CN116496288A - 一种小白菊内酯Boc保护的胺类衍生物及其制备方法和用途 - Google Patents
一种小白菊内酯Boc保护的胺类衍生物及其制备方法和用途 Download PDFInfo
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- CN116496288A CN116496288A CN202310186339.4A CN202310186339A CN116496288A CN 116496288 A CN116496288 A CN 116496288A CN 202310186339 A CN202310186339 A CN 202310186339A CN 116496288 A CN116496288 A CN 116496288A
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- boc
- amino acid
- parthenolide
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- amino
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Classifications
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Abstract
本发明涉及一种合成的药用化合物,具体涉及一种小白菊内酯Boc保护的胺类衍生物,其为在小白菊内酯的基础上引入带有Boc保护的氨基酸基团,本发明同时涉及其制备方法及在治疗制备癌症药物中的应用,本发明制备的化合物可以提高对肿瘤细胞的选择性,增加药物的溶解度和穿透性,减小药物对细胞的毒性,减弱代谢,同时,与小白菊内酯药物分子相比表现出缓慢释放性能,其带有Boc保护的氨基酸修饰的前药安全性问题亦可控。
Description
技术领域
本发明涉及一种药用化合物,尤其涉及一种小白菊内酯Boc保护的胺类衍生物,同时,涉及其制备方法和用途。
背景技术
肿瘤极大地威胁着人类的健康,根据有关统计显示,全球每年760万人死于癌症。白血病又称“血癌”,是造血系统的一种恶性的疾病,由于白血病是一种遗传性疾病,白血病在青少年中的发生率相对较高,因此其危害比较突出。白血病发生的主要原因是造血细胞失去了进一步分化成熟的能力,导致大量的幼稚细胞聚集在骨髓和其他的造血组织中,从而使正常造血受到抑制。
小白菊内酯(Parthenolide,PTL)是一种从菊科植物中提取出来的倍半萜类化合物,具有独特的抗炎及抗肿瘤的生物活性,能显著地抑制脑胶质瘤、胸腺癌、结直肠癌、淋巴瘤等癌细胞的生长并促进其凋亡。PTL具有独特的化学结构,能抑制细胞转录因子NF-κB、STATs、JNK的表达,而诱发ROS反应,这可能是PTL抗炎及抗肿瘤功能的分子机制。PTL对正常的细胞无毒害,却表现了对多种肿瘤细胞的广谱的细胞毒性和促凋亡效应,提示了其作为重要肿瘤抑制药物的开发前景。
但目前公开的小白菊内酯及其衍生物存在水溶性差,代谢不稳定,服用剂量过大,生物利用度低等问题。
发明内容
本发明所要解决的技术问题是提供一种小白菊内酯衍Boc保护的胺类生物及其制备方法和用途,解决现在小白菊内酯毒性高,生物利用率低的问题。
技术方案
一种小白菊内酯Boc保护的胺类衍生物,结构式如下:
其中,R基团为氨基酸/带有氨基被保护的氨基酸、氨基酸衍生物/带有氨基被保护的氨基酸衍生物或2~8个氨基酸/带有氨基被保护的氨基酸聚集体的肽链。
进一步,所述R基团选自:
天然的L构型的α-氨基酸、或天然的D构型的α-氨基酸,以及这些氨基酸所对应的酯类衍生物;
或非天然的L构型的α-氨基酸、非天然的D构型的α-氨基酸,以及这些氨基酸所对应的酯类衍生物;
或非天然的各种β-氨基酸、γ-氨基酸或非天然的氨基与羧基相隔不超过10个碳原子的氨基酸或非天然的D构型的氨基酸,以及这些氨基酸所对应的酯类衍生物。
进一步,R基团选自天然的L构型的α-氨基酸或天然的D构型的α-氨基酸,或天然的氨基酸衍生物,常见的天然的L构型的α-氨基酸主要选自以下氨基酸:
a、烷基类氨基酸:包括L-苯丙氨酸(L-Phe),丙氨酸(L-Ala),甘氨酸(Gly),亮氨酸(L-Leu),异亮氨酸(L-Ile),缬氨酸(L-Val);
b、含有氨基的氨基酸:包括组氨酸(L-His),精氨酸(L-Arg),谷氨酰胺(L-Gln),赖氨酸(L-Lys),脯氨酸(L-Pro),天冬酰胺(L-Asn),色氨酸(L-Trp);
c、含有两个羧基的氨基酸:包括天冬氨酸(L-Asp)和谷氨酸(L-Glu);
d、含有巯基的氨基酸:包括半胱氨酸(L-Cys)和蛋氨酸(L-Met);
e、含有羟基的氨基酸:包括丝氨酸(L-Ser),酪氨酸(L-Tyr)和苏氨酸(L-Thr)。
上述氨基酸结构如下:
。
,其中R 为下列任意一种:
一种小白菊内酯Boc保护的胺类衍生物,包括:称取小白菊内酯(4.03 mmol,1.00g,1.00eq),使用2 eq的二氧化硒进行氧化,所得氧化产物与1eq的Boc保护的氨基酸或带有Boc保护的氨基酸衍生物或带有保护基的氨基聚集体发生缩合,得到小白菊内酯的Boc保护的胺类衍生物,反应通式为:
。
一种药物组合物,所述药物组合物包含:所述的小白菊内酯Boc保护的胺类衍生物加入药学可接受的助剂、稀释剂或载体制备而成。
所述的一种小白菊内酯Boc保护的胺类衍生物,用于在治疗各类肿瘤疾病的药物中的应用。
优选地,所述化合物用于治疗急性髓系白血病、脑胶质瘤、前列腺癌、肺癌、乳腺癌、肝癌、胃癌、宫颈癌、结肠癌和上皮癌。
有益效果
氨基酸是生命活动中最基本的物质,是生命代谢的物质基础,氨基酸代谢普遍存在于机体的各组织和细胞中,具有参与机体蛋白质的合成,能量代谢等重要的生理功能。肿瘤细胞对氨基酸的需求远大于正常组织。在肿瘤生长过程中,肿瘤组织为满足自身合成蛋白质和细胞增殖的需求,源源不断地将机体血浆中的多种必需氨基酸和非必需氨基酸转运到肿瘤组织和细胞。因此可利用恶性肿瘤细胞对氨基酸转运率增加,将氨基酸引入抗肿瘤药物分子中,可提高其对肿瘤细胞的选择性,达到杀死肿瘤组织和细胞的目的。
本发明设计在药物分子中引入带有保护基的氨基酸基团,提高了对肿瘤细胞的选择性,增强药物的溶解度和穿透性,缓解药物对细胞的毒性,减弱代谢;该先导化合物相较于结构修饰前的小白菊内酯药物分子,表现出缓慢释放性能,同时由于氨基酸的安全性,其氨基酸修饰的前药安全性问题亦可控。后续生物活性实验,本技术方案所提供的小白菊内酯氨基酸类衍生物具有更好的肿瘤细胞凋亡诱导效果,更高的生物利用率,相比于小白菊内酯更具有医疗应用前景。
附图说明
图1是本发明小白菊内酯衍生物的结构通式;
图2是本发明小白菊内酯的苯丙氨酸衍生物氢谱结构示意图;
图3是本发明小白菊内酯的苯丙氨酸衍生物碳谱结构示意图;
