CN115141171B - 3,6-二酰胺取代的α-倒捻子素衍生物、其制备方法及应用 - Google Patents
3,6-二酰胺取代的α-倒捻子素衍生物、其制备方法及应用 Download PDFInfo
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- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
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- 238000009987 spinning Methods 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- BHLXTPHDSZUFHR-UHFFFAOYSA-N varespladib Chemical compound CCC1=C(C(=O)C(N)=O)C2=C(OCC(O)=O)C=CC=C2N1CC1=CC=CC=C1 BHLXTPHDSZUFHR-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
- C07D311/82—Xanthenes
- C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
- C07D311/86—Oxygen atoms, e.g. xanthones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
Abstract
本发明公开了3,6‑二酰胺取代的α‑倒捻子素衍生物、其制备方法及应用，属于药物化学领域，涉及A环的3位及B环的6位均被乙酰胺类官能团取代。其制备方法简单，条件温和，收率高。活性试验结果表明，本发明公开的衍生物对食管癌KYSE 30、直肠癌HCT 116、胃癌HGC 27细胞系有明显的抑制活性，可应用于制备抗食管癌、直肠癌、胃癌等消化道癌症的药物。其化学结构通式见下：，R1、R2各自独立地选自氢、C1‑3的烷基、羟基、、2,2,2‑三氟乙基、羟乙基、丙腈基、氯乙基、环丙基、、，NR1R2还为或，A为CH2、O或NH。
Description
技术领域
本发明属于药物化学领域，具体涉及一种3,6-二酰胺取代的α-倒捻子素衍生物、其制备方法及应用。
背景技术
基于一些天然产物的结构修饰是筛选抗癌药物行之有效的方法，帕比司他是瑞士诺华开发的一种组蛋白脱乙酰酶抑制剂，该药于2015年经FDA批准上市，主要用于治疗多发性骨髓瘤，为口服制剂(Bhutani et al,J.Med.Chem.64：2339-2381；2021)。异-康普瑞汀A-4(isoCA-4)衍生物(isoCA-4-1、isoCA-4-2)具有很强的微管蛋白聚合酶和HDAC抑制活性，对结肠癌HCT 116细胞系显示较强的体外抗增殖活性，IC50值依次为22±0.58和8±0.02nM(Lamaa et al,J.Med.Chem.61：6574-6591；2018)。上述化合物的侧链均存在异羟肟酸结构，为活性必需基团。
α-倒捻子素是从植物山竹果皮中提取的一种氧杂蒽酮类化合物，能参与蛋白激酶磷酸化的各种致癌进程，对肿瘤细胞有一定的抑制作用。发明人研究发现，α-倒捻子素对食管癌KYSE 30、结肠癌HCT 116、胃癌HGC 27细胞系体外增殖抑制活性的IC50值分别为16.48±1.26、11.77±0.97、10.8±0.78μM。为提高α-倒捻子素的抗肿瘤活性，考虑在A环3位和B环6位同时引入系列乙酰胺结构进行修饰，以期提高其抗肿瘤活性。
本发明公开的3,6-二酰胺取代的α-倒捻子素衍生物开发为治疗食管癌、胃癌、直肠癌等消化道癌症的新型药物具有潜在的应用价值，对开发自主知识产权药物具有重要意义，目前未见相关文献报道。
发明内容
本发明目的在于提供一种3,6-二酰胺取代的α-倒捻子素衍生物、其制备方法及应用。
为实现本发明目的，技术方案如下：
一种3,6-二酰胺取代的α-倒捻子素衍生物，具有如下结构通式：
R1、R2各自独立地选自氢、C1-3的烷基、羟基、2,2,2-三氟乙基、羟乙基、丙腈基、氯乙基、环丙基、/>NR1R2还为/>A为CH2、O或NH。
优选地，具体为如下结构的化合物：
上述的3,6-二酰胺取代的α-倒捻子素衍生物的制备方法，合成路线如下：
合成过程如下：
(1)将化合物1(α-倒捻子素)溶于反应溶剂中，加入碱、碘化钾和化合物2，加热至110±10℃，搅拌发生Williamson醚化反应，冷却至室温，过滤，旋干，残留物经硅胶柱层析分离，得到化合物3；
(2)在0±5℃下，将化合物3加入新鲜的羟胺溶液发生氨解反应，反应完毕，旋干，得残留物，加入纯水，溶解残留物，用酸溶液(具体用盐酸)调节反应液pH至6～7，析出沉淀，抽滤，生成化合物4a，或在室温下，化合物3溶于反应溶剂中，再加入碱溶液发生酯的水解，反应完成后，用酸(具体用盐酸)调节反应液pH至5～6，旋干，得到羧酸4b；
