèi)部比普通杯芳烴有更多絡(luò)合位點(diǎn)；其次，由于比橋亞甲基多了兩個(gè)原子，對(duì)叔丁基單氧雜二同杯[4]芳烴的空腔比對(duì)叔丁基杯[4]芳烴的大；最后，因醚鍵的柔順和自由旋轉(zhuǎn)則它的構(gòu)象更多，相應(yīng)的衍生物也就更豐富。近年來，由于對(duì)叔丁基單氧雜二同杯[4]芳烴具有獨(dú)特化學(xué)和物理性質(zhì)，引起了很多化學(xué)工作者對(duì)其研究的高度興趣，在杯芳烴的下沿引入各種基團(tuán)，構(gòu)成以杯環(huán)為骨架，并帶有特種基團(tuán)如親酯性、親水性和離子載體的主體與不同大小、性質(zhì)的客體分子相匹配。在分子識(shí)別方面，設(shè)計(jì)具有特定的基團(tuán)、杯環(huán)大小、杯環(huán)柔韌性和構(gòu)象的對(duì)叔丁基單氧雜二同杯[4]芳烴衍生物將會(huì)產(chǎn)生特殊的分子識(shí)別優(yōu)勢(shì)。對(duì)叔丁基單氧雜二同杯[4]芳烴的文獻(xiàn)報(bào)道非常有限，主要是由于母體的合成收率較低，衍生化反應(yīng)種類較少，此外，對(duì)叔丁基單氧雜二同杯[4]芳烴衍生物文獻(xiàn)報(bào)道主要用于分子離子識(shí)別，藥學(xué)方面的應(yīng)用尚未開展，因此本研究設(shè)計(jì)合成未見文獻(xiàn)報(bào)道的酰胺取代的對(duì)叔丁基單氧雜二同杯[4]芳烴衍生物，獲得結(jié)構(gòu)新穎的且水溶性優(yōu)良的氧雜杯芳烴衍生物；并選擇常見腫瘤細(xì)胞對(duì)已合成化合物進(jìn)行mtt或srb實(shí)驗(yàn)，研究所合成化合物對(duì)人癌細(xì)胞是否有細(xì)胞毒作用以及作用強(qiáng)弱，從中篩選出具有抗腫瘤活性以及活性較強(qiáng)的化合物。技術(shù)實(shí)現(xiàn)要素：本發(fā)明的目的是提供一類具有抗腫瘤活性的對(duì)叔丁基單氧雜二同杯[4]芳烴類衍生物。本發(fā)明的另一目的是提供上述對(duì)叔丁基單氧雜二同杯[4]芳烴類衍生物的制備方法及其在抗腫瘤方面的應(yīng)用。本發(fā)明的目的可以通過以下措施達(dá)到：一類對(duì)叔丁基單氧雜二同杯[4]芳烴類衍生物，其為式(i)所示的化合物或其藥學(xué)上可接受的鹽，其中，w、x、y或z分別獨(dú)立地為o或nh，r1、r2、r3或r4分別獨(dú)立地為h或r5，或者r1與r3相連構(gòu)成r6，或者r2與r4相連構(gòu)成r6，并且r1、r2、r3和r4不同時(shí)為h或r5，r5為n為1～3，r7為取代或非取代的c1～8烷基或取代或非取代的c3～8環(huán)烷基，其取代基選自：羥基、芳基、氨基、氰基或硝基，r8為h或r7，r6為m為1～3，r9為c1～6亞烷基，r10為h或c1～4烷基。在一種優(yōu)選方案中，w、x、y或z分別獨(dú)立地為o，r2或r4分別獨(dú)立地為h，r1或r3分別獨(dú)立地為r5，或者r1與r3相連構(gòu)成r6。在另一種優(yōu)選方案中，本發(fā)明的化合物可選自式(ii)化合物或式(iii)化合物，在本發(fā)明的式(i)、式(ii)或式(iii)化合物中，在一種優(yōu)選方案中，r5為更優(yōu)選的，r5為在本發(fā)明的式(i)、式(ii)或式(iii)化合物中，在一種優(yōu)選方案中，r6為更優(yōu)選的，r6為在本發(fā)明的式(i)、式(ii)或式(iii)化合物中，在一種優(yōu)選方案中，n為1或2。在本發(fā)明的式(i)、式(ii)或式(iii)化合物中，在一種優(yōu)選方案中，m為1或2。在本發(fā)明的式(i)、式(ii)或式(iii)化合物中，在一種優(yōu)選方案中，r9為c2～4亞烷基，r10為h。在本發(fā)明的式(i)、式(ii)或式(iii)化合物中，在一種優(yōu)選方案中，r7為取代或非取代的c1～6烷基或c3～6環(huán)烷基，其取代基選自：羥基、吡啶基、苯基、氨基或硝基。在一種優(yōu)選的方案中，r7為c4～6烷基、羥基取代的c1～4烷基、吡啶基取代的c1～4烷基、苯基取代的c1～4烷基、氨基取代的c2～6烷基或c5～6環(huán)烷基。在一種進(jìn)一步的優(yōu)選的方案中，r7為c4～5烷基、羥基取代的c1～2烷基、吡啶基取代的c1～2烷基、苯基取代的c1～2烷基、氨基取代的c4～6烷基或c5～6環(huán)烷基。在本發(fā)明的式(i)、式(ii)或式(iii)化合物中，在一種優(yōu)選方案中，r8為h或r7。在一種進(jìn)一步的優(yōu)選的方案中，r8為h、c4～5烷基或羥基取代的c1～2烷基。本發(fā)明的化合物，優(yōu)選采用式(ii)或式(iii)化合物中的如下具體化合物：本發(fā)明還包括藥物組合物，它以本發(fā)明中的任意化合物或其藥學(xué)上可接受的鹽為活性成分或主要活性成分，輔以藥用載體制成藥物上可接受的制劑。本發(fā)明的化合物或其藥學(xué)上可接受的鹽可應(yīng)用于制備抗癌藥物方面，特別是應(yīng)用于制備肺癌、乳腺癌、子宮頸癌或肝癌藥物方面。本發(fā)明中的式(ii)或式(iii)化合物可以由化合物1與相應(yīng)的胺反應(yīng)制得，其反應(yīng)溫度可在20～150℃范圍內(nèi)進(jìn)行調(diào)整，反應(yīng)溶劑可以直接以相應(yīng)的胺為溶劑，也可以選用常規(guī)的有機(jī)合成的反應(yīng)溶劑，例如乙醇、苯、甲苯、氯仿等。