图4是本发明小白菊内酯衍生物DTry的细胞周期实验数据图;
图5是本发明小白菊内酯衍生物DTry的细胞周期实验数据图。
具体实施方式
下面结合具体实施例和附图1~5,进一步阐述本发明。
小白菊内酯的氧化
称取小白菊内酯(4.03 mmol,1.00g,1.00 eq),加入2 eq的二氧化硒,在3ml二氯甲烷溶液中进行反应。室温反应6h,反应结束后,用饱和硫代硫酸钠盐溶液进行淬灭,用100ml饱和硫代硫酸钠盐溶液萃取3次,收集合并有机相,减压蒸除溶剂,经柱层析得到白色固体2。反应通式如下:
。
实施例1
化合物4a的制备方法
取2(1.14 mmol,300.00 mg,1.00eq),1-羟基苯并三唑(1.26 mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5 mmol,3.05 eq),DMF(10mL),Boc-D-苯丙氨酸(1.25mmol,332.25mg,1.10eq)于100ml圆底烧瓶中。室温下搅拌反应8 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1 h,过滤,减压蒸除溶剂,经柱层析分离得到白色固体目标产物4a,0.213g。
1H NMR (400 MHz, DMSO) δ 7.42 (d,J= 7.7 Hz, 1H), 7.32 – 7.19 (m, 5H),6.07 (d,J= 3.4 Hz, 1H), 5.63 – 5.53 (m, 2H), 4.58 (d,J= 12.6 Hz, 1H), 4.41(d,J= 12.7 Hz, 1H), 4.18 (dd,J= 14.8, 8.3 Hz, 1H), 4.05 (dt,J= 14.2, 8.2 Hz,2H), 2.94 (qd,J= 13.7, 7.9 Hz, 3H), 2.79 (d,J= 9.5 Hz, 1H), 2.27 (td,J= 13.0,6.3 Hz, 2H), 2.07 (d,J= 11.4 Hz, 2H), 1.60 (t,J= 11.0 Hz, 1H), 1.47 (s, 3H),1.39 – 1.25(m, 9H), 1.18 (t,J= 7.1 Hz, 1H).13C NMR (100 MHz, DMSO) δ 172.1,169.4, 155.47, 139.6, 137.5, 134.6, 129.3, 129.0, 128.2, 126.5, 119.3, 80.6,78.3, 67.0, 62.6, 59.9, 55.6, 41.7, 36.5, 36.3,28.1, 24.7, 23.8, 23.2, 20.7,17.4, 14.1。
MS:511.0(M+H)。
实施例2
化合物4e的制备
取2(1.14 mmol,300.00 mg,1.00eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-D-蛋氨酸(1.25mmol,311.25mg,1.10eq)。室温下搅拌反应10 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1 h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体4e,0.23g。
1H NMR (400 MHz, CDCl3) δ 6.18 (d,J= 3.0 Hz, 1H), 5.65 (s, 1H), 5.53(s, 1H), 4.64 (d,J= 12.4 Hz, 1H), 4.49 (d,J= 12.5 Hz, 1H), 4.32 (s, 1H), 4.10– 3.96 (m, 1H), 3.80 (t,J= 9.3 Hz, 1H), 2.80 (dd,J= 14.6, 12.9 Hz, 2H), 2.49(t,J= 7.3 Hz, 2H), 2.41 – 2.03 (m, 10H), 1.98 (dd,J= 4.9, 2.1 Hz, 1H), 1.88(dd,J= 13.9, 7.1 Hz, 1H), 1.48 (s, 3H), 1.38 (s, 9H), 1.23 – 1.16 (m, 1H).13CNMR (100 MHz, CDCl3) δ 172.2, 169.3, 155.3, 138.6, 134.3,130.8, 120.4, 80.9,80.0, 67.4, 63.2, 59.9, 52.9, 42.5, 36.5, 31.7, 30.0, 28.2, 25.5, 24.2, 23.7,17.9, 15.5。
MS:496.0(M+H)。
实施例3
化合物4b的制备
取2(1.14 mmol,300.00 mg,1.00eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-L-苯丙氨酸(1.25mmol,332.25mg,1.10eq)。室温下搅拌反应7 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1 h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体4b,0.203g。
1H NMR (400 MHz, DMSO) δ 7.30 – 7.18 (m, 5H), 6.81 – 6.75(d, J = 8.6Hz, 1H), 5.86 – 5.82 (t, J = 2.0 Hz, 1H), 5.73 – 5.69 (t, J =1.9 Hz, 1H),5.66 – 5.59 (ddq, J = 6.6, 5.7, 1.0 Hz, 1H), 4.67 – 4.61 (dd, J =6.3, 4.7 Hz,1H), 4.58 – 4.54 (p, J = 1.1 Hz, 2H), 4.54 – 4.46 (dt, J =8.6, 7.2 Hz, 1H),3.12 – 3.05 (m, 1H), 3.08 – 2.99 (m, 2H), 2.89 – 2.84 (d, J = 4.6 Hz, 1H),2.40 – 2.33 (tq, J = 7.6, 0.9 Hz, 2H), 2.21 – 2.05 (m, 2H), 1.94 – 1.84(dq, J= 12.6, 7.5 Hz, 1H), 1.84 – 1.67 (m, 2H), 1.66 – 1.57 (dt, J = 13.0, 7.5 Hz,1H), 1.43 – 1.39 (s, 3H).13C NMR (100 MHz, CDCl3) δ 173.1, 171.7, 157.6,139.8, 137.7,135.5, 130.1, 129.5, 128.8, 127.3, 120.8, 80.8, 79.4, 69.3,64.9, 61.4, 55.6, 44.6, 37.9, 37.3, 28.8, 28.4, 28.3, 25.5, 18.4。
