CN114957243A - 一类β-卡波林NO供体衍生物及应用 - Google Patents
一类β-卡波林NO供体衍生物及应用 Download PDFInfo
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- CN114957243A CN114957243A CN202110213358.2A CN202110213358A CN114957243A CN 114957243 A CN114957243 A CN 114957243A CN 202110213358 A CN202110213358 A CN 202110213358A CN 114957243 A CN114957243 A CN 114957243A
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- 238000005406 washing Methods 0.000 description 1
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Abstract
本发明公开了一类β‑卡波林NO供体衍生物及应用,属于天然药物及药物化学领域。具体涉及一系列具有抗肿瘤活性的β‑卡波林NO供体衍生物的制备方法和在抗肿瘤药物方面新用途。本发明所述的β‑卡波林NO供体衍生物及其药学上可接受的盐如通式I所示。其中,n、R和R1如权利要求书和说明书中所述。
Description
技术领域
本发明属于天然药物及药物化学领域,涉及一类β-卡波林NO供体衍生物及应用,具体涉及一系列具有抗肿瘤活性的NO供体型β-卡波林衍生物的制备方法及其在抗肿瘤方面的用途。
背景技术
β-卡波林生物碱(β-carboline)具有较好的抗肿瘤活性,但也存在以下问题:①溶解度差,β-卡波林在很多溶剂中的溶解度比较低;②生物利用度低,β-卡波林通过口服方式给药很难被机体所吸收,然而通过静脉注射途径时,血浆中的β-卡波林可快速被清除;③半衰期较短,研究发现细胞内的β-卡波林在谷胱甘肽硫转移酶的作用条件下,可快速与谷胱甘肽结合随后被排除细胞;④β-卡波林在动物研究中存在一定的神经毒性,这些缺点都限制了β-卡波林作为药物在临床上的应用。因此很多研究者对β-卡波林生物碱进行结构修饰。目的是获得活性更强、毒性更低、选择性更好的抗肿瘤候选化合物。
一氧化氮(NO)供体型药物的研究备受关注。呋咱氮氧化合物(furoxan)是一类重要的NO供体,可快速释放较大剂量NO。
发明内容
本发明以β-卡波林为先导化合物,设计并合成了β-卡波林NO供体衍生物,并测试了合成衍生物在抗肿瘤方面的生物活性。
本发明要解决的技术问题是寻找抗肿瘤活性好的β-卡波林NO供体衍生物及其药学上可接受的盐,并进一步提供一种药物组合物。
为解决上述技术问题,本发明提供如下技术方案:
一种β-卡波林NO供体衍生物及其药学上可接受的盐,具有如下I的结构通式:
其中,n为1-4的整数;R为含有1-8个碳原子的烷烃基、烯烃基或炔烃基;R1为氢,或含有1-4个碳原子的烷基,或含有4-12个碳原子的芳基或取代芳基、杂环芳基或取代杂环芳基,所述杂环芳基的芳杂环中包含1-3个N、O或S的杂原子,所述取代芳基或取代杂环芳基中的取代基为卤素或含有1-3个碳原子的烷氧基。
优选地,n为1-3的整数;R为含有1-7个碳原子的烷烃基、烯烃基或炔烃基;R1为氢,或含有1-3个碳原子的烷基,或含有4-10个碳原子的芳基或取代芳基、杂环芳基或取代杂环芳基,所述杂环芳基的芳杂环中包含1-2个N、O或S的杂原子,所述取代芳基或取代杂环芳基中的取代基为卤素或含有1-3个碳原子的烷氧基。
更优选地,n为1-2的整数;R为含有2-6个碳原子的烷烃基、烯烃基或炔烃基;R1为氢,或含有1-2个碳原子的烷基,或含有4-8个碳原子的芳基或取代芳基、杂环芳基或取代杂环芳基,所述杂环芳基的芳杂环中包含1-2个N、O或S的杂原子,所述取代芳基或取代杂环芳基中的取代基为卤素或含有1-2个碳原子的烷氧基。
进一步地,
本发明优选如下衍生物及其药学上可接受的盐结构式如a~r所示:
本发明的衍生物可用下列方法制备得到:
化合物L-色氨酸1在NaOH溶液中与37%的甲醛溶液37℃反应,得中间体2a;L-色氨酸1在1,2-二氯乙烷中与乙醛或对甲氧基苯甲醛、三氟乙酸110℃反应得到中间体2b-c。然后将中间体2a-c溶解于甲醇中,在冰浴条件下滴加SOCl2,回流反应得到中间体3a-c。再将3a-c溶于N,N-二甲基甲酰胺中,与高锰酸钾室温反应得到中间体4a-c。最后4a-c在NaOH条件下进行水解得到化合物5a-c;
将苯硫酚6与氯乙酸在碱性条件下反应得苯硫乙酸7,然后经30%H2O2氧化生成苯磺酰乙酸8。化合物8在发烟HNO3存在下100℃加热环合成3,4-二苯磺酰基呋咱氮氧化物9,化合物9在NaH催化的条件下,以THF为反应溶剂分别与乙二醇、1,3-丙二醇、1,4-丁二醇、1,6-己二醇、二乙二醇、丁炔二醇反应生成化合物10a-f;