(3)将化合物4b溶于反应溶剂中，室温下，加入酰胺缩合剂、碱，与胺类化合物5发生酰胺缩合反应，反应完成后，反应液倾入冰水中，淬灭，析出固体，抽滤，水洗涤，得产物，若未能析出固体，采用乙酸乙酯萃取，经硅胶柱层析分离纯化，生成化合物6。
优选地，步骤(1)中，化合物1、碱、碘化钾和化合物2的摩尔比为1:(10～12):(0.60～0.65):(2～3)；
步骤(2)中，制备化合物4a时，化合物3与羟胺的摩尔比为1:10～12，新鲜的羟胺溶液是指新鲜的羟胺甲醇溶液，其浓度为1～2mmol/mL；制备化合物4b时，化合物3与碱的摩尔比为1:3～4；碱溶液的浓度为1mol/L；
步骤(3)中，化合物4b、酰胺缩合剂、碱和化合物5的摩尔比为1:(2～3):(2～3):(3～3.5)。
优选地，步骤(1)中，所用的碱为碳酸钾、碳酸钠、氢氧化钠、氢氧化锂、氢化钠中的一种或两种以上的混合物；所用的反应溶剂为丙酮、乙腈或甲醇；
步骤(2)中，化合物4b制备时所用的碱为氢氧化钠、氢氧化锂、氢氧化钾中的一种或两种，所用的反应溶剂为甲醇、乙醇中的一种或两种；
步骤(3)中，所用的酰胺缩合剂为HATU、HBTU、HOBt、DCC、EDCI、DIC中的一种或两种，碱为DIPEA、三乙胺、DBU中的一种或两种，反应溶剂为N,N-二甲基甲酰胺或N,N-二甲基乙酰胺。
上述3,6-二酰胺取代的α-倒捻子素衍生物在制备抗肿瘤药物中的应用。
进一步地，所述抗肿瘤药物为治疗食管癌、直肠癌和胃癌等消化道癌的药物。
本发明3,6-二酰胺取代的α-倒捻子素衍生物的制备方法简单，条件温和，收率高。活性试验结果表明，本发明公开的衍生物对食管癌KYSE 30、直肠癌HCT 116、胃癌HGC 27细胞系有明显的抑制活性，可应用于制备抗食管癌、直肠癌、胃癌等消化道癌症的药物。
附图说明
图1、图4为本发明衍生物4a、6a、6e、6f、6k的MTT法测试(KYSE30)结果；
图2、图5为本发明衍生物4a、6c、6e、6f、6g的MTT法测试(HCT 116)结果；
图3、图6为本发明衍生物4a、6g的MTT法测试(HGC 27)结果；
图7为α-倒捻子素(化合物1)抑制KYSE 30、HCT 116、HGC 27克隆形成结果；
图8为本发明衍生物4a抑制KYSE 30、HCT 116、HGC 27克隆形成结果；
图9为本发明衍生物6a抑制KYSE 30克隆形成结果；
图10为本发明衍生物6c抑制HCT 116克隆形成结果；
图11为本发明衍生物6e抑制KYSE 30、HCT 116克隆形成结果；
图12为本发明衍生物6f抑制KYSE 30、HCT 116克隆形成结果；
图13为本发明衍生物6g抑制HCT 116、HGC 27克隆形成结果；
图14为本发明衍生物6k抑制KYSE 30克隆形成结果；
注：图7至14中，与对照组相比，*表示P<0.05；**表示P<0.01；***表示P<0.001。
具体实施方式
下面结合实施例对本发明做进一步描述，实施例中柱层析时的溶剂为体积比。
实施例1：化合物6a-6p的制备
(1)α-倒捻子素的提取(为现有技术，依据文献Jung et al,J.Agric.FoodChem.54：2077-2082；2006提取)，具体过程如下：
将山竹果皮粉碎，过《中国药典》6号筛，取10kg山竹果皮粉末，用95％乙醇(60L)65℃回流提取3次，每次2小时。合并提取液，过滤，旋蒸，浓缩，得深黄色残留物。将该残留物以水溶解，依次以正己烷萃取(3×3L)，二氯甲烷萃取(3×3L)，正丁醇萃取(3×3L)。分取二氯甲烷层，旋干，得到残留物504g，经硅胶柱层析(200～300目)分离，正己烷/乙酸乙酯30:1、20:1、10:1、5:1、2:1和乙酸乙酯为洗脱剂进行梯度洗脱，以及氯仿/甲醇30:1、20:1、10:1、5:1梯度洗脱，TLC显示共获得12个组分，依次采用硅胶柱层析(洗脱剂：石油醚/乙酸乙酯5:1～2:1)和Sephadex-LH 20(洗脱剂：甲醇)对组分5和6再次分离、纯化，得黄色固体18.46g，鉴定为α-倒捻子素。m.p.:181.2～183.3℃；1H NMR(400MHz,DMSO-d6)δ13.72(s,1H),11.02(s,1H),10.83(s,1H),6.80(s,1H),6.34(s,1H),5.18(dd,J＝6.7,5.3Hz,2H),4.01(d,J＝6.4Hz,2H),3.70(s,3H),3.21(d,J＝7.0Hz,2H),1.78(s,3H),1.73(s,3H),1.62(s,6H).13CNMR(101MHz,DMSO-d6)δ181.77,162.78,160.32,157.37,155.05,154.62,143.79,136.84,130.90,130.82,124.14,122.91,110.37,110.08,102.31,102.25,92.73,60.62,26.17,26.04,25.96,21.42,18.46,18.16.