相應(yīng)的，式(i)化合物也可以采用與化合物1結(jié)構(gòu)相似的原料與相應(yīng)的胺進(jìn)行制備。除非另外說明，在說明書和權(quán)利要求中使用的以下術(shù)語具有下面討論的含義：“烷基”表示1‐20個(gè)碳原子的飽和的脂烴基，包括直鏈和支鏈基團(tuán)(本申請(qǐng)書中提到的數(shù)字范圍，例如“1‐20”，是指該基團(tuán)，此時(shí)為烷基，可以含1個(gè)碳原子、2個(gè)碳原子、3個(gè)碳原子等，直至包括20個(gè)碳原子)。含1－4個(gè)碳原子的烷基稱為低級(jí)烷基。當(dāng)?shù)图?jí)烷基沒有取代基時(shí)，稱其為未取代的低級(jí)烷基。更優(yōu)選的是，烷基是有1‐10個(gè)碳原子的中等大小的烷基(即c1～10烷基)，例如甲基、乙基、丙基、2‐丙基、正丁基、異丁基、叔丁基、戊基等。進(jìn)一步優(yōu)選的烷基是有1‐8或1‐6個(gè)碳原子，最好是，烷基為有1‐4個(gè)碳原子的低級(jí)烷基，例如甲基、乙基、丙基、2‐丙基、正丁基、異丁基或叔丁基等。烷基可以是取代的或未取代的?！皝喭榛北硎咀鳛闃蚪拥耐榛鶊F(tuán)，它可以包括1‐10個(gè)碳原子，特別是1‐6個(gè)碳原子或是1‐4個(gè)碳原子，最優(yōu)選為2‐3個(gè)碳原子。例如亞甲基、亞乙基、亞丙基、亞丁基等，在亞烷基基團(tuán)上還可以有其他烷基取代基團(tuán)?！碍h(huán)烷基”表示全部為碳的單環(huán)或稠合的環(huán)(“稠合”環(huán)意味著系統(tǒng)中的每個(gè)環(huán)與系統(tǒng)中的其它環(huán)共享毗鄰的一對(duì)碳原子)基團(tuán)，其中一個(gè)或多個(gè)環(huán)不具有完全連接的π電子系統(tǒng)；環(huán)烷基可采用含3‐8個(gè)碳原子的環(huán)烷基(即c3～8環(huán)烷基)，進(jìn)一步可采用含3‐6個(gè)碳原子的環(huán)烷基，最優(yōu)選采用含5‐6個(gè)碳原子的環(huán)烷基；環(huán)烷基的實(shí)例(不局限于)為環(huán)丙烷、環(huán)丁烷、環(huán)戊烷、環(huán)戊烯、環(huán)己烷、金剛烷、環(huán)己二烯、環(huán)庚烷和環(huán)庚三烯。環(huán)烷基可為取代的和未取代的?！胺蓟北硎?至12個(gè)碳原子的全碳單環(huán)或稠合多環(huán)基團(tuán)，具有完全共軛的π電子系統(tǒng)。芳基的非限制性實(shí)例有吡啶基、苯基、萘基和蒽基。芳基可以是取代的或未取代的?！傲u基”表示“-oh”基團(tuán)?！鞍被北硎尽?nh2”基團(tuán)?！扒杌北硎尽?cn”基團(tuán)?！跋趸北硎尽?no2”基團(tuán)?！皌-bu”表示叔丁基。本發(fā)明中所指的“藥學(xué)上可接受的鹽”表示保留母體化合物的生物有效性和性質(zhì)的那些鹽。這類鹽包括：(1)與酸成鹽，通過母體化合物的游離堿與無機(jī)酸或有機(jī)酸的反應(yīng)而得，無機(jī)酸包括鹽酸、氫溴酸、硝酸、磷酸、偏磷酸、硫酸、亞硫酸和高氯酸等，有機(jī)酸包括乙酸、三氟乙酸、丙酸、丙烯酸、己酸、環(huán)戊烷丙酸、羥乙酸、丙酮酸、草酸、(d)或(l)蘋果酸、富馬酸、馬來酸、苯甲酸、羥基苯甲酸、γ‐羥基丁酸、甲氧基苯甲酸、鄰苯二甲酸、甲磺酸、乙磺酸、萘‐1‐磺酸、萘‐2‐磺酸、對(duì)甲苯磺酸、水楊酸、酒石酸、檸檬酸、乳酸、肉桂酸、十二烷基硫酸、葡糖酸、谷氨酸、天冬氨酸、硬脂酸、扁桃酸、琥珀酸或丙二酸等。(2)存在于母體化合物中的酸性質(zhì)子被金屬離子代替或者與有機(jī)堿配位化合所生成的鹽，金屬例子例如堿金屬離子、堿土金屬離子或鋁離子，有機(jī)堿例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、n‐甲基葡糖胺、奎寧等。本發(fā)明中的“藥物組合物”指將本發(fā)明中的化合物中的一個(gè)或多個(gè)或其藥學(xué)上可接受的鹽、溶劑化物、水合物或前藥與別的化學(xué)成分，例如藥學(xué)上可接受的載體，混合。藥物組合物的目的是促進(jìn)給藥給動(dòng)物的過程。本發(fā)明中的“藥用載體”指的是對(duì)有機(jī)體不引起明顯的刺激性和不干擾所給予化合物的生物活性和性質(zhì)的藥物組合物中的非活性成分，例如但不限于：碳酸鈣、磷酸鈣、各種糖(例如乳糖、甘露醇等)、淀粉、環(huán)糊精、硬脂酸鎂、纖維素、碳酸鎂、丙烯酸聚合物或甲基丙烯酸聚合物、凝膠、水、聚乙二醇、丙二醇、乙二醇、蓖麻油或氫化蓖麻油或多乙氧基氫化蓖麻油、芝麻油、玉米油、花生油等。本發(fā)明的化合物對(duì)肺癌細(xì)胞、乳腺癌細(xì)胞、子宮頸癌細(xì)胞或肝癌細(xì)胞具有較好的生長(zhǎng)抑制活性，為抗腫瘤藥物，特別是抗肺癌、乳腺癌、子宮頸癌或肝癌藥物的研發(fā)提供了新的方向。具體實(shí)施方式以下結(jié)合實(shí)施例對(duì)本發(fā)明的內(nèi)容做進(jìn)一步說明，但本發(fā)明的保護(hù)范圍并不局限于下述各實(shí)施例。實(shí)施例1:化合物1a-1b的合成7,13,19,25-四叔丁基-28,30-二羥基-27,29-二乙氧羰甲氧基單氧雜二同杯[4]芳烴(化合物1，下同)(1.0mmol)和過量的乙醇胺或二乙醇胺(過量100％)溶于乙醇和甲苯混合溶液中(1：1，50ml)回流72h，反應(yīng)結(jié)束后，旋蒸除去溶劑，向油狀物中加入少量乙醇，再加入少量蒸餾水析出固體，抽濾得到粗產(chǎn)品，經(jīng)過薄層層析得到產(chǎn)物1a-1b。