将化合物5a-c溶于无水二氯甲烷,依次加入EDCI、DMAP,分别与10a-f室温反应得到目标化合物11a-f、12a-f、13a-f。
一种药物组合物,所述药物组合物含有治疗有效量的所述的通式I所示的β-卡波林NO供体衍生物及其药学上可接受的盐和药学上可接受的载体。
通式I所示的β-卡波林NO供体衍生物及其药学上可接受的盐在制备治疗肿瘤疾病的药物中的应用。
进一步地,所述的肿瘤为乳腺癌肿瘤或结肠癌肿瘤。
一种药物组合物在制备治疗肿瘤疾病的药物中的应用。
进一步地,所述的肿瘤为乳腺癌肿瘤或结肠癌肿瘤。
药理试验证明,本发明的β-卡波林NO供体衍生物具有很好的抗肿瘤细胞增殖作用,可以用于进一步制备抗肿瘤药物。
具体实施方式
下述非限定性实施例可以使本领域的普通技术人员更全面地理解本发明,但不以任何方式限制本发明。
本发明实施例的衍生物合成路线如下:
(1)将5g化合物L-色氨酸1(24.51mmol)溶解于0.4N的NaOH溶液中,然后加入3mL37%甲醛溶液(36.97mmol),37℃反应三天。TLC监测,反应基本完全,冷却,然后加入冰乙酸,有沉淀生成,抽滤,烘干,得中间体2a 4.64g。将4.64g中间体2a(21.48mmol)溶解于无水甲醇中,在冰浴条件下滴加3.68mL SOCl2(50.67mmol),然后回流反应6h。TLC监测,反应完全,冷却,将反应液浓缩,然后加入50mL饱和的碳酸氢钠溶液,用乙酸乙酯萃取3次,饱和食盐水洗1次,无水硫酸钠干燥,过滤,浓缩,得中间体3a 3.5g。将3.5g中间体3a(15.22mmol)溶解于DMF中,在冰浴条件下加入7g高锰酸钾(44.3mmol),反应1h后转移至室温反应14h。TLC监测,反应完全,抽滤,将滤液旋干,用乙酸乙酯萃取3次,饱和食盐水洗1次,无水硫酸钠干燥,过滤,浓缩,得中间体4a 2.6g,硅胶柱色谱分离(DCM:MeOH=40:1),得纯中间体4a2.0g。将2.0g纯中间体4a溶解于甲醇/二氯甲烷中,加入5mL2N的NaOH溶液,加热反应2h。TLC监测,反应完全,冷却,然后加入4M的盐酸溶液调pH至4-5,有沉淀生成,抽滤,烘干,得化合物5a 1.8g。
(2)将75mL苯硫酚6(0.6mol)与78g(0.8mol)氯乙酸在碱性条件(3N NaOH溶液)下反应得40g苯硫乙酸7,然后经50mL 30%H2O2氧化生成苯磺酰乙酸8。30g化合物8在发烟HNO3存在下100℃加热环合成10g 3,4-二苯磺酰基呋咱氮氧化物9,360mg化合物9在NaH催化的条件下,以THF为反应溶剂与乙二醇反应生成化合物10a 190mg。
(3)将55mg化合物5a(0.26mmol)用5mL无水DCM溶解,加入催化量的DMAP搅拌15min,然后加入21mg NO中间体10a(0.07mmol)和3当量的EDCI,室温搅拌12h,TLC监测,反应不继续进行,然后加入10mL蒸馏水和1mL 0.6M的盐酸溶液,DCM萃取3次,饱和食盐水洗1次,无水硫酸钠干燥,过滤,浓缩,得粗产物47mg,硅胶柱色谱分离(DCM:MeOH=100:1,70:1),得到目标化合物11a。灰白色固体,产率15%。1H NMR(600MHz,DMSO-d6)δ:12.13(s,1H,Ar-NH),8.98(s,1H,1-CH),8.93(s,1H,4-CH),8.37(m,1H,Ar-H),7.99(m,2H,Ar-H),7.69(m,2H,Ar-H),7.62(m,1H,Ar-H),7.55(m,2H,Ar-H),7.33(m,1H,Ar-H),4.84(m,2H,O-CH2-CH2-O),4.73(m,2H,O-CH2-CH2-O);13C NMR(150MHz,DMSO-d6)δ:164.70,158.43,140.50,136.98,136.63,135.47(×2),133.28,129.33(×2),128.30,127.77(×2),126.94,121.61,120.32,119.82,117.49,112.00,110.12,69.04,61.62;HRMS(ESI)m/z calcd forC22H17N4O7S[M+H]+481.0818,found 481.0818。
实施例2
实施例1步骤(2)中,将乙二醇替换成1,3-丙二醇,合成化合物10b,其余步骤参照实施例1,制备得化合物11b,灰白色固体,产率20%。1H NMR(600MHz,CDCl3)δ:9.81(s,1H,Ar-NH),9.18(s,1H,1-CH),8.90(s,1H,4-CH),8.22(m,1H,Ar-H),8.05(m,2H,Ar-H),7.71(m,1H,Ar-H),7.65(m,2H,Ar-H),7.60(m,2H,Ar-H),7.39(m,1H,Ar-H),4.67(m,4H,2×O-CH2),2.46(m,2H,-CH2);13C NMR(150MHz,CDCl3)δ:158.85,141.37,138.02,137.30,135.59(×2),132.77,129.68(×2),129.55,128.51(×2),122.08,121.40,121.32,118.19,112.46,110.48,68.21,61.78,28.17;HRMS(ESI)m/z calcd for C23H19N4O7S[M+H]+495.0974,found 495.0963。