MS:511.0(M+H)。
实施例4
化合物4c的制备
取2(1.14 mmol,300.00 mg,1.00eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-D-色氨酸(1.25mmol,380.00mg,1.10eq)。室温下搅拌反应10 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1 h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体4c,0.303g。
1H NMR (400 MHz, DMSO) δ 10.95 (s, 1H),7.51 (d,J= 7.8 Hz, 1H), 7.44 –7.35 (m, 2H), 7.22 (d,J= 2.0 Hz, 1H), 7.12 (t,J= 7.2 Hz, 1H), 7.03 (t,J= 7.3Hz, 1H), 6.09 (d,J= 3.4 Hz, 1H), 5.59 (d,J= 2.9 Hz, 1H), 5.49 (t,J= 7.6 Hz,1H), 4.51 (d,J= 12.5 Hz, 1H), 4.39 (d,J= 12.6 Hz, 1H), 4.25 (dd,J= 14.9, 7.3Hz, 1H), 4.15 – 4.05 (m, 2H), 3.17 – 3.04 (m, 2H), 2.75 – 2.70(m, 1H), 2.11 –2.04 (m, 4H), 1.56 (td,J= 12.2, 4.1 Hz, 1H), 1.49 (s, 3H), 1.40 (s, 8H), 1.31(s, 1H), 1.27 – 1.16 (m, 2H), 1.13 (t,J= 7.0 Hz, 1H).13C NMR (100 MHz, DMSO) δ172.5, 169.5,155.45, 139.6, 136.1, 134.6, 129.3, 127.0, 123.8, 121.0, 119.3,118.5, 117.9, 111.5, 109.5, 80.6, 78.3, 67.1, 62.6, 59.9, 55.0, 41.6, 36.2,34.7, 27.8, 26.9,24.7, 23.8, 23.2, 20.8, 17.4。
MS:550.0(M+H)。
实施例5
化合物4d的制备
取2(1.14 mmol,300.00 mg,1.00 eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-L-色氨酸(1.25mmol,380.00mg,1.10eq)。室温下搅拌反应24 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1 h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体4d,0.298g。
1H NMR (400 MHz, DMSO) δ 10.90 (s, 1H),7.95 (s, 1H), 7.48 (d, J = 7.9Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H), 7.08 – 7.02 (m,1H),6.99 – 6.92 (m, 1H), 6.02 (d, J = 3.4 Hz, 1H), 5.54 (d, J = 3.1 Hz, 1H),5.42 – 5.34 (m, 1H),4.53 (d, J = 12.7 Hz, 1H), 4.32 (d, J = 12.8 Hz, 1H),4.03 (dt, J = 9.4, 8.2 Hz, 1H), 3.76 (t, J = 6.6 Hz, 1H), 3.08 – 2.96(m, 2H),2.89 (s, 1H), 2.77 – 2.72 (m, 1H), 2.31 – 1.94 (m, 6H), 1.68 – 1.58 (m, 1H),1.58 – 1.35(m, 4H), 1.20 – 1.03 (m, 1H).13C NMR (100 MHz, DMSO) δ 174.6,169.7, 140.0, 136.5, 134.9,129.4, 127.7, 124.2, 121.3, 119.8, 118.7, 118.7,111.8, 109.8, 81.1, 66.9, 63.0, 60.4, 55.3, 42.2, 36.7, 30.6, 24.9, 24.1,23.6, 17.9。
MS:550.0(M+H)。
实施例6
化合物4g的制备
取2(1.14 mmol,300.00 mg,1.00eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-D-缬氨酸(1.25mmol,271.25mg,1.10eq)。室温下搅拌反应10 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1 h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体4g,0.246g。
1H NMR (400 MHz, CDCl3) δ 6.24 (d,J= 3.5 Hz, 1H), 5.69 (t,J= 8.0 Hz,1H), 5.54 (d,J= 3.0 Hz, 1H), 4.96 (d,J= 8.7 Hz, 1H), 4.70 (d,J= 12.4 Hz, 1H),4.49 (d,J= 12.5 Hz, 1H), 4.17 (dd,J= 8.8, 4.7 Hz, 1H), 2.87 (d,J= 9.0 Hz,1H), 2.82 (d,J= 9.4 Hz, 1H), 2.45 – 2.39 (m, 1H), 2.31 – 2.14 (m, 4H), 1.70 –1.62 (m, 1H), 1.52 (s, 3H), 1.42 (s, 10H),1.27 – 1.04 (m, 2H), 0.92 (dd,J=28.4, 6.9 Hz, 6H).13C NMR (100 MHz, CDCl3) δ 172.3, 169.3, 155.7, 138.6,134.4, 130.9, 120.4, 80.9, 79.9, 67.2, 63.2, 59.9, 58.7, 42.6, 36.5, 31.0,28.3, 25.6, 24.2, 23.8, 19.1,17.9, 17.6。
MS:462.0(M+H)。
实施例7
化合物4h的制备
取2(1.14 mmol,300.00 mg,1.00 eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-L-正亮氨酸(1.25mmol,288.75mg,1.10eq)。室温下搅拌反应8 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1 h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体4h,0.21g。