(2)制备化合物3
在厚壁耐压瓶中，依次将溴乙酸乙酯(化合物2，660μL，5.93mmol)、无水碳酸钾(4.09g，29.63mmol)、碘化钾(300mg，1.81mmol)，加入α-倒捻子素(化合物1，1.22g，2.96mmol)的乙腈(15mL)溶液中，110℃搅拌反应3h。TLC跟踪反应完全(体积比，石油醚/乙酸乙酯＝5:1)，冷却至室温，过滤，旋干，得棕色残留物。经硅胶柱层析分离(体积比，石油醚/乙酸乙酯＝5:1)，得淡黄色固体1.15g，即为化合物3，收率66.4％。m.p.:98.4～101.3℃；1H NMR(400MHz,CDCl3)δ13.46(s,1H),6.60(s,1H),6.17(s,1H),5.29(ddd,J＝7.1,5.9,1.1Hz,1H),5.23(ddd,J＝6.6,5.4,1.1Hz,1H),4.77(s,2H),4.71(s,2H),4.29(m,4H),4.14(d,J＝6.5Hz,2H),3.87(s,3H),3.42(d,J＝7.1Hz,2H),1.85(s,3H),1.81(s,3H),1.68(s,6H),1.32(td,J＝7.1,4.7Hz,6H).13C NMR(101MHz,CDCl3)δ182.00,168.15,167.74,161.44,160.28,156.09,154.90,154.86,144.19,138.03,132.01,131.83,122.98,122.10,112.95,112.21,104.53,98.96,89.21,65.57,65.41,61.79,61.59,61.09,26.22,25.93,25.87,21.51,18.21,17.85,14.18.
(3)制备通式4所示的化合物(4a)
配制新鲜的羟胺溶液(为现有技术，依据文献Lamaa et al,J.Med.Chem.61：6574-6591；2018配制)：在0℃条件下，将氢氧化钾(11.2g，199.6mmol)的甲醇(28mL)溶液缓缓滴入盐酸羟胺(9.34g，134.4mmol)的甲醇(48mL)溶液中。滴毕，0℃搅拌反应2h。过滤，除去沉淀，滤液为游离的羟胺溶液(1.77mmol/mL)，储藏于-15℃中，备用。
在0℃条件下，将339.1mg化合物3一次性加入到3.5mL上述游离羟胺溶液中。加毕，升至室温，搅拌反应2h。旋干，得残留物，加入纯水，溶解残留物，1mol/L盐酸溶液调节反应液pH至6～7，析出沉淀，抽滤，得淡黄色固体302mg，即为化合物4a，收率93％。m.p.:177.1～179.3℃；1H NMR(600MHz,DMSO-d6)δ13.48(s,1H),10.91(s,1H),10.84(s,1H),9.13(s,1H),9.11(s,1H),7.01(s,1H),6.54(s,1H),5.26–5.11(m,2H),4.71(s,2H),4.63(s,2H),4.04(d,J＝6.3Hz,2H),3.77(s,3H),3.31(d,J＝7.3Hz,2H),1.79(s,3H),1.74(s,3H),1.63(s,6H).13C NMR(151MHz,DMSO-d6)δ182.01,164.20,164.04,162.39,159.45,157.36,155.00,154.90,144.33,136.62,131.29,131.18,123.74,122.58,111.81,111.58,103.73,100.37,90.71,66.79,66.53,60.95,26.08,26.02,25.96,21.49,18.47,18.18.HRMS(ESI)[M+H]+,calcd for C28H33N2O10:557.2130,found:557.2132.