实施例3
实施例1步骤(2)中,将乙二醇替换成1,4-丁二醇,合成化合物10c,其余步骤参照实施例1,制备得化合物11c,灰白色固体,产率10%。1H NMR(600MHz,CDCl3)δ:9.09(s,1H,1-CH),8.89(s,1H,4-CH),8.22(m,1H,Ar-H),8.05(m,2H,Ar-H),7.70(m,1H,Ar-H),7.63(m,2H,Ar-H),7.58(m,2H,Ar-H),7.38(m,1H,Ar-H),4.59(m,2H,O-CH2),4.53(m,2H,O-CH2),2.09(m,4H,2×-CH2);13C NMR(150MHz,CDCl3)δ:165.78,158.95,140.95,138.00,137.30,135.57(×2),133.23,129.63(×2),129.37,129.21,128.52(×2),122.04,121.48,121.24,118.02,112.21,110.48,71.03,64.86,25.40,25.20;HRMS(ESI)m/z calcd forC24H19N4O7S[M-H]-507.0974,found 507.0975。
实施例4
实施例1步骤(2)中,将乙二醇替换成1,6-己二醇,合成化合物10d,其余步骤参照实施例1,制备得化合物11d,灰白色固体,产率25%。1H NMR(600MHz,CDCl3)δ:9.28(s,1H,1-CH),8.91(s,1H,4-CH),8.23(m,1H,Ar-H),8.04(m,2H,Ar-H),7.74(m,1H,Ar-H),7.66(m,2H,Ar-H),7.61(m,2H,Ar-H),7.40(m,1H,Ar-H),4.53(t,2H,O-CH2),4.43(t,2H,O-CH2),1.92(m,4H,2×-CH2),1.58(m,4H,2×-CH2);13C NMR(150MHz,CDCl3)δ:159.01,141.55,138.06,137.07,135.60(×2),132.39,129.92,129.64(×2),129.12,128.50(×2),122.15,121.50,121.26,118.02,112.53,110.46,71.45,65.87,28.67,28.32,25.56,25.35;HRMS(ESI)m/z calcd for C26H25N4O7S[M+H]+537.1444,found537.1443。
实施例5
实施例1步骤(2)中,将乙二醇替换成二乙二醇,合成化合物10e,其余步骤参照实施例1,制备得化合物11e,灰白色固体,产率24%。1H NMR(600MHz,CDCl3)δ:10.15(s,1H,Ar-NH),9.15(s,1H,1-CH),8.90(s,1H,4-CH),8.19(m,1H,Ar-H),8.00(m,2H,Ar-H),7.67(m,2H,Ar-H),7.61(m,1H,Ar-H),7.53(m,2H,Ar-H),7.35(m,1H,Ar-H),4.66(m,2H,O-CH2),4.54(m,2H,O-CH2),3.98(m,2H,CH2-O-CH2),3.94(m,2H,CH2-O-CH2);13C NMR(150MHz,CDCl3)δ:165.49,158.88,141.39,137.96,137.49,135.52(×2),133.06,129.57(×2),129.42,129.25,128.48(×2),122.02,121.34,121.14,118.27,112.54,110.44,70.51,69.46,68.37,64.50;HRMS(ESI)m/z calcd for C24H21N4O8S[M+H]+525.1080,found 525.1080。
实施例6
实施例1步骤(2)中,将乙二醇替换成丁炔二醇,合成化合物10f,其余步骤参照实施例1,制备得化合物11f,灰白色固体,产率30%。1H NMR(600MHz,DMSO-d6)δ:12.13(s,1H,Ar-NH),9.00(s,1H,1-CH),8.96(s,1H,4-CH),8.42(m,1H,Ar-H),8.02(m,2H,Ar-H),7.88(m,1H,Ar-H),7.75(m,2H,Ar-H),7.68(m,1H,Ar-H),7.62(m,1H,Ar-H),7.33(m,1H,Ar-H),5.30(m,2H,O-CH2),5.16(m,2H,O-CH2);13C NMR(150MHz,DMSO-d6)δ:164.27,157.51,140.43,137.06,136.43,135.67,135.20,133.39,129.52(×2),128.24,127.84(×2),126.94,121.74,120.33,119.80,117.55,111.91,110.15,83.84,78.87,58.61,51.74;HRMS(ESI)m/z calcd for C24H17N4O7S[M+H]+505.0818,found 505.0804。