1H NMR (400 MHz, DMSO) δ 7.30 (d,J= 7.4 Hz, 1H), 6.05 (d,J= 3.3 Hz,1H), 5.60 (t,J= 5.9 Hz, 2H), 4.74 (d,J= 12.7 Hz, 1H), 4.40 (d,J= 12.8 Hz,1H), 4.10 (t,J= 9.2 Hz, 1H), 3.90 (dd,J= 13.9, 7.8 Hz, 1H), 3.01 (t,J= 8.9Hz, 1H), 2.85 (d,J= 9.5 Hz, 1H), 2.35 – 2.19 (m, 4H), 2.08 (dd,J= 18.0, 6.9Hz, 2H), 1.61 (d,J= 7.3 Hz, 3H), 1.48 (s, 3H), 1.36 (d,J= 16.0 Hz, 10H), 1.27(d,J= 3.9 Hz, 4H), 0.85 (t,J= 6.5 Hz, 3H).13C NMR (100 MHz, DMSO) δ 173.2,169.8,156.1, 140.2, 135.5, 129.5, 119.5, 81.1, 78.6, 67.0, 63.1, 60.3, 54.1,42.2, 36.8, 30.6, 28.6, 28.13, 25.0, 24.1, 23.6, 22.1, 17.9, 14.2。
MS:478.0(M+H)。
实施例8
化合物4i的制备
取2(1.14 mmol,300.00 mg,1.00 eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-L-异亮氨酸(1.25mmol,288.75mg,1.10eq)。室温下搅拌反应8 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体4i,0.256g。
1H NMR (400 MHz, DMSO) δ 7.22 (d,J= 7.9 Hz, 1H), 6.05 (d,J= 3.1 Hz,1H), 5.66 – 5.55 (m, 2H), 4.77 (d,J= 12.6 Hz, 1H), 4.41 (d,J= 12.8 Hz, 1H),4.05 (dt,J= 14.2, 8.1 Hz, 2H), 3.88 (t,J= 7.3 Hz, 1H), 3.01 (t,J= 8.7 Hz,1H), 2.86 (d,J= 9.4 Hz, 1H), 2.37 – 2.22 (m, 4H), 2.10 (t,J= 10.7 Hz, 2H),1.49 (s, 3H), 1.42 – 1.35 (m, 10H),1.25 – 1.12 (m, 2H), 0.93 (t,J= 12.2 Hz,1H), 0.86 – 0.81 (m, 6H).3C NMR (100 MHz, DMSO) δ 172.1, 169.3, 155.7, 139.8,135.1,129.1, 118.9, 80.7, 78.1, 66.3, 62.6, 59.8, 58.5, 41.8, 36.4, 35.7,28.1, 27.9, 24.9, 24.6, 23.6, 20.7, 17.4, 15.4, 14.0, 11.0。
MS:478.0(M+H)。
实施例9
化合物4j的制备
取2(1.14 mmol,300.00 mg,1.00eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-D-亮氨酸(1.25mmol,288.75mg,1.10eq)。室温下搅拌反应10 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1 h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体4j,0.270。
1H NMR (400 MHz, CDCl3) δ 6.24 (d,J= 3.3 Hz, 1H), 5.69 (t,J= 8.1 Hz,1H), 5.58 (d,J= 3.0 Hz, 1H), 4.84 (d,J= 12.2 Hz, 2H), 4.39 (d,J= 12.3 Hz,1H), 3.84 (t,J= 9.3 Hz, 1H), 2.84 (d,J= 9.4 Hz, 2H), 2.43 – 2.12 (m, 6H),1.68 (dd,J= 10.8, 7.9 Hz, 3H), 1.57 – 1.40 (m, 14H), 0.93 (d,J= 6.5 Hz, 6H).13C NMR (100 MHz, CDCl3) δ 172.5, 168.3, 154.5, 137.7, 133.8, 130.0, 119.3,80.0, 79.0, 66.1, 62.3, 58.9, 51.2, 41.6, 40.2, 35.6, 27.2, 24.4, 23.8, 23.0,22.8,21.8, 20.7, 16.9。
MS:478.0(M+H)。
实施例10
化合物4k的制备
取2(1.14 mmol,300.00 mg,1.00eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-L-亮氨酸(1.25mmol,288.75mg,1.10eq)。室温下搅拌反应10 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1 h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体4k,0.283g。
1H NMR (400 MHz, DMSO) δ 7.32 (d,J= 7.6 Hz, 1H), 6.04 (d,J= 3.3 Hz,1H), 5.66 – 5.52 (m, 2H), 4.75 (d,J= 12.6 Hz, 1H), 4.38 (d,J= 12.7 Hz, 1H),4.11 (t,J= 9.2 Hz, 1H), 3.99 – 3.90 (m, 1H), 3.01 (t,J= 9.0 Hz, 1H), 2.85 (d,J= 9.5 Hz, 1H), 2.38 – 2.16 (m, 4H),2.08 (dd,J= 18.2, 7.2 Hz, 2H), 1.69 –1.47 (m, 6H), 1.45 – 1.34 (m, 10H), 0.96 – 0.77 (m, 7H).13C NMR (100 MHz,DMSO) δ 173.1, 169.4, 155.6, 139.8, 135.1, 129.3, 119.0, 80.6, 78.2, 66.6,62.6, 59.9, 52.1, 41.8, 36.4, 28.1, 27.9, 24.5, 24.3, 23.7, 23.2,22.7, 21.2,17.5。