(4)制备通式4所示的化合物(4b)
将化合物3(1.51g，2.59mmol)溶于乙醇(13mL)中，加入1mol/L氢氧化钠溶液(8mL)，室温反应过夜，TLC跟踪反应(石油醚/乙酸乙酯＝5:1)，1mol/L盐酸调节反应液pH至5～6，旋干，得黄色固体1.24g，即为化合物4b，可直接用于下一步反应，收率：91.1％。
(5)制备通式6所示的化合物(6a-6q)
室温下，在化合物4b(65.1mg，0.12mmol)的无水DMF(3mL)中，分别加入HATU(95.1mg，0.25mmol)、DIPEA(40μL，0.25mmol)，搅拌充分溶解，再分别加入0.37mmol的乙胺盐酸盐(5a)、甲胺盐酸盐(5b)、氯化铵(5c)、高丝氨酸内酯盐酸盐(5d)、2,2,2-三氟乙胺(5e)、乙醇胺(5f)、3-氨基丙腈(5g)、二乙胺(5h)、二甲胺盐酸盐(5i)、二(2-氯乙基)胺盐酸盐(5j)、环丙胺(5k)、2-氨氧基乙醇(5l)、盐酸胍(5m)、哌啶盐酸盐(5n)、盐酸哌嗪(5o)、吗啉(5p)，室温反应过夜。TLC跟踪反应完全(石油醚：乙酸乙酯＝1:1或二氯甲烷：甲醇＝30:1)，反应液倾入冰水中，淬灭，析出白色固体，抽滤，纯水洗涤，得产物；或乙酸乙酯萃取，经硅胶柱层析(石油醚：乙酸乙酯＝2:1或二氯甲烷：甲醇＝40:1)分离纯化。最终，生成类白色、白色、淡黄色或浅棕色固体产物。
化合物6a：析出类白色固体45.2mg，收率：64.8％。m.p.:203.4～206.5℃；1H NMR(400MHz,CDCl3)δ13.48(s,1H),6.76(s,1H),6.74(br s,1H),6.53(br s,1H),6.30(s,1H),5.24–5.18(m,2H),4.61(s,2H),4.57(s,2H),4.14(d,J＝6.3Hz,2H),3.84(s,3H),3.43–3.35(m,6H),1.86(s,3H),1.82(s,3H),1.72(s,3H),1.70(s,3H),1.21(t,J＝7.3Hz,3H),1.16(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3)δ182.01,167.27,166.77,160.86,160.18,155.66,155.19,155.14,144.17,138.36,132.45,132.31,122.75,122.70,113.33,111.54,104.67,100.29,89.68,68.09,67.19,61.31,34.18,26.26,25.92,25.72,21.53,18.23,18.00,14.81,14.73.
化合物6b：析出淡黄色固体43.2mg，收率：65.1％。m.p.:193.3～196.9℃；1H NMR(400MHz,CDCl3)δ13.47(s,1H),6.79(br s,1H),6.73(s,1H),6.60(br s,1H),6.27(s,1H),5.21–5.17(m,2H),4.62(s,2H),4.58(s,2H),4.13(d,J＝6.4Hz,2H),3.83(s,3H),3.42(d,J＝6.5Hz,2H),2.95(d,J＝4.9Hz,3H),2.89(d,J＝4.8Hz,3H),1.86(s,3H),1.82(s,3H),1.73(s,3H),1.70(s,4H).13C NMR(101MHz,CDCl3)δ181.96,168.20,167.67,160.86,160.15,155.59,155.12,155.11,144.10,138.33,132.32,132.30,122.96,122.76,113.26,111.48,104.63,100.04,89.59,67.93,67.10,61.37,26.25,26.12,26.07,25.91,25.71,21.53,18.23,17.91.
化合物6c：析出类白色固体36.8mg，收率：58.4％。m.p.:208.2～210.5℃；1H NMR(400MHz,DMSO-d6)δ13.44(s,1H),7.47-7.32(m,4H),6.89(s,1H),6.44(s,1H),5.14-5.08(m,2H),4.66(s,2H),4.56(s,2H),3.97(d,J＝6.4Hz,2H),3.71(s,3H),3.26(d,J＝7.1Hz,2H),1.72(s,3H),1.67(s,3H),1.56(s,6H).13C NMR(101MHz,DMSO-d6)δ182.01,169.49,169.18,162.24,159.41,157.35,155.03,154.92,144.27,136.52,131.35,131.17,123.77,122.73,111.67,111.42,103.65,100.38,90.75,67.77,67.57,60.96,26.08,26.04,25.95,21.52,18.48,18.19.