1a:whitesolid,m.p.:139.7-142.3℃,yield:87.23％.1hnmr(cdcl3,400mhz)δ1.03,1.20,1.26,1.29(4s,36h),3.44-3.53(m,5h),3.59-3.64(m,2h),3.79(s,4h),4.17-4.29(m,4h),4.38(d,1h,j＝10.2hz),4.52-4.68(m,5h),4.84(d,1h,j＝10hz),6.85(d,1h,j＝1.6hz),6.92(d,1h,j＝2.4hz),7.02(d,2h,j＝2hz),7.16(d,1h,j＝2hz),7.21-7.24(m,2h),7.31(s,1h),7.38(d,2h,j＝2.4hz),8.78(d,1h,j＝0.4hz),8.84(s,1h)；13cnmr(cdcl3,100mhz)δ31.0,31.2,31.4,31.5,31.9,34.0,34.1,34.2,42.5,62.0,62.2,70.8,72.1,73.9,74.4,76.7,77.0,77.2,77.3,122.7,124.7,125.9,126.0,126.3,127.1,127.4,127.7,127.8,128.0,128.8,129.3,131.9,132.1,133.6,143.1,143.8,148.1,148.4,148.8,149.9,151.2,152.6,169.4,169.7；ir(kbr)v3389,3366,2959,2870,1666,1545,1485,1447,1362,874；msm/z:hrms(esi)calcd:forc53h72n2nao9([m+na]+):903.5130,found:903.5145.1b:whitesolid,m.p.:210.7-212.5℃,yield:86.73％.1hnmr(dmso,400mhz)δ1.11(s,9h),1.19(d,18h,j＝6.4hz,),1.24(s,9h),3.36-3.45(t,6h),3.54-3.62(m,10h),3.67(s,2h),3.87-3.91(t,1h),4.19(d,1h,j＝9.2hz),4.26(d,1h,j＝10hz),4.35,4.38(abq,2h,j＝6hz),4.56(d,1h,j＝12.8hz),4.65-4.75(m,2h),4.78(s,1h),5.03(s,1h),5.06(d,1h,j＝6hz),5.32(d,1h,j＝13.2hz),6.89(d,1h,j＝2.4hz),7.00(d,1h,j＝2hz),7.02(d,1h,j＝2hz),7.13(s,1h),7.16(s,1h),7.22(d,1h,j＝2hz),7.36(s,1h),7.48(d,1h,j＝2hz),7.71(s,1h),8.61(s,1h)；13cnmr(dmso,100mhz)δ30.3,31.4,31.6,31.8,31.9,34.0,34.3,34.3,39.4,39.8,40.0,40.2,40.4,40.6,48.6,48.8,49.9,50.6,58.7,59.1,59.3,73.1,122.8,125.7,126.7,127.2,127.9,128.1,129.8,133.0,133.4,134.4,140.7,141.0,146.1,146.8,150.0,152.1,152.4,155.3,169.3,169.6；ir(kbr)v3389,3045,2957,2870,1643,1485,1443,1364,876；msm/z:hrms(esi)calcd:forc57h80n2nao11([m+na]+):991.5654,found:991.5674.實(shí)施例2:化合物1c-1e的合成7,13,19,25-四叔丁基-28,30-二羥基-27,29-二乙氧羰甲氧基單氧雜二同杯[4]芳烴1(1.0mmol)溶于2-氨甲基吡啶、3-氨甲基吡啶或4-氨甲基吡啶(2ml)中，加熱到70℃反應(yīng)72h,反應(yīng)結(jié)束后，加入少量蒸餾水析出固體，抽濾得到粗產(chǎn)品，經(jīng)過薄層層析得到產(chǎn)物1c-1e.1c:lightyellowsolid,m.p.:134.8-136.2℃,yield:87.28％.1hnmr(cdcl3,400mhz)δ1.091.22(2s,18h),1.25(d,18h,j＝2hz),3.35(t,2h,j＝14.4hz),4.08-4.21(m,3h),4.25-4.32(m,2h),4.50-4.52(m,2h),4.55-4.59(m,2h),4.62-4.69(m,4h),4.81-4.89(m,3h),6.81(d,1h,j＝2.4hz),6.89(d,1h,j＝2hz),6.94-6.97(m,1h),7.00(d,1h,j＝2.4hz),7.01-7.04(m,1h),7.06(s,2h),7.13(d,1h,j＝2hz),7.17(s,2h),7.31(d,1h,j＝8hz),7.37-7.41(m,2h),7.47-7.55(m,2h),7.80(s,1h),8.21(d,1h,j＝4.4hz),8.38(d,1h,j＝4.4hz),8.97(t,1h),9.22(t,1h)；13cnmr(cdcl3,100mhz)δ31.0,32.2,31.1,31.3,31.4,31.5,31.6,33.8,33.9,34.2,45.0,44.9,71.1,72.3,73.7,74.5,121.9,122.0,122.1,136.3,136.4,149.0,149.1,157.0,157.6,122.3,124.2,125