MS:478.0(M+H)。
实施例11
化合物4Z的制备
取2(1.14 mmol,300.00 mg,1.00 eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-L-蛋氨酸(1.25mmol,311.25mg,1.10eq)。室温下搅拌反应24 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1 h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体4Z,0.14g。
1H NMR (400 MHz, CDCl3) δ 6.20 – 6.15 (m, 1H), 5.64 (s, 1H), 5.52 (d,J= 3.0 Hz, 1H), 4.74 (d,J= 11.7 Hz, 1H), 4.39 (d,J= 12.2 Hz, 1H), 4.30 (s,1H), 3.82 – 3.74 (m, 1H), 2.77 (dd,J= 8.6, 2.6 Hz, 2H), 2.47 (td,J= 7.3, 2.8Hz, 2H), 2.41 – 2.22 (m, 4H), 2.18 – 2.00 (m, 6H), 1.91 – 1.81 (m, 1H), 1.65– 1.58 (m, 1H), 1.48 (d,J= 3.7 Hz, 3H), 1.41 – 1.34 (m, 9H).13C NMR (100 MHz,CDCl3) δ 173.8, 171.7, 157.6, 139.8, 135.5,130.1, 120.8, 80.8, 79.4, 69.3,64.9, 61.4, 52.9, 44.6, 37.3, 30.4, 29.6, 28.8, 28.4, 28.3, 25.5, 18.4, 14.8。
MS:496.0(M+H)。
实施例12
化合物4m的制备
取2(1.14 mmol,300.00 mg,1.00eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-4-氨基丁酸(1.25mmol,253.75mg,1.10eq)。室温下搅拌反应12 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体4m,0.180g。
1H NMR (400 MHz, CDCl3) δ 6.24 (d, J =3.5 Hz, 1H), 5.67 (t, J = 8.1Hz, 1H), 5.56 (d, J = 3.2 Hz, 1H), 4.64 (d, J = 12.4 Hz, 2H), 4.45 (d, J =12.5 Hz, 1H), 3.84 (t, J = 9.3 Hz, 1H), 3.14 (dd, J= 12.9, 6.4 Hz, 2H), 2.85(d, J = 3.1 Hz, 1H), 2.41 – 2.25 (m, 6H), 1.79 (p, J = 7.1 Hz, 3H), 1.71 –1.61 (m, 1H), 1.53 (s, 3H), 1.42 (s, 11H), 1.25 (dd, J = 14.1, 7.0 Hz, 1H).13CNMR (100 MHz, CDCl3) δ 173.3, 169.7, 156.3, 139.1, 135.2, 131.0, 120.8, 81.4,79.7, 67.1, 63.7, 60.3, 43.0, 40.2, 37.0, 31.8, 28.8, 26.0, 25.7, 24.7, 24.2,18.4。
MS:450.0(M+H)。
实施例13
化合物4n的制备
取2(1.14 mmol,300.00 mg,1.00eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-7-氨基庚酸(1.25mmol,306.25mg,1.10eq)。室温下搅拌反应10 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体目标产物4n,0.220g。
1H NMR (400 MHz, CDCl3) δ 6.23 (d, J =3.5 Hz, 1H), 5.66 (t, J = 8.0Hz, 1H), 5.53 (d, J = 3.2 Hz, 1H), 4.63 (d, J = 12.4 Hz, 1H), 4.43 (d, J =12.5 Hz, 1H), 3.83 (t, J = 9.3 Hz, 1H), 3.71 – 3.63 (m, 1H), 3.07 (dd, J =13.0, 6.4 Hz, 2H), 2.91 – 2.85 (m, 1H), 2.83 (d, J = 9.4 Hz, 1H), 2.45 – 2.11(m, 9H), 1.59 (dt, J = 11.1, 7.4 Hz, 3H), 1.53 (s,3H), 1.46 – 1.38 (m, 12H),1.32 – 1.29 (m, 3H).13C NMR (100 MHz, CDCl3) δ 173.4, 169.4, 156.0, 138.8,135.0,130.7, 120.3, 81.1, 79.1, 66.6, 63.3, 60.0, 42.7, 40.5, 36.6, 34.2,29.9, 28.8, 28.5, 26.4, 25.8, 24.8, 24.5, 23.8, 18.0。
MS:492.0(M+H)。
实施例14
化合物4p的制备
取2(1.14 mmol,300.00 mg,1.00eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-D-天冬酰胺(1.25mmol,290.00mg,1.10eq)。室温下搅拌反应24 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体4p0.150g。
1H NMR (400 MHz, DMSO) δ 7.70 (d, J =8.1 Hz, 1H), 6.06 (d, J = 3.0Hz, 1H), 5.63 (s, 2H), 4.70 (d, J = 12.6 Hz, 1H), 4.48 (d, J = 12.8 Hz, 1H),4.39 (dd, J = 14.0, 8.5 Hz, 1H), 4.13 – 4.00 (m, 3H), 3.02 – 2.91(m, 3H),2.85 (d, J = 9.5 Hz, 1H), 2.34 – 2.22 (m, 4H), 1.49 (s, 4H), 1.41 (s, 9H),1.18 (t, J = 7.1 Hz, 3H).13C NMR (100 MHz, DMSO) δ 170.3, 169.5,169.4, 155.2,139.6, 134.5, 129.3, 119.3, 80.72, 78.9, 67.5, 62.6, 59.8, 50.0, 41.8, 36.3,28.0, 24.6, 23.5, 23.2, 20.7, 19.7, 17.5, 14.0。