化合物6d：析出淡黄色固体30.2mg，收率：36.4％。m.p.:214.7～217.4℃；1H NMR(400MHz,DMSO-d6)δ13.52(s,1H),8.68(d,J＝8.0Hz,1H),8.59(d,J＝8.1Hz,1H),7.02(s,1H),6.55(s,1H),5.19(dd,J＝17.6,7.0Hz,2H),4.86(s,2H),4.76(d,J＝3.6Hz,2H),4.72–4.68(m,2H),4.38(t,J＝8.8Hz,2H),4.24(dt,J＝15.7,7.7Hz,2H),4.05(d,J＝6.2Hz,2H),3.79(s,3H),2.90(s,1H),2.74(s,1H),2.44-2.41(m 2H),2.30–2.19(m,2H),1.80(s,3H),1.74(s,3H),1.63(s,6H).13C NMR(101MHz,DMSO-d6)δ182.06,175.48,175.43,167.63,167.47,162.79,162.12,159.47,157.22,155.04,144.37,136.56,131.37,131.21,123.73,122.56,111.87,111.63,103.79,100.72,91.01,67.91,67.75,65.84,65.80,61.04,48.38,48.31,28.51,28.48,26.11,26.04,25.98,21.57,18.48,18.22.
化合物6e：析出白色固体58.4mg，收率：70.7％。m.p.:207.8～211.2℃；1H NMR(400MHz,DMSO-d6)δ13.52(s,1H),8.84(t,J＝6.3Hz,1H),8.74(t,J＝6.4Hz,1H),6.95(s,1H),6.48(s,1H),5.20–5.17(m,2H),4.90(s,2H),4.80(s,2H),4.01(ddd,J＝11.7,9.5,4.1Hz,6H),3.78(s,3H),1.79(s,3H),1.73(s,3H),1.63(d,J＝4.9Hz,6H).13C NMR(101MHz,DMSO-d6)δ182.03,168.37,168.20,162.13,159.47,157.22,155.00,154.90,144.31,136.62,131.38,131.22,123.71,122.48,111.83,111.60,103.76,100.43,99.99,90.77,67.72,67.49,60.94,26.09,26.03,26.02,25.95,25.10,25.04,21.54,18.47,18.11.
化合物6f：经硅胶柱层析(石油醚：乙酸乙酯＝2:1)，分离纯化。淡黄色固体54.1mg，收率：73.5％。m.p.:208.3～211.4℃；1H NMR(400MHz,DMSO-d6)δ13.56(s,1H),8.11(t,J＝5.6Hz,1H),7.97(t,J＝5.7Hz,1H),7.03(s,1H),6.56(s,1H),5.22(dt,J＝8.1,7.0Hz,2H),4.86–4.77(m,4H),4.72(s,2H),4.08(d,J＝6.4Hz,2H),3.82(s,3H),3.54–3.45(m,4H),3.37(d,J＝7.3Hz,2H),3.27(m,4H),1.83(s,3H),1.78(s,3H),1.67(s,6H).13C NMR(101MHz,DMSO-d6)δ182.02,167.34,167.11,162.22,159.43,157.29,155.06,154.94,144.30,136.52,131.42,131.18,123.76,122.56,111.73,111.46,103.70,100.48,90.81,67.99,67.81,60.97,60.06,41.74,26.08,26.03,25.97,21.55,18.48,18.18.
化合物6g：析出淡黄色固体43.2mg，收率：57.1％。m.p.:134.7～138.5℃；1H NMR(400MHz,CDCl3)δ13.45(s,1H),7.41(t,J＝6.0Hz,1H),7.01(t,J＝6.1Hz,1H),6.74(s,1H),6.27(s,1H),5.21(t,J＝5.5Hz,2H),4.64(s,2H),4.60(s,2H),4.12(d,J＝6.2Hz,2H),3.85(s,3H),3.66(dd,J＝12.5,6.3Hz,2H),3.59(dd,J＝12.8,6.4Hz,2H),3.42(d,J＝6.4Hz,2H),2.71(t,J＝4.6Hz,2H),2.68(t,J＝4.8Hz,2H),1.85(s,3H),1.83(s,3H),1.74(s,3H),1.69(s,3H).13CNMR(101MHz,CDCl3)δ181.92,168.31,167.69,160.60,160.28,155.44,155.09,155.07,144.17,138.59,132.65,132.39,122.67,117.70,117.50,113.48,111.61,104.76,100.28,100.00,89.60,67.96,67.10,61.61,35.68,35.32,26.27,25.91,25.79,21.52,18.43,18.24,18.21,18.03.