.5,125.6,125.9,126.4,126.8,126.9127.2,127.6,127.7,128.9,129.4,132.0,133.9,142.3,143.0,147.8,148.1,149.2,145.0,151.8,153.1,168.4,168.9；ir(kbr)v3369,3049,2960,2866,1682,1591,1483,1437,1364,874；msm/z:hrms(esi)calcd:forc61h74n4nao7([m+na]+):997.5450,found:997.5470.1d:whitesolid,m.p.:134.7-135.8℃,yield:79.23％.1hnmr(cdcl3,400mhz)δ1.15,1.240(2s,18h),1.27(d,18h,j＝2.8hz),3.36-3.40(m,2h),3.49(d,1h,j＝13.6hz),3.97(d,1h,j＝13.2hz),4.03(t,1h),4.10(d,1h,j＝13.2hz),4.20(d,1h,j＝10.4hz),4.28(d,1h,j＝10hz),4.41-4.48(m,4h),4.56(d,1h,j＝15.2hz),4.72(d,1h,j＝15.2hz),4.76-4.84(m,3h),4.85-4.90(m,1h),6.84(d,1h,j＝2.4hz),6.93-6.96(m,2h),7.03(d,1h,j＝2.8hz),7.11(d,1h,j＝2.4hz),7.13-7.19(m,4h),7.31(d,1h,j＝7.6hz),7.42(d,1h,j＝2.4hz),7.60(m,1h),7.73-7.76(m,1h),7.87(s,1h),8.36-8,38(m,1h),8,48-8.50(m,1h),8,63(d,1h,j＝2hz),8.70(d,1h,j＝2hz),9.14(d,1h,j＝0.8hz),9.43(s,1h)；13cnmr(cdcl3,100mhz)δ31.1,32.2,31.5,33.9,34.2,40.9,41.0,71.1,72.2,73.7,74.4,122.2,123.3,123.4,124.5,135.9,136.0,148.9,149.5,151.0,152.8,125.67,125.9,126.2,126.7,126.8,127.1,127.2,127.6,128.6,129.4,131.4,132.2,133.2,133.7,143.0,143.6,148.2,148.4,148.6,148.8,149.6,149.8,168.2,168.7；ir(kbr)v3360,3045,2961,2868,1678,1483,1364,1298,874；msm/z:hrms(esi)calcd:forc61h74n4nao7([m+na]+):997.5450,found:997.5474.1e:lightyellowsolid,m.p.:138.6-140.4℃,yield:98.10％.1hnmr(cdcl3,400mhz)δ1.16,1.24(2s,18h),1.28(d,18h,j＝3.2hz),3.40,3.43(dd,2h,j＝6.4,7.2hz),3.53(d,1h,j＝13.6hz),3.94(d,1h,j＝13.6hz),4.08-4.19(m,3h),4.23-4.28(m,2h),4.36-4.46(m,3h),4.56(d,1h,j＝15.2hz),4.69(d,1h,j＝15.2hz),4.74-4.92(m,4h),6.85(d,1h,j＝1.2hz),7.02(t,2h),7.13(s,1h),7.17(t,2h),7.23(s,3h),7.33(t,3h),7.44(d,1h,j＝1.6hz),8.00(s,1h),8.33(d,2h,j＝5.2hz),8.50(d,2h,j＝5.6hz),9.18(s,1h),9.55(d,1h,j＝0.8hz)；13cnmr(cdcl3,100mhz)δ30.0,32.2,31.1,31.2,31.5,33.9,34.2,34.3,42.3,42.6,71.2,72.1,73.5,74.3,122.2,123.0,132.2,133.6,148.8,149.2,124.5,125.7,126.0,126.1,126.8,126.9,127.1,127.2,127.6,128.6,129.5,131.4,143.2,143.8,148.1,146.8,148.3,148.3,149.9,150.0,168.4,168.9；ir(kbr)v3352,3049,2961,2868,1682,1601,1485,1284,876；msm/z:hrms(esi)calcd:forc61h74n4nao7([m+na]+):997.5450,found:997.5475.實(shí)施例3:化合物1f-1g的合成7,13,19,25-四叔丁基-28,30-二羥基-27,29-二乙氧羰甲氧基單氧雜二同杯[4]芳烴1(1.0mmol)溶于丁二胺或己二胺(2ml)中，室溫下反應(yīng)24h，反應(yīng)結(jié)束后，加入少量蒸餾水析出固體，抽濾得到粗產(chǎn)品，經(jīng)過薄層層析得到產(chǎn)物1f-1g。