MS:479.0(M+H)。
实施例15
化合物4q的制备
取2(1.14 mmol,300.00 mg,1.00eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-D-谷氨酰胺(1.25mmol,307.50mg,1.10eq)。室温下搅拌反应20 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体目标产物4q0.150g。
1H NMR (400 MHz, CDCl3) δ 6.23 (d,J= 3.5 Hz, 1H), 5.59 (d,J= 3.1 Hz,1H), 5.41 (d,J= 7.9 Hz, 1H), 4.67 (d,J= 12.3 Hz, 1H), 4.52 (d,J= 12.4 Hz,1H), 4.23 (td,J= 8.7, 4.3 Hz, 1H), 3.84 (t,J= 9.3 Hz, 1H), 2.94 – 2.80 (m,2H), 2.45 – 2.25 (m, 6H), 2.22 – 2.10 (m, 3H), 1.92 (dt,J= 15.6, 6.7 Hz, 1H),1.66 (t,J= 11.4 Hz, 1H), 1.53 (s, 3H), 1.46 – 1.37 (m, 10H).13C NMR (100 MHz,DMSO) δ 171.5, 170.4, 169.5, 155.6, 139.6, 134.6, 129.0, 119.9, 80.7, 78.6,66.9, 62.6, 60.0, 52.7, 41.7, 36.3, 28.1, 26.3, 24.6, 23.6, 23.2,20.8, 17.5,14.1, 13.6。
MS:493.0(M+H)。
实施例16
化合物4u的制备
取2(1.14 mmol,300.00 mg,1.00 eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1 eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-D-脯氨酸(1.25mmol,268.75mg,1.10eq)。室温下搅拌反应8 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体目标产物4u0.274g。
1H NMR (400 MHz, DMSO) δ 6.05 (dd,J= 11.3, 3.3 Hz, 1H), 5.66 – 5.55(m, 2H),4.75 (dd,J= 25.1, 12.6 Hz, 1H), 4.41 (dd,J= 16.9, 12.8 Hz, 1H), 4.22– 4.06 (m, 2H), 3.42 – 3.26 (m, 3H), 3.01 (d,J= 8.4 Hz, 1H), 2.87 – 2.81 (m,1H), 2.37 – 2.06 (m, 7H), 1.90 – 1.77 (m, 3H), 1.64 (dd,J= 20.8, 11.6 Hz,1H), 1.48 (s, 3H), 1.36 (d,J= 24.2 Hz, 9H).13C NMR (100 MHz, DMSO) δ 172.9,169.8,153.9, 140.1, 135.4, 130.2, 119.6, 81.0, 79.2, 67.2, 63.0, 60.4, 59.0,46.5, 42.1, 36.7, 30.8, 29.8, 28.4, 28.3, 24.9, 24.4, 24.1, 23.5, 17.8。
MS:462.0(M+H)。
实施例17
化合物4v的制备
取2(1.10 mmol,300.00 mg,1.00eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-D-甘氨酸(1.10mmol,321.00mg,1.00eq)。室温下搅拌反应8 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体目标产物4v0.310g。
1H NMR (400 MHz, DMSO) δ 7.28 (t,J= 5.6 Hz, 1H), 6.05 (s, 1H), 5.62(d,J= 10.1 Hz, 2H), 4.66 (d,J= 12.3 Hz, 1H), 4.45 (d,J= 12.6 Hz, 1H), 4.11(t,J= 9.1 Hz, 1H), 3.69 (d,J= 5.7 Hz, 2H), 2.84 (d,J= 9.4 Hz, 1H), 2.35 –2.23 (m, 3H), 2.12 – 2.05 (m, 2H), 1.69 – 1.31 (m, 16H).13C NMR (100 MHz,CDCl3) δ 170.2, 169.3, 155.7, 138.6, 134.4, 131.1, 120.4, 81.0, 80.1, 67.4,63.2, 59.9, 42.6, 42.4,36.5, 28.2, 25.6, 24.2, 24.0, 23.8, 23.6, 17.9。
MS:422.0(M+H)。
实施例18
化合物4x的制备
取2(1.14 mmol,300.00 mg,1.00 eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1 eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-L-组氨酸(1.25mmol,318.75mg,1.10eq)。室温下搅拌反应24 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体目标产物4x0.150g。
1H NMR (400 MHz, DMSO) δ 12.02 (s, 1H),7.55 (s, 1H), 7.29 (s, 1H),6.85 (s, 1H), 6.04 (t,J= 3.5 Hz, 1H), 5.70 – 5.35 (m, 2H), 4.64 (dd,J= 37.1,12.6 Hz, 1H), 4.35 (d,J= 12.8 Hz, 1H), 4.26 – 4.20 (m, 1H), 4.09 (td,J= 9.2,2.9 Hz, 1H), 3.03 – 2.76 (m, 4H), 2.25 – 2.02 (m, 4H), 1.69 – 1.14(m, 16H).13CNMR (100 MHz, DMSO) δ 172.3, 169.6, 155.7, 139.9, 135.3, 135.2, 135.1, 129.4,124.1, 119.6, 81.0,78.7, 67.0, 63.0, 60.1, 54.4, 42.3, 36.8, 28.5, 25.1,24.0, 23.6, 18.0。