化合物6h：析出淡黄色固体41.9mg，收率：54.8％。m.p.:103.6～105.8℃；1H NMR(400MHz,CDCl3)δ13.51(s,1H),6.69(s,1H),6.41(s,1H),5.25(br s,2H),4.85(s,2H),4.77(s,2H),4.13(d,J＝6.4Hz,2H),3.86(s,3H),3.46–3.38(m,10H),1.84(s,3H),1.79(s,3H),1.67(s,6H),1.30(t,J＝7.1Hz,3H),1.17(dd,J＝12.8,6.8Hz,9H).13C NMR(101MHz,CDCl3)δ182.07,166.51,165.51,161.82,160.15,156.64,155.09,155.02,144.10,137.68,131.83,131.64,123.18,122.32,112.68,111.57,104.46,99.33,89.89,68.52,66.93,61.09,41.54,41.33,40.45,40.30,26.20,25.92,25.83,21.54,18.21,17.86,14.44,14.39,12.91,12.79.
化合物6i：析出浅黄色固体46.8mg，收率：67.2％。m.p.:46.5～50.3℃；1H NMR(400MHz,CDCl3)δ13.48(s,1H),6.69(s,1H),6.38(s,1H),5.22(t,J＝5.9Hz,2H),4.87(s,2H),4.79(s,2H),4.13(d,J＝6.2Hz,2H),3.86(s,3H),3.39(d,J＝6.8Hz,2H),3.13(s,3H),3.11(s,3H),3.03(s 3H),2.99(s,3H),1.84(s,3H),1.79(s,3H),1.67(s,6H).13C NMR(101MHz,CDCl3)δ182.05,167.37,166.42,161.56,160.11,156.48,155.05,155.00,144.06,137.69,131.84,131.63,123.15,122.40,112.69,111.54,104.45,99.36,89.76,68.28,66.89,61.13,36.74,36.35,35.80,35.78,26.19,25.92,25.83,21.49,18.21,17.82.
化合物6j：经柱硅胶层析(石油醚：乙酸乙酯＝2:1)分离纯化。类白色固体41.4mg，收率：47.5％。m.p.:101.3～105.6℃；1H NMR(400MHz,DMSO-d6)δ13.53(s,1H),8.76(dd,J＝4.4,1.3Hz,2H),8.53(dd,J＝8.4,1.3Hz,2H),7.51(dd,J＝8.4,4.4Hz,3H),7.17(s,1H),6.61(s,1H),6.09(s,1H),5.21(d,J＝8.3Hz,3H),5.11(s,2H),4.48(d,J＝4.7Hz,4H),4.05(d,J＝5.6Hz,2H),3.99(dd,J＝10.8,6.1Hz,4H),3.94(s,2H),3.78(s,3H),3.38(dd,J＝11.2,6.2Hz,13H),1.79(s,3H),1.75(s,3H),1.63(s,9H).
化合物6k：经硅胶柱层析(石油醚：乙酸乙酯＝2:1)，分离纯化。淡黄色固体32.4mg，收率：44.7％。m.p.:206.8～209.7℃；1H NMR(400MHz,DMSO-d6)δ13.52(s,1H),8.26(d,J＝4.1Hz,2H),6.96(s,1H),6.50(s,1H),5.18(d,J＝7.0Hz,2H),4.72(s,2H),4.62(s,2H),4.05(d,J＝6.4Hz,2H),3.77(s,3H),3.31(d,J＝7.3Hz,2H),2.69(s,2H),1.79(s,3H),1.73(s,3H),1.63(s,6H),0.81(s,2H),0.77(s,2H),0.60(m,2H),0.56(m,2H).13C NMR(101MHz,DMSO-d6)δ182.03,168.40,168.18,162.06,159.33,157.48,155.06,154.95,131.35,131.20,123.76,122.58,115.02,111.47,103.67,100.38,90.75,68.06,67.73,60.91,26.04,25.96,25.67,22.63,18.48,18.17,6.16,6.14.