实施例7
实施例1步骤(1)中合成2a的步骤替换成:化合物L-色氨酸1在1,2-二氯乙烷中与乙醛、三氟乙酸110℃反应得到中间体2b。
其余步骤参照实施例1的合成方法制备得化合物12a,灰白色固体,产率17%。1HNMR(600MHz,CDCl3)δ:8.77(s,1H,4-CH),8.49(s,1H,Ar-NH),8.19(m,1H,Ar-H),8.05(m,2H,Ar-H),7.60(m,2H,Ar-H),7.57(m,1H,Ar-H),7.45(m,2H,Ar-H),7.37(m,1H,Ar-H),4.86(s,4H,O-CH2-CH2-O),2.91(s,3H,-CH3);13C NMR(150MHz,CDCl3)δ:165.87,158.94,142.31,140.30,138.21,136.99,136.42,135.64,129.72(×2),129.09,128.70(×2),128.24,122.35,122.25,121.46,117.01,112.04,110.61,69.16,62.20,20.68;HRMS(ESI)m/zcalcd for C23H19N4O7S[M+H]+495.0974,found 495.0974。
实施例8
实施例1步骤(1)中合成2a的步骤替换成:化合物L-色氨酸1在1,2-二氯乙烷中与乙醛、三氟乙酸110℃反应得到中间体2b。
实施例1步骤(2)中,将乙二醇替换成1,3-丙二醇。
其余步骤参照实施例1的合成方法制备得化合物12b,灰白色固体,产率11%。1HNMR(600MHz,CDCl3)δ:8.75(s,1H,4-CH),8.73(s,1H,Ar-NH),8.18(m,1H,Ar-H),8.06(m,2H,Ar-H),7.73(m,1H,Ar-H),7.62(m,2H,Ar-H),7.59(m,2H,Ar-H),7.36(m,1H,Ar-H),4.63(m,4H,2×O-CH2),2.86(s,3H,-CH3),2.43(m,2H,-CH2);13C NMR(150MHz,CDCl3)δ:166.27,159.01,142.27,140.42,138.24,137.32,136.46,135.76,129.87(×2),128.99,128.67(×2),128.26,122.35,122.17,121.29,116.70,112.09,110.62,68.39,61.44,28.38,20.60;HRMS(ESI)m/z calcd for C24H21N4O7S[M+H]+509.1131,found 509.1122。
实施例9
实施例1步骤(1)中合成2a的步骤替换成:化合物L-色氨酸1在1,2-二氯乙烷中与乙醛、三氟乙酸110℃反应得到中间体2b。
实施例1步骤(2)中,将乙二醇替换成1,4-丁二醇。
其余步骤参照实施例1的合成方法制备得化合物12c,灰白色固体,产率15%。1HNMR(600MHz,CDCl3)δ:9.01(s,1H,Ar-NH),8.76(s,1H,4-CH),8.19(m,1H,Ar-H),8.06(m,2H,Ar-H),7.72(m,1H,Ar-H),7.63(m,2H,Ar-H),7.59(m,2H,Ar-H),7.37(m,1H,Ar-H),4.55(m,4H,2×O-CH2),2.95(s,3H,-CH3),2.07(m,4H,2×-CH2);13C NMR(150MHz,CDCl3)δ:165.89,159.10,142.16,140.74,138.17,136.72,136.34,135.75,129.82(×2),129.26,128.70(×2),128.50,122.21(×2),121.43,116.65,112.30,110.61,71.24,64.95,25.61,25.34,20.46;HRMS(ESI)m/z calcd for C25H23N4O7S[M+H]+523.1287,found 523.1282。
实施例10
实施例1步骤(1)中合成2a的步骤替换成:化合物L-色氨酸1在1,2-二氯乙烷中与乙醛、三氟乙酸110℃反应得到中间体2b。
实施例1步骤(2)中,将乙二醇替换成1,6-己二醇。