MS:502.0(M+H)。
实施例19
化合物4E的制备
取2(1.14 mmol,300.00 mg,1.00eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),双Boc-L-赖氨酸(1.25mmol,432.5mg,1.10eq)。室温下搅拌反应12 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体4E 0.320g。
1H NMR (400 MHz, CDCl3) δ 6.24 (d,J= 3.4 Hz, 1H), 5.69 (t,J= 8.1 Hz,1H), 5.58 (d,J= 3.1 Hz, 1H), 5.09 (t,J= 8.6 Hz, 1H), 4.81 (d,J= 12.3 Hz, 1H),4.60 (s, 1H), 4.41 (d,J= 12.3 Hz, 1H), 4.19 (dd,J= 12.4, 7.8 Hz, 1H), 3.84(t,J= 9.3 Hz, 1H), 3.09 (dd,J= 12.6, 6.3 Hz, 2H), 2.87 – 2.78 (m, 2H), 2.43 –2.28 (m, 4H), 2.17 (ddd,J= 11.3, 10.0, 6.1 Hz, 2H), 1.80 (dd,J= 13.1, 7.9 Hz,2H), 1.65 (dd,J= 14.3, 7.2 Hz, 2H), 1.53 (s, 3H), 1.42 (s, 20H), 1.25 (dd,J=14.3, 7.1 Hz, 2H).13C NMR (100 MHz, CDCl3) δ 173.3, 169.8, 156.5, 156.0,139.0, 135.2, 131.6, 120.8, 81.4, 80.4, 79.6, 67.6,63.7, 60.3, 53.9, 43.0,40.3, 37.0, 32.2, 30.0, 28.8, 28.7, 25.8, 24.4, 24.2, 22.9, 18.4。
MS:593.0(M+H)。
实施例20
化合物4H的制备
取2(1.14 mmol,300.00 mg,1.00eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-D-酪氨酸(1.25mmol,351.25mg,1.10eq)。室温下搅拌反应24 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体目标产物4H0.152g。
1H NMR (400 MHz, CDCl3) δ 6.96 (d,J= 8.4 Hz, 2H), 6.77 (d,J= 8.4 Hz,2H), 6.25 (d,J= 3.3 Hz, 1H), 5.58 (dd,J= 9.1, 5.9 Hz, 2H), 5.09 – 5.01 (m,1H), 4.58 – 4.29 (m, 4H), 3.04 – 2.94 (m, 2H), 2.89 (d,J= 8.1 Hz, 1H), 2.73(s, 1H), 2.16 (dd,J= 11.7, 6.2 Hz, 4H), 1.52 (s, 4H), 1.43 (s, 12H).13C NMR(100 MHz, CDCl3) δ 172.3, 169.6, 155.6, 155.1, 138.5, 134.2, 131.7, 130.5,130.2, 127.2, 120.8,115.6, 81.0, 80.2, 68.5, 63.2, 60.3, 55.3, 42.5, 37.8,36.3, 28.3, 25.9, 24.9, 23.8, 17.9。
MS:528.0(M+H)。
实施例21
化合物4J的制备
取2(1.14 mmol,300.00 mg,1.00eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-L-苯甘氨酸(1.25mmol,313.75mg,1.10eq)。室温下搅拌反应10h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体目标产物4J0.211g。
1H NMR (400 MHz, CDCl3) δ 7.35 (s, 5H), 6.21 (dd,J= 6.5, 3.4 Hz, 1H),5.48 (ddd,J= 27.4, 23.8, 8.7 Hz, 3H), 5.31 – 5.20 (m, 1H), 4.75 (dd,J= 18.5,12.6 Hz, 1H), 4.53 – 4.38 (m, 1H),2.68 (dd,J= 51.6, 9.4 Hz, 2H), 2.36 – 1.98(m, 6H), 1.63 – 1.22 (m, 14H).13C NMR (100 MHz, CDCl3) δ 171.1, 169.3, 154.9,138.6, 136.5, 134.4, 130.1, 129.0, 128.7, 127.1, 120.2, 80.8, 80.3,67.8,63.1, 59.8, 57.9, 42.6, 42.4, 36.4, 28.2, 25.4, 24.2, 23.9, 23.7, 23.6, 17.9,17.9。
MS:498.0(M+H)。
实施例22
化合物4K的制备
取2(1.14 mmol,300.00 mg,1.00eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-D-苯甘氨酸(1.25mmol,313.75mg,1.10eq)。室温下搅拌反应10 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体目标产物4K0.190g。
1H NMR (400 MHz, CDCl3) δ 7.26 (d,J= 7.9 Hz, 5H), 6.10 (d,J= 2.8 Hz,1H), 5.60 – 5.41 (m, 2H), 5.32 (d,J= 8.9 Hz, 1H), 5.18 (s, 1H), 4.67 (dd,J=21.8, 12.6 Hz, 1H), 4.38 (dd,J= 43.4, 12.5 Hz, 1H), 2.80 – 2.51 (m, 2H), 2.19(dd,J= 36.8, 10.4 Hz, 2H), 2.09 – 1.91 (m, 4H),1.53 – 1.14 (m, 14H).13C NMR(100 MHz, CDCl3) δ 171.0, 169.3, 154.9, 138.7, 136.1, 134.4, 130.8, 129.9,128.9, 128.6, 127.2, 127.1, 120.0,80.7, 80.1, 67.0, 63.0, 59.8, 57.9, 42.4,36.4, 28.2, 25.3, 24.2, 23.9, 23.5, 20.9, 17.9。