化合物6l：析出淡黄色固体43.1mg，收率：55.6％。m.p.:193.2～195.6℃；1H NMR(400MHz,DMSO-d6)δ13.44(s,1H),11.41(s,1H),6.98(s,1H),6.49(s,1H),5.13(d,J＝10.2Hz,2H),4.70(s 2H),4.61(s 2H),3.99(d,J＝6.2Hz,2H),3.79(s,2H),3.71(s,2H),3.52(s,2H),3.26(d,J＝7.9Hz,2H),1.74(s,3H),1.68(s,3H),1.57(s,6H).13C NMR(101MHz,DMSO-d6)δ182.03,164.77,164.6,162.17,159.44,157.23,155.03,154.97,144.26,136.64,131.35,131.24,123.70,122.49,111.87,111.55,103.78,100.41,90.72,77.78,66.65,66.28,60.95,58.90,26.08,26.04,25.98,21.49,18.48,18.17.
化合物6m：析出淡黄色固体36.4mg，收率：49.8％。m.p.:199.2～201.6℃；1H NMR(400MHz,CDCl3)δ13.48(s,1H),9.23(s,4H),8.08–7.99(m,1H),7.50(dt,J＝15.4,7.5Hz,1H),6.46(s,1H),6.02(s,1H),5.31–5.19(m,2H),4.78(s 2H)4,73(s 2H),4.11(s,2H),3.85(s,3H),3.42(d,J＝5.6Hz,2H),2.95(s,1H),2.88(s,1H),1.84(s,3H),1.79(s,3H),1.70(s 3H)1.67(s 3H).13C NMR(101MHz,CDCl3)δ181.84,165.82,162.63,160.51,160.46,155.94,154.91,154.89,147.67,143.99,143.93,132.94,132.40,132.16,122.88,122.07,112.06,112.04,98.61,98.31,88.73,68.01,67.93,61.20,26.26,25.92,25.90,21.48,18.24,17.91.
化合物6n：析出浅棕色固体50.5mg，收率：63.7％。m.p.:58.8～63.5℃；1H NMR(400MHz,CDCl3)δ13.50(s,1H),6.72(s,1H),6.43(s,1H),5.22(d,J＝1.3Hz,2H),4.86(s,2H),4.78(s,2H),4.13(d,J＝6.4Hz,2H),3.85(s,3H),3.62–3.49(m,10H),3.38(d,J＝6.9Hz,2H),1.84(s,3H),1.79(s,3H),1.68(s,18H).13C NMR(101MHz,CDCl3)δ182.08,165.69,164.70,161.66,160.10,156.59,155.11,155.05,144.05,137.65,131.84,131.65,123.18,122.33,112.66,111.42,104.45,99.35,89.79,68.62,67.19,61.11,46.56,46.14,43.40,43.29,26.62,26.55,26.20,25.93,25.85,25.55,25.49,24.43,24.39,21.51,18.22,17.86.
化合物6o：经硅胶柱层析(二氯甲烷：甲醇＝40:1)，分离纯化。黄色固体40.9mg，收率：51.5％。m.p.:201.2～206.4℃；1H NMR(400MHz,CDCl3)δ13.34(s,1H),6.59(s,1H),6.27(s,1H),5.11(d,J＝1.3Hz,2H),4.79(s,2H),4.74(s,2H),4.0(d,J＝6.3Hz,2H),3.73(s,3H),3.67–3.53(m,8H),3.26(d,J＝6.7Hz,2H),2.89-2.81(m 8H)1.85(s,3H),1.79(s,3H),1.68(s,6H),1.18(s,1H).13C NMR(101MHz,CDCl3)δ181.87,166.31,162.55,160.87,160.60,156.24,154.91,154.87,143.94,136.5,132.0,131.96,122.98,122.15,112.61110.62,104.96,99.54,89.64,68.42,67.36,61.14,54.89,50.91,44.90,42.32,38.63,36.51,25.92,25.87,25.84,21.50,18.24,17.89.
化合物6p：析出淡黄色固体47.1mg，收率：59.1％。m.p.:81.3～85.7℃；1H NMR(400MHz,CDCl3)δ13.50(s,1H),6.74(s,1H),6.42(s,1H),5.22(d,J＝1.3Hz,2H),4.86(s,2H),4.80(s,2H),4.13(d,J＝6.3Hz,2H),3.83(s,3H),3.73–3.61(m,16H),3.36(d,J＝6.7Hz,2H),1.85(s,3H),1.79(s,3H),1.68(s,6H).13C NMR(101MHz,CDCl3)δ182.01,166.05,165.21,161.31,160.22,156.28,155.03,155.01,144.07,137.94,132.0,131.83,123.02,122.25,112.88,111.48,104.55,99.46,89.69,68.37,67.28,66.81,66.66,61.14,45.97,45.68,42.58,42.46,26.20,25.93,25.85,21.48,18.23,17.90.