其余步骤参照实施例1的合成方法制备得化合物12d,灰白色固体,产率13%。1HNMR(600MHz,CDCl3)δ:8.75(s,1H,4-CH),8.56(s,1H,Ar-NH),8.18(m,1H,Ar-H),8.05(m,2H,Ar-H),7.74(m,1H,Ar-H),7.62(m,2H,Ar-H),7.58(m,2H,Ar-H),7.36(m,1H,Ar-H),4.49(t,2H,O-CH2),4.43(t,2H,O-CH2),2.91(s,3H,-CH3),1.91(m,4H,2×-CH2),1.56(m,2H,-CH2),1.26(m,2H,-CH2);13C NMR(150MHz,CDCl3)δ:166.34,159.17,142.13,140.44,138.26137.66,136.32,135.75,129.80(×2),128.99,128.67(×2),128.32,122.36,122.16,121.27,116.50,112.09,110.61,71.61,65.48,28.86,28.49,25.73,25.51,20.66;HRMS(ESI)m/z calcd for C27H27N4O7S[M+H]+551.1600,found551.1606。
实施例11
实施例1步骤(1)中合成2a的步骤替换成:化合物L-色氨酸1在1,2-二氯乙烷中与乙醛、三氟乙酸110℃反应得到中间体2b。
实施例1步骤(2)中,将乙二醇替换成二乙二醇。
其余步骤参照实施例1的合成方法制备得化合物12e,灰白色固体,产率10%。1HNMR(600MHz,CDCl3)δ:8.91(s,1H,Ar-NH),8.75(s,1H,4-CH),,8.15(m,1H,Ar-H),8.04(m,2H,Ar-H),7.68(m,1H,Ar-H),7.57(m,2H,Ar-H),7.53(m,2H,Ar-H),7.33(m,1H,Ar-H),4.63(t,2H,O-CH2),4.55(t,2H,O-CH2),3.95(m,4H,CH2-O-CH2),2.81(s,3H,-CH3);13C NMR(150MHz,CDCl3)δ:166.33,159.01,142.31,140.47,138.12137.07,136.46,135.71,129.77(×2),128.90,128.66(×2),128.14,122.27,122.16,121.16,116.80,112.12,110.56,70.65,69.69,68.50,64.37,20.46;HRMS(ESI)m/z calcd for C25H23N4O8S[M+H]+539.1237,found 539.1231。
实施例12
实施例1步骤(1)中合成2a的步骤替换成:化合物L-色氨酸1在1,2-二氯乙烷中与乙醛、三氟乙酸110℃反应得到中间体2b。
实施例1步骤(2)中,将乙二醇替换成丁炔二醇。
其余步骤参照实施例1的合成方法制备得化合物12f,灰白色固体,产率11%。1HNMR(600MHz,CDCl3)δ:8.84(s,1H,Ar-NH),8.80(s,1H,4-CH),,8.19(m,1H,Ar-H),8.08(m,2H,Ar-H),7.73(m,1H,Ar-H),7.63(m,2H,Ar-H),7.59(m,2H,Ar-H),7.37(m,1H,Ar-H),5.09(m,4H,2×O-CH2),2.89(s,3H,-CH3);13C NMR(150MHz,CDCl3)δ:165.51,158.09,142.36,140.46,138.06,136.67,136.61,135.83,129.87(×2),129.07,128.80(×2),128.29,122.33,122.20,121.38,117.18,112.14,110.72,84.46,78.82,58.85,52.95,20.61;HRMS(ESI)m/z calcd for C25H19N4O7S[M+H]+519.0974,found 519.0961。
实施例13
实施例1步骤(1)中合成2a的步骤替换成:化合物L-色氨酸1在1,2-二氯乙烷中与对甲氧基苯甲醛、三氟乙酸110℃反应得到中间体2c。
其余步骤参照实施例1的合成方法制备得化合物13a,灰白色固体,产率17%。1HNMR(600MHz,CDCl3)δ:9.00(s,1H,Ar-NH),8.82(s,1H,4-CH),8.22(m,1H,Ar-H),8.04(m,2H,Ar-H),7.89(d,J=8.60Hz,2H,Ar-H),7.60(m,2H,Ar-H),7.53(m,1H,Ar-H),7.42(m,2H,Ar-H),7.37(m,1H,Ar-H),7.02(d,J=8.60Hz,2H,Ar-H),4.86(s,4H,O-CH2-CH2-O),3.84(s,3H,-CH3);13C NMR(150MHz,CDCl3)δ:165.96,160.69,158.92,143.07,140.81,138.20,137.33,135.60(×2),135.15,130.06,129.81(×2),129.72(×2),129.19,128.68(×2),122.26,122.12,121.41,116.94,114.78(×2),112.21,110.61,69.18,62.23,55.57;HRMS(ESI)m/z calcd for C29H23N4O8S[M+H]+587.1237,found587.1224。