1f:whitesolid,m.p.:129.4-131.2℃,yield:96.18％.1hnmr(cdcl3,400mhz)δ1.16(s,9h),1.25(t,27h),1.32(d,2h,j＝11.2hz),1.41(t,2h),1.45(d,3h,j＝33.2hz),1.65(d,5h,j＝62.0hz),3.22(d,2h,j＝33.2hz),3.43(t,2h),3.60(d,2h,j＝54.8hz),4.10(d,1h,j＝13.6hz),4.19(t,2h),4.35(s,1h),4.39(t,2h),4.44(d,1h,j＝9.2hz),4.50(d,1h,j＝11.2hz),4.58(d,1h,j＝10.0hz),4.77,4.83(dd,2h,j＝14.8hz),4.96(d,1h,j＝10.4hz),6.87(d,1h,j＝2.4hz),7.01(d,1h,j＝2.4hz),7.04(d,1h,j＝2.0hz),7.14(d,1h,j＝2.4hz),7.16(d,1h,j＝2.4hz),7.23(t,2h,j＝2.4hz),7.46(d,1h,j＝2.4hz),8.24(s,1h),8.74(s,1h),9.00(t,1h)；13cnmr(cdcl3,100mhz)δ26.4,26.9,31.0,31.1,31.3,31.5,31.5,31.5,31.6,32.4,33.9,33.9,34.3,34.3,39.2,39.5,41.9,42.0,71.2,71.9,73.8,74.5,122.2,124.4,125.7,126.0,126.0,126.9,127.0,127.2,127.3,127.4,127.6,128.6,129.6,131.5,132.4,133.7,143.0,143.7,148.0,148.6,148.9,149.5,151.4,153.2,168.0,168.5；ir(kbr)v3369.4,3193.9,2958.6,2866.0,1674.3,1483.2,1296.1,873.7；msm/z:hrms(esi)calcd:forc57h83n4o7([m+h]+):935.6256,found:935.6284.1g:whitesolid,m.p.:123.3-125.9℃,yield:63.30％.1hnmr(cdcl3,400mhz)δ1.16(s,9h),1.24(s,18h),1.26(s,9h),1.31(d,10h,j＝12.0hz),1.62(m,5h),1.97(d,1h,j＝3.6hz),2.52(t,2h,j＝6.0hz),2.59(t,2h,j＝6.4hz),2.8(t,1h,j＝7.2hz),3.21(m,3h),3.43(t,3h,j＝12.8hz),3.60(m,3h),4.09(t,1h),4.16(m,2h),4.35(m,2h),4.74(t,2h,j＝15.6hz),4.93(d,1h,j＝13.0hz),6.87(d,1h,j＝2.0hz),7.02(m,2h),7.14(m,2h),7.22(m,2h),7.45(d,1h,j＝2.4hz),8.22,(s,h),8.70,8.97(2s,2h)；13cnmr(cdcl3,100mhz)δ26.5,26.5,26.9,26.97,29.1,29.5,31.1,31.3,31.4,31.5,33.6,33.7,33.9,34.0,34.3,34.3,39.2,39.5,42.0,42.1,72.0,73.8,74.5,122.2,124.3,126.0,126.9,127.0,127.2,127.4,127.6,128.6,129.6,131.5,132.3,133.7,142.9,143.6,148.0,148.6,148.9,149.4,151.5,153.2,167.9,168.4；ir(kbr)v3350.1,3215.1,2956.7,2862.2,1674.1,1483.2,1298.0,817.8；msm/z:hrms(esi)calcd:forc61h91n4o7([m+h]+):991.6882,found:991.6883.實(shí)施例4:化合物1h-1i的合成7,13,19,25-四叔丁基-28,30-二羥基-27,29-二乙氧羰甲氧基單氧雜二同杯[4]芳烴1(1.0mmol)溶于乙二胺或丙二胺(2ml)中，冰浴下反應(yīng)1h，然后將冰浴撤去常溫反應(yīng)24h。反應(yīng)結(jié)束后，加入少量蒸餾水析出固體，抽濾得到粗產(chǎn)品，經(jīng)過薄層層析得到產(chǎn)物1h-1i。1h:whitesolid,m.p.:204.8-206.3℃,yield:86.60％.1hnmr(cdcl3,400mhz)δ1.16,1.24(2s,18h),1.26(d,18h,j＝2.4hz),3.16(m,2h),3.38,3.42(dd,2h,j＝2.8hz),3.58(d,1h,j＝13.6hz),4.01(d,1h,j＝13.6hz),4.18(m,3h),4.24(d,1h,j＝9.6hz),4.28(d,1h,j＝14.0hz),4.42(m,3h),4.67(d,1h,j＝14.4hz),4.77(t,2h),4.89(d,1h,j＝9.6hz),6.89(d,1h,j＝2.4hz),7.01,7.02(dd,2h,j＝2.4hz),7.08(d,1h,j＝2.4hz),7.13(d,2h,j＝3.2hz),7.26(s,1h),7.28(d,1h,j＝2.4hz),7.53,8.11(2s,2h),8.31(m,1h),8.62(m,1h)；13cnmr(cdcl3,100mhz)δ29.5,30.5,31.2,31.3,31.5,31.5,31.6,33.9,33.9,34.3,34.3,39.2,39.6,71.3,72.8,73.7,74.0,122.6,124.4,125.8,126.1,126.2,126.4,126.8,127.1,127.8,128.0,128.9,129.6,131.4,131.8,134.1,143.0,143.1,147.5,147.8,148.7,149.1,151.9,152.2,167.8,168