实施例2：MTT法测定
将食管癌KYSE 30、结肠癌HCT 116、胃癌HGC 27细胞系接种于96孔板(均为2000个/孔)中，每孔200μL，每个浓度5个重复，37℃5％CO2培养箱培养24h后，取不同体积衍生物的DMSO溶液(50mM)加至对应的细胞培养基中处理细胞，使α-倒捻子素或衍生物的终浓度为0、0.001、0.01、0.1、1、10、100μΜ，加药72h后加入20μL 5mg/mL的MTT溶液并在培养箱中孵育2h，弃去96孔板中含有MTT溶液的培养基，测量570nm波长下的吸光度值，计算各衍生物的IC50值，结果详见图1～6和表1。
表1本发明衍生物抑制食管癌、结肠癌、胃癌细胞系IC50(μM)
结果表明，测定结果呈一定的浓度依赖性，化合物4a对上述3个细胞系均有较强的抑制活性，活性最优；化合物6a、6e、6f、6k对KYSE 30显示较强的抑制活性(图1、图4)，化合物6c、6e、6f、6g对HCT 116显示较强的抑制活性(图2、图5)，化合物6g对HGC 27显示较强的抑制活性(图3、图6)，见表1。
实施例3：克隆形成实验
将KYSE 30、HCT 116、HGC 27细胞系种于6孔板(均为1500个/孔)中，每孔1mL，在CO2培养箱中培养24h后。取不同体积各个衍生物的DMSO溶液(50mM)加至对应的细胞培养基中处理细胞，衍生物4a在培养基中的终浓度为0、0.625、1.25、2.5μM，6a的终浓度为0、1.25、2.5、5，化合物1及其余衍生物的终浓度为0、5、10、20μM，连续培养7天，待克隆慢慢长大。弃去培养基，PBS缓冲液洗去残留培养基。每孔加入1mL0.2％的结晶紫溶液，室温染色10min后用蒸馏水反复洗涤染色后的6孔板，后将平板倒置与干净滤纸控干水分，拍照并统计每孔克隆数量，计算处理后细胞增殖能力被抑制的比率，结果详见图7至14。
结果表明，测定结果呈明显的浓度依赖性，大部分衍生物的抑制活性强于α-倒捻子素(图7)。其中，4a可较强的抑制上述3个细胞系的克隆形成，活性最优(图8)。6a可抑制KYSE 30的克隆形成(图9)，6c可抑制HCT 116的克隆形成(图10)，6e、6f均可抑制KYSE 30和HCT 116的克隆形成(图11、12)，6g可抑制HCT 116和HGC 27的克隆形成(图13)，6k可抑制KYSE 30的克隆形成(图14)。
Claims (3)
1.3,6-二酰胺取代的α-倒捻子素衍生物，其特征在于，具体为如下结构的化合物：
。
2.权利要求1所述的3,6-二酰胺取代的α-倒捻子素衍生物在制备抗肿瘤药物中的应用，其特征在于，所述抗肿瘤药物为治疗食管癌、直肠癌和胃癌的药物。
3.根据权利要求2所述的应用，其特征在于，所述3,6-二酰胺取代的α-倒捻子素衍生物在制备抑制肿瘤细胞增殖药物中的应用，所述肿瘤细胞为食管癌细胞KYSE 30、结肠癌细胞HCT 116、胃癌细胞HGC 27。
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| CN104114547A (zh) * | 2011-09-08 | 2014-10-22 | 新加坡科技研究局 | 呫吨酮化合物的衍生物 |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104114547A (zh) * | 2011-09-08 | 2014-10-22 | 新加坡科技研究局 | 呫吨酮化合物的衍生物 |
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| Chaomei Liu et al..Synthesis and anticancer potential of novel xanthone derivatives with 3,6-substituted chains.Bioorganic & Medicinal Chemistry.2016,第24卷4263-4271. * |
| Kaixuan Jiang et al..Design, synthesis, and biological evaluation of 1,3,6,7-tetrahydroxyxanthone derivatives as phosphoglycerate mutase 1 inhibitors.Bioorganic & Medicinal Chemistry Letters.2021,第36卷第3页Scheme 1，Fig. 4. * |
| miR-299-3p和PGAM1在胃癌组织中的表达及与临床病理特征和预后的关系;陈文霞等;中国卫生工程学;第19卷(第6期);849-853 * |
| 沉默PGAM1 基因对食管癌细胞生物学功能的影响;吴丹婷等;临床肿瘤学杂志;第23卷(第9期);769-774 * |
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| CN115141171A (zh) | 2022-10-04 |
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