实施例14
实施例1步骤(1)中合成2a的步骤替换成:化合物L-色氨酸1在1,2-二氯乙烷中与对甲氧基苯甲醛、三氟乙酸110℃反应得到中间体2c。
实施例1步骤(2)中,将乙二醇替换成1,3-丙二醇。
其余步骤参照实施例1的合成方法制备得化合物13b,灰白色固体,产率10%。1HNMR(600MHz,CDCl3)δ:8.95(s,1H,Ar-NH),8.79(s,1H,4-CH),8.21(m,1H,Ar-H),8.06(m,2H,Ar-H),7.86(d,J=8.80Hz,2H,Ar-H),7.71(m,1H,Ar-H),7.61(m,2H,Ar-H),7.58(m,2H,Ar-H),7.37(m,1H,Ar-H),7.00(d,J=8.80Hz,2H,Ar-H),4.67(t,2H,O-CH2),4.64(t,2H,O-CH2),3.84(s,3H,-CH3),2.44(m,2H,-CH2);13C NMR(150MHz,CDCl3)δ:166.36,160.56,159.05,142.99,140.73,138.22,137.94,135.74(×2),135.15,130.32,129.86(×2),129.73(×2),129.04,128.66(×2),122.29,122.06,121.25,116.61,114.67(×2),112.11,110.62,68.36,61.23,55.54,28.33;HRMS(ESI)m/z calcd for C30H25N4O8S[M+H]+601.1393,found 601.1398。
实施例15
实施例1步骤(1)中合成2a的步骤替换成:化合物L-色氨酸1在1,2-二氯乙烷中与对甲氧基苯甲醛、三氟乙酸110℃反应得到中间体2c。
实施例1步骤(2)中,将乙二醇替换成1,4-丁二醇。
其余步骤参照实施例1的合成方法制备得化合物13c,灰白色固体,产率10%。1HNMR(600MHz,CDCl3)δ:8.91(s,1H,Ar-NH),8.81(s,1H,4-CH),8.22(m,1H,Ar-H),8.05(m,2H,Ar-H),7.90(d,J=8.70Hz,2H,Ar-H),7.69(m,1H,Ar-H),7.61(m,2H,Ar-H),7.57(m,2H,Ar-H),7.37(m,1H,Ar-H),7.03(d,J=8.70Hz,2H,Ar-H),4.56(m,4H,2×O-CH2),3.85(s,3H,-CH3),2.09(m,4H,-CH2-CH2);13C NMR(150MHz,CDCl3)δ:166.45,160.60,159.10,142.95,140.75,138.25,138.14,135.71(×2),135.10,130.33,129.82(×2),129.78(×2),129.05,128.68(×2),122.32,122.10,121.26,116.54,114.73(×2),112.12,110.61,71.32,64.78,55.56,25.71,25.32;HRMS(ESI)m/z calcd for C31H27N4O8S[M+H]+615.1550,found 615.1536。
实施例16
实施例1步骤(1)中合成2a的步骤替换成:化合物L-色氨酸1在1,2-二氯乙烷中与对甲氧基苯甲醛、三氟乙酸110℃反应得到中间体2c。
实施例1步骤(2)中,将乙二醇替换成1,6-己二醇。
其余步骤参照实施例1的合成方法制备得化合物13d,灰白色固体,产率15%。1HNMR(600MHz,CDCl3)δ:8.99(s,1H,Ar-NH),8.80(s,1H,4-CH),8.22(m,1H,Ar-H),8.05(m,2H,Ar-H),7.93(d,J=8.80Hz,2H,Ar-H),7.73(m,1H,Ar-H),7.62(m,2H,Ar-H),7.59(m,2H,Ar-H),7.37(m,1H,Ar-H),7.06(d,J=8.80Hz,2H,Ar-H),4.50(t,2H,O-CH2),4.43(t,2H,O-CH2),3.87(s,3H,-CH3),1.92(m,4H,2×-CH2),1.59(m,4H,-CH2-CH2);13C NMR(150MHz,CDCl3)δ:166.36,160.71,159.18,142.81,140.89,138.31,138.11,135.73(×2),134.99,129.89,129.85(×2),129.79(×2),129.13,128.67(×2),122.32,122.09,121.30,116.46,114.81(×2),112.22,110.62,71.62,65.48,55.60,28.84,28.53,25.80,25.52;HRMS(ESI)m/z calcd for C33H31N4O8S[M+H]+643.1863,found643.1859。