.7；ir(kbr)v3373.3,3180.4,3049.3,2960.5,2868.0,1691.5,1529.5,1483.2,1363.6,1296.1,873.7；msm/z:hrms(esi)calcd:forc51h66n2nao7([m+na]+):841.4762,found:841.4771.1i:whitesolid,m.p.:189.5-191.4℃,yield:92.00％.1hnmr(cdcl3,400mhz)δ1.16(s,9h),1.25(t,27h),2.33(d,2h,j＝35.6hz),3.26(s,2h),3.41,3.44(dd,2h,j＝1.2hz),3.57(d,1h,j＝13.6hz),3.66(d,1h,j＝14.8hz),3.76(d,1h,j＝16.8hz),4.05(d,1h,j＝14.0hz),4.15(d,1h,j＝13.2hz),4.24(m,2h),4.31(d,1h,j＝12.8hz),4.39(t,2h),4.72(t,2h),4.84(m,2h),6.90(s,1h),7.03(s,2h),7.13(d,2h,j＝13.2hz),7.32(s,1h),7.50,8.16(2s,2h),8.50,8.69(2s,2h)；13cnmr(cdcl3,100mhz)δ23.2,30.0,31.0,31.1,31.3,31.5,31.5,32.3,33.9,34.3,34.3,36.1,36.11,71.0,72.4,73.8,74.0,122.7,124.7,125.9,125.9,126.2,126.3,126.5,126.8,126.9,127.5,128.0,129.1,129.6,131.2,131.9,133.7,143.1,143.3,148.0,148.2,148.7,149.1,151.8,152.6,168.2,169.3；ir(kbr)v3377.1,3049.3,2960.5,2868.0,1689.5,1598.9,1483.2,1442.7,1298.0,873.7；msm/z:hrms(esi)calcd:forc52h68n2nao7([m+na]+):855.4919,found:855.4922。實(shí)施例5:化合物1j-1o的合成7,13,19,25-四叔丁基-28,30-二羥基-27,29-二乙氧羰甲氧基單氧雜二同杯[4]芳烴1(1.0mmol)溶于乙醇/氯仿混合溶液(6ml,2:1)中，冰浴下攪拌，將相應(yīng)的脂肪胺溶于乙醇中，然后緩慢滴入反應(yīng)液中，反應(yīng)1h后，撤去冰浴，常溫反應(yīng)5h。反應(yīng)結(jié)束后，減壓蒸去溶液，加入少量乙醇溶解，再加入少量蒸餾水析出固體，抽濾得到粗產(chǎn)品，經(jīng)過薄層層析得到產(chǎn)物1j-1o。1j:whitesolid,m.p.:183.7-186.4℃,yield:72.01％.1hnmr(cdcl3,400mhz)δ1.12,1.20(2s,18h),1.25(d,18h,j＝2hz),3.32(t,2h,j＝12.8hz),3.42(d,1h,j＝13.6hz),3.90(d,1h,j＝13.6hz),4.01,4.04(dd,2h,j＝4.4hz),4.13,4.17(dd,2h,j＝10hz),4.29(t,2h),4.41-4.57(m,4h),4.66(t,2h),4.72,4.76(dd,1h,j＝6.4hz),4.81,4.84(dd,1h,j＝6.4hz),6.79(d,1h,j＝2.4hz),6.92(d,1h,j＝2.4hz),6.98(d,1h,j＝2.8hz),7.04-7.11(m,6h),7.13(s,1h),7.15(d,1h,j＝2.4hz),7.20(t,3h),7.27(d,1h,j＝1.6hz),7.28(s,1h),7.37,7.39(dd,2h,j＝2hz),7.74(s,1h),8.93(t,1h),9.25,9.26(dd,1h,j＝5.6hz)；13cnmr(cdcl3,100mhz)δ31.1,31.2,31.5,31.6,32.2,33.9,34.2,43.6,43.8,71.0,72.2,73.8,74.5,122.3,124.5,125.5,125.7,126.1,126.6,126.7,126.9,127.0,127.2,127.3,127.5,128.4,128.5,128.7,129.4,131.4,132.1,133.7,137.4,138.0,142.6,143.2,148.0,148.3,148.7,149.6,151.3,153.0,168.1,168.5；ir(kbr)v3448,3389,2955,2870,1670,1485,1438.80；msm/z:hrms(esi)calcd:forc63h77n2o7([m+h]+):973.5725,found:973.5716.1k:whitesolid,m.p.:114.6-115.9℃,yield:67.05％.1hnmr(cdcl3,400mhz)δ1.15,1.24(2s,18h),1.28(d,18h,j＝4hz),2.88-3.04(m,4h),3.27(d,1h,j＝13.2hz),3.32(d,1h,j＝12.8hz),3.46-3.58(m,3h),3.84-3.98(m,4h),4.14(d,1h,j＝13.2hz),4.18(d,1h,j＝10.4hz),4.32(d,1h,j＝10hz),4.37(d,1h,j＝14.8hz),4.43(d,1h,j＝8.8hz),4.46(d,1h,j＝3.6hz),4.73(d,1h,j＝7.6hz),4.76(d,1h,j＝8hz),4.88