实施例17
实施例1步骤(1)中合成2a的步骤替换成:化合物L-色氨酸1在1,2-二氯乙烷中与对甲氧基苯甲醛、三氟乙酸110℃反应得到中间体2c。
实施例1步骤(2)中,将乙二醇替换成二乙二醇。
其余步骤参照实施例1的合成方法制备得化合物13e,灰白色固体,产率13%。1HNMR(600MHz,CDCl3)δ:9.27(s,1H,Ar-NH),8.79(s,1H,4-CH),8.18(m,1H,Ar-H),8.06(m,1H,Ar-H),8.02(m,2H,Ar-H),7.83(d,J=8.70Hz,2H,Ar-H),7.61(m,2H,Ar-H),7.56(m,2H,Ar-H),7.35(m,1H,Ar-H),6.91(d,J=8.70Hz,2H,Ar-H),4.65(t,2H,O-CH2),4.57(t,2H,O-CH2),3.99(m,4H,-CH2-O-CH2),3.77(s,3H,-CH3);13C NMR(150MHz,CDCl3)δ:166.21,160.53,159.04,142.86,140.98,138.16,137.40,135.68(×2),135.04,129.78(×2),129.76(×2),129.08,128.72,128.65(×2),122.19,122.04,121.22,116.70,114.53(×2),112.33,110.57,70.77,69.72,68.63,64.60,55.47;HRMS(ESI)m/z calcd forC31H27N4O9S[M+H]+631.1499,found 631.1486。
实施例18
实施例1步骤(1)中合成2a的步骤替换成:化合物L-色氨酸1在1,2-二氯乙烷中与对甲氧基苯甲醛、三氟乙酸110℃反应得到中间体2c。
实施例1步骤(2)中,将乙二醇替换成丁炔二醇。
其余步骤参照实施例1的合成方法制备得化合物13f,灰白色固体,产率19%。1HNMR(600MHz,CDCl3)δ:8.97(s,1H,Ar-NH),8.84(s,1H,4-CH),8.22(m,1H,Ar-H),8.07(m,2H,Ar-H),7.89(d,J=8.70Hz,2H,Ar-H),7.70(m,1H,Ar-H),7.62(m,2H,Ar-H),7.59(m,2H,Ar-H),7.38(m,1H,Ar-H),7.03(d,J=8.70Hz,2H,Ar-H),5.11(m,4H,2×O-CH2),3.85(s,3H,-CH3);13C NMR(150MHz,CDCl3)δ:165.57,160.67,158.10,143.15,140.78,138.05,137.22,135.83(×2),135.27,130.11,129.88(×2),129.81(×2),129.17,128.79(×2),122.28,122.12,121.39,117.09,114.78(×2),112.20,110.72,84.58,78.78,58.90,55.58,52.91;HRMS(ESI)m/z calcd for C31H23N4O8S[M+H]+611.1237,found 611.1244。
下面是本发明部分化合物的药理实验结果:
实验设备与试剂
仪器超净工作台(苏净集团安泰公司)
恒温培养箱(Thermo electron Corporation)
酶标仪(BIO-RAD公司)
倒置生物显微镜(重庆光学仪器厂)
试剂细胞培养基RPMI-1640、DMEM(高糖)(GIBCO公司)
胎牛血清(杭州四季清有限公司)
CCK-8(Biosharp公司产品)
DMSO(Sigma公司)
细胞株人乳腺癌细胞MCF-7、人乳腺癌细胞MDA-MB-231、
人结肠癌细胞SW620
实验方法
细胞抑制活性实验方法
细胞在37℃、5%CO2饱和湿度的培养箱中常规培养。培养液为含10%热灭活胎牛血清,青霉素100U/mL和链霉素100U/mL的高糖DMEM细胞培养基。48h更换培养液,细胞贴壁后,用0.25%胰蛋白酶消化传代。实验用细胞均处于对数生长期,CCK-8法表明细胞活力>95%。
取处于对数生长期状态良好的细胞一瓶,加入消化液(0.125%胰蛋白酶+0.01%EDTA)消化,计数2~4×104cell/mL,制成细胞悬液接种于96孔板上,100μL/孔,置恒温CO2培养箱中培养24小时。换液,加入受试药物,100μL/孔,培养72小时。将CCK-8加入96孔板中,50μL/孔,培养箱中孵育4小时。吸去上清液,加DMSO,200μL/孔,平板摇床上震荡10分钟。受试物考察0.001至100μM以十倍浓度递增的6个浓度,用酶联免疫监测仪在波长为450nm处测定每孔的吸光度,分别计算各浓度下的细胞抑制率。
抑制率计算方法:
药敏孔相对OD值=药敏孔绝对OD值﹣空白对照孔绝对OD值
实验结果
表1实施例对2种人乳腺癌和1种人结肠癌细胞株抗增殖活性的IC50值(μM)
药理试验证明,本发明的目标衍生物具有更好的抗乳腺癌和结肠癌细胞增殖活性,可以用于进一步制备抗肿瘤药物。
Claims (8)
2.根据权利要求1所述的通式I所示的β-卡波林NO供体衍生物及其药学上可接受的盐,其特征在于:
通式I中,n为1-3的整数;R为含有1-7个碳原子的烷烃基、烯烃基或炔烃基;R1为氢,或含有1-3个碳原子的烷基,或含有4-10个碳原子的芳基或取代芳基、杂环芳基或取代杂环芳基,所述杂环芳基的芳杂环中包含1-2个N、O或S的杂原子,所述取代芳基或取代杂环芳基中的取代基为卤素或含有1-3个碳原子的烷氧基。
3.根据权利要求1所述的通式I所示的β-卡波林NO供体衍生物及其药学上可接受的盐,其特征在于:
通式I中,n为1-2的整数;R为含有2-6个碳原子的烷烃基、烯烃基或炔烃基;R1为氢,或含有1-2个碳原子的烷基,或含有4-8个碳原子的芳基或取代芳基、杂环芳基或取代杂环芳基,所述杂环芳基的芳杂环中包含1-2个N、O或S的杂原子,所述取代芳基或取代杂环芳基中的取代基为卤素或含有1-2个碳原子的烷氧基。
5.一种药物组合物,其特征在于:所述药物组合物含有治疗有效量的权利要求1-4中任一项所述的通式I所示的β-卡波林NO供体衍生物及其药学上可接受的盐和药学上可接受的载体。
6.权利要求1-4中任一项所述的通式I所示的β-卡波林NO供体衍生物及其药学上可接受的盐在制备治疗肿瘤疾病的药物中的应用。
7.权利要求5所述的药物组合物在制备治疗肿瘤疾病的药物中的应用。
8.根据权利要求6或7所述的应用,其特征在于:所述的肿瘤为乳腺癌肿瘤或结肠癌肿瘤。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102000072A (zh) * | 2009-09-01 | 2011-04-06 | 奇复康药物研发(苏州)有限公司 | 偶联有一氧化氮供体的抗肿瘤天然药物及其医药用途 |
CN106432235A (zh) * | 2016-10-19 | 2017-02-22 | 南通大学 | 靶向CDK和DNA的β‑咔啉衍生物及其制备方法和医药用途 |
CN110981882A (zh) * | 2019-11-07 | 2020-04-10 | 沈阳药科大学 | 一类白屈菜碱一氧化氮供体衍生物及其制备方法和用途 |
CN110981881A (zh) * | 2019-11-07 | 2020-04-10 | 沈阳药科大学 | 白屈菜碱一氧化氮供体衍生物及其制备方法和用途 |
CN111333639A (zh) * | 2020-04-20 | 2020-06-26 | 四川大学 | 咔啉衍生物/类似物及其制备方法和用途 |
CN111961048A (zh) * | 2020-08-26 | 2020-11-20 | 南通大学 | 含取代β-咔啉结构的三氟甲基吡唑酰胺及其制备方法和应用 |
-
2021
- 2021-02-25 CN CN202110213358.2A patent/CN114957243B/zh active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102000072A (zh) * | 2009-09-01 | 2011-04-06 | 奇复康药物研发(苏州)有限公司 | 偶联有一氧化氮供体的抗肿瘤天然药物及其医药用途 |
CN106432235A (zh) * | 2016-10-19 | 2017-02-22 | 南通大学 | 靶向CDK和DNA的β‑咔啉衍生物及其制备方法和医药用途 |
CN110981882A (zh) * | 2019-11-07 | 2020-04-10 | 沈阳药科大学 | 一类白屈菜碱一氧化氮供体衍生物及其制备方法和用途 |
CN110981881A (zh) * | 2019-11-07 | 2020-04-10 | 沈阳药科大学 | 白屈菜碱一氧化氮供体衍生物及其制备方法和用途 |
CN111333639A (zh) * | 2020-04-20 | 2020-06-26 | 四川大学 | 咔啉衍生物/类似物及其制备方法和用途 |
CN111961048A (zh) * | 2020-08-26 | 2020-11-20 | 南通大学 | 含取代β-咔啉结构的三氟甲基吡唑酰胺及其制备方法和应用 |
Non-Patent Citations (1)
Title |
---|
XU HU 等: "Discovery of β-carboline-(phenylsulfonyl)furoxan hybrids as potential anti-breast cancer agents", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 40, pages 127952 * |
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