(d,1h,j＝10.4hz),6.85(d,1h,j＝1.6hz),6.94-6.99(m,2h),7.03-7.22(m,14h),7.43(d,1h,j＝2hz),7.48,8.05(2s,2h),8.79(t,1h,j＝5.2hz),9.01(t,1h,j＝5.6hz)；13cnmr(cdcl3,100mhz)δ31.1,31.3,31.6,32.4,33.9,34.2,35.1,35.5,40.5,40.6,71.1,72.0,73.9,74.4,122.2,124.2,125.5,125.9,126.0,126.1,126.2,126.8,127.0,127.2,127.3,127.5,128.2,128.4,128.5,128.7,129.6,131.6,132.4,133.8,138.6,138.9,142.8,143.5,147.9,148.5,148.8,149.3,151.4,153.0,168.0,168.5；ir(kbr)v3346,2961,2905,2866,1682,1537,1483,1445,1364；msm/z:hrms(esi)calcd:forc65h80n2nao7([m+na]+):1023.5860,found:1023.5870.1l:whitesolid,m.p.:128.-130.8℃,yield:86.52％.1hnmr(cdcl3,400mhz)δ0.90-0.98(m,12h),1.16(s,9h),1.25(d,27h,j＝7.6hz),1.85,1.98(2s,2h),2.99(d,2h,j＝38hz),3.42(t,3h),3.56(d,2h,j＝13.6hz),4.08(d,1h,j＝15.2hz),4.21(d,2h,j＝12.4hz,4.35-4.48(m,4h),4.59(d,1h,j＝10.4hz),4.77,4.83(dd,2h,j＝15.6hz),4.96(d,1h,j＝10.4hz),6.85(s,1h),7.02(d,2h,j＝6hz),7.14(d,2h,j＝11.2hz),7.21(s,2h),7.47(d,2h,j＝14.4hz),8.09(s,1h),8.62,8.94(2s,2h)；13cnmr(cdcl3,100mhz)δ20.4,20.5,28.5,20.7,30.9,31.1,31.3,31.5,32.4,33.9,34.2,34.3,46.8,47.0,71.2,72.0,73.9,74.5,122.1,124.2,125.5,125.9,126.0,126.9,127.0,127.2,127.3,127.4,127.6,128.6,129.6,131.7,132.3,133.8,142.8,143.4,147.8,148.5,148.8,149.5,151.5,153.2,168.0,168.6；ir(kbr)v3350,3194,2961,2870,1680,1483,1364；msm/z:hrms(esi)calcd:forc57h80n2nao7([m+na]+):927.5858,found:927.5873.1m:whitesolid,m.p.:119.5-120.8℃,yield:91.85％.1hnmr(cdcl3,400mhz)δ0.84(t,3h,j＝7.2hz),0.92(t,3h,j＝7.2hz),1.17(s,9h),1.26(d,27h,j＝8.4hz),1.32-1.43(m,4h),1.57-1.71(m,4h,3.19-3.31(m,2h),3.44(t,2h,j＝14hz),3.50-3,57(m,2h),3.61-3.66(m,1h),4.11(d,1h,j＝13.2hz),4.17-4.24(m,2h),4.35-4.42(m,3h),4.49(d,1h,j＝15.2hz),4.63(d,1h,j＝10hz),4.73,4.78(dd,2h,j＝15.2hz),4.93(d,1h,j＝10.4hz),6.88(d,1h,j＝2hz),7.02,7.05(dd,2h,j＝1.6hz),7.15,7.17(dd,2h,j＝1.6hz),7.22,7.24(dd,2h,j＝1.6hz),7.46(d,1h,j＝2hz),7.55,8.14(2s,2h),8.67(t,1h,j＝5.2hz),8.89-8.92(m,1h)；13cnmr(cdcl3,100mhz)δ13.7,13.8,20.2,20.2,31.1,31.3,31.4,31.5,31.6,32.3,33.9,34.3,34.3,39.1,39.3,71.1,72.1,74.0,74.5,122.2,124.4,125.6,125.9,126.0,127.1,127.2,127.3,127.4,127.6,128.7,129.6,131.6,132.3,133.8,142.8,143.5,148.0,148.5,148.9,149.6,151.5,153.2,167.8,168.3；ir(kbr)v3350,3049,2959,2868,1682,1537,1298,874；msm/z:hrms(esi)calcd:forc57h80n2nao7([m+na]+):927.5858,found:927.5874.1n:lightyellowsolid,m.p.:117.7-119.3℃,yield:72.36％.1hnmr(cdcl3,400mhz)δ0.67(t,3h,j＝7.2hz),0.82(t,3h,j＝7.2hz),1.16(s,9h),1.25(t,27h),1.37(d,7h,j＝42.4hz),1.60(d,5h,j＝56.4hz),3.15-3.25(m,2h),3.43(t,2h),3.50-3.65(m,3h),4.09(d,1h,j＝13.6hz),4.18,4.22(dd,2h,j＝13.2,10.4hz),4.37(d,2h,j＝14.4hz),4.41(d,1h,j＝10.4hz),4.47(d,1h,j＝14.8hz),4.61(d,1h,j＝10hz),4.77(t,2h),4.93(d,1h,j＝10.4hz),6.87(d,1h,j＝2hz),7.01(d,1h,j＝2.4hz),7.04(d,1h,j＝2.4hz),7.14,7.16(dd,1h,j＝2hz),7.22,7.23(dd,2h,j＝2.4hz),7.46(d,1h,j＝2.4hz),7.54(s,1h),8.19(s,1h),8.68,8.95(2s,2h)；13cnmr(cdcl3,100mhz)δ13.8,14.0,22.4,22.5,28.9,29.3,31.0,31.1,31.3,31.4,31.5,32.4,33.9,34.3,39.4,39.6,71.2,72.1,73.9,74.5,122.2,124.4,125.6,126.0,126.9,127.0,127.2,127.3,127.4,127.7,128.7,129.6,131.6,132.3,133.8,142.9,143.5,147.9,148.5,148.9,149.5,151.5,152.2,167.8,168.3；ir(kbr)v3348,3049,2959,2868,1682,1599,1537,1485,1445,874；msm/z:hrms(esi)calcd:forc59h84n2nao7([m+na]+):956.3100,found:955.6174.1o:whitesolid,m.p.:145.9-148.2℃,yield:83.61％.1hnmr(dmso,400mhz)δ1.12,1.22(2s,18h),1.25(d,18h,j＝6.8hz),1.51-1.72(m,12h),1.91(d,4h,j＝16.8hz),3.47,3.50(dd,2h,j＝6.4hz),3.58(d,1h,j＝13.2hz),4.21,4.25(dd,5h,j＝13.2,10.4hz),4.34-4.42(m,3h),4.47(d,1h,j＝14.8hz),4.57(d,1h,j＝14.8hz),4.66,4.71(dd,2h,j＝14.8,10.4hz),4.93(d,1h,j＝10hz),6.95,7.05,7.10(3s,3h),7.29(d,2h,j＝8.4hz),7.35(s,1h),7.46(s,1h),7.60(s,2h),8.14(s,1h),8.32(d,1h,j＝7.6hz),8.47(d,1h,j＝7.2hz)；3cnmr(dmso,100mhz)δ24.1,30.0,31.3,31.5,31.8,32.3,32.4,32.8,33.0,34.1,34.4,50.7,50.8,71.5,74.1,74.5,122.3,126.1,126.3,127.1,127.3,127.5,128.2,128.3,129.4,129.5,132.9,134.1,142,1,142.5,147.2,147.4,149.5,151.1,151.8,153.9,167.6,168.1；ir(kbr)v3342,3049,2961,2870,1682,1529,1483；msm/z:hrms(esi)calcd:forc59h80n2nao7([m+na]+):951.5858,found:951.5862.實(shí)施例6：srb法：細(xì)胞以含10％胎牛血清的培養(yǎng)液培養(yǎng)，使細(xì)胞一直處于對(duì)數(shù)生長(zhǎng)期。細(xì)胞接種于96孔培養(yǎng)板，密度1-5×104/ml。37℃，5％co2培養(yǎng)箱預(yù)培養(yǎng)24小時(shí)，藥物設(shè)5－7個(gè)濃度，每個(gè)濃度設(shè)3個(gè)復(fù)孔，連續(xù)作用72小時(shí)。藥物作用結(jié)束后，用三氯乙酸(tca)固定細(xì)胞，清洗后加入srb工作液，洗滌，用trisbase溶解與蛋白結(jié)合的srb，spectramax190細(xì)胞標(biāo)儀565nm波長(zhǎng)下測(cè)定每個(gè)小孔的od值?？瞻讓?duì)照孔加20μl培養(yǎng)液。根據(jù)od值，計(jì)算細(xì)胞生長(zhǎng)抑制率：抑制率(％)＝(對(duì)照組od值-用藥組od值)/對(duì)照組od值×100％然后計(jì)算出化合物的ic50值，相關(guān)結(jié)果見下表1和2。表1各化合物對(duì)不同癌細(xì)胞的ic50值化合物a549(um)mcf-7(um)hela(um)hepg2(um)1a2.0±0.51.0±0.10.8±0.22.7±0.41b3.9±0.54.4±0.71.1±0.53.8±0.31c3.6±1.59.4±1.310.8±1.522.7±3.01d2.6±0.51.0±0.47.9±1.08.8±0.81e2.4±0.31.2±0.23.9±0.617.6±1.21f3.3±0.75.4±2.62.3±0.15.0±0.81g0.7±0.11.8±0.71.9±0.12.6±0.2表2各化合物對(duì)a549癌細(xì)胞的ic50值化合物a549(um)1h12.4±2.21i2.9±0.71j6.8±0.51k12.6±2.01l16.9±3.21m4.5±1.41n1.7±0.41o10.1±1.8注：a級(jí)：1a,1b,1c,1d,1e,1f,1g。b級(jí)：1h,1i,1j,1k,1l,1m,1n,1o。當(dāng)前第1頁12