MS:498.0(M+H)。
实施例23
化合物4W的制备
取2(1.14 mmol,300.00 mg,1.00eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Boc-D-组氨酸(1.25mmol,318.75mg,1.10eq)。室温下搅拌反应24 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体目标产物4W,0.175g。
1H NMR (400 MHz, DMSO) δ 7.51 (s, 1H),7.11 (d,J= 7.0 Hz, 1H), 6.79(s, 1H), 6.10 – 6.00 (m, 1H), 5.56 (dd,J= 17.7, 5.0 Hz, 2H), 4.65 (dd,J=38.8, 12.7 Hz, 1H), 4.40 – 4.25 (m, 2H), 4.08 – 3.94 (m, 1H), 2.99 – 2.81 (m,4H), 2.26 – 2.07(m, 4H), 1.70 – 1.28 (m, 16H).13C NMR (100 MHz, DMSO) δ 172.3,169.6, 155.7, 139.9, 135.3,135.2, 135.1, 129.4, 124.1, 119.6, 81.0, 78.7,67.0, 63.0, 60.1, 54.4, 42.3, 36.8, 28.5, 25.1, 24.0, 23.6, 18.0。
MS:502.0(M+H)。
实施例24
化合物4M制备
取2(1.14 mmol,300.00 mg,1.00eq),1-羟基苯并三唑(1.26mmol,170.00mg,1.1eq),EDC•HCL(1.26 mol,240mg,1.11 eq),DIPEA(3.5mmol,3.05eq),DMF(10mL),Fmoc-Trt-D-半胱氨酸(1.25mmol,731.25mg,1.10eq)。室温下搅拌反应12 h。反应结束后,加入少量水饱和NaHCO3溶液,用乙酸乙酯萃取3次,酯层用饱和NaCl溶液洗2次。加入无水硫酸钠干燥1h,过滤,减压蒸除溶剂,经柱层析得到淡黄色固体目标产物4M,0.390g。
1H NMR (400 MHz, CDCl3) δ 7.76 (dd,J= 7.4, 3.3 Hz, 2H), 7.59 (d,J= 6.1Hz, 2H), 7.41 – 7.17 (m, 20H), 6.18 (d,J= 3.4 Hz, 1H), 5.65 (t,J= 7.8 Hz,1H), 5.47 (d,J= 2.7 Hz, 1H), 5.22 (d,J= 7.4 Hz, 1H), 4.72 (d,J= 12.3 Hz, 1H),4.49 – 4.31 (m, 3H), 4.29 – 4.04 (m, 3H), 3.80 (t,J= 9.3 Hz, 1H), 3.67 (t,J=5.5 Hz, 1H), 2.80 (d,J= 4.1 Hz, 1H), 2.63 (d,J= 5.9 Hz, 1H), 2.42 – 2.06 (m,7H), 1.53 (d,J= 12.6 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 170.4, 169.3, 155.6,144.1, 143.6, 141.3, 138.5, 134.4, 130.8, 129.9, 128.1,128.0, 127.9, 127.9,127.8, 127.8, 127.2, 127.1, 127.0, 126.9, 125.1, 125.0, 120.5, 120.0, 80.9,67.5, 67.2, 64.4, 63.2, 59.9, 53.1, 47.0, 42.5, 36.5, 33.0,30.6, 28.9, 25.4,17.9。
MS:832.0(M+H)。
体外细胞活性筛选实验1
本发明选取所制备的小白菊内酯的氨基酸衍生物进行活性测试,并以小白菊为阳性对照组,步骤包括:取指数生长期的人髓性单核白血病细胞MV4-11,使用含10%FBS+1%P/S的培养基重悬,充分混匀后制成单细胞悬液,然后使用全自动细胞计数仪进行细胞计数。按一定的倍数稀释细胞悬液,调整细胞浓度至 1×105/ml。用移液器吸取100μL(1×104个)稀释后的细胞悬液,加入96 孔板,在最外围一圈孔内加入200 μL PBS 溶液,避免液体挥发影响实验结果。将待测化合物分别用DMSO配成20mM的母液,分别取出1μL加入到999 μL相应培养基中,混匀。12h(细胞贴壁后)吸出原有培养基,依次加入上述浓度的培养基100μL于96孔板中,每个化合物设置三个复孔,每板设置一个空白对照。置入37℃的CO2培养箱中孵育,72h后取出,并向各孔中分别加入10μLCCK-8溶液,放入培养箱中孵育2h后,将酶标仪测定在450nm处的吸光度,计算IC50.试验结果如下表:
细胞周期实验
取指数生长期的人髓性单核白血病细胞MV-4-11细胞接种到6孔板中。24小时后,用含有不同浓度的DTry(2.5-20μM)的新鲜培养基替换细胞。收集细胞,然后用PBS洗涤,并用碘化丙啶(PI)染色。通过流式细胞术测定细胞凋亡。
细胞周期实验数据表明(附图4、5),当小白菊内酯的氨基酸衍生物DTry浓度达到2.5uM时,S期占比达到26%,开始降低;能够明显有效阻止该细胞从S期向G2期的转变,能够明显诱导MV4-11凋亡。根据上述小白菊内酯氨基酸衍生物活性测试的结果以及细胞周期实验结果可知,所合成化合物对这种肿瘤细胞均具有较强的诱导凋亡能力,在抗肿瘤药物中具有明显的技术应用价值。
应当理解的是,本发明的上述具体实施方式仅仅用于示例性说明或解释本发明的原理,而不构成对本发明的限制。因此,在不偏离本发明的精神和范围的情况下所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。此外,本发明所附权利要求旨在涵盖落入所附权利要求范围和边界、或者这种范围和边界的等同形式内的全部变化和修改例。
Claims (9)
1.一种小白菊内酯Boc保护的胺类衍生物,结构式如式Ⅰ所示:
,
其中,R基团为氨基酸、带有氨基被保护的氨基酸、氨基酸衍生物、带有氨基被保护的氨基酸衍生物、2~8个氨基酸肽链或带有氨基被保护的2~8个氨基酸肽链中的一种。
2.如权利要求1所述的一种小白菊内酯Boc保护的胺类衍生物,其特征在于,所述氨基保护基为叔丁氧羰基。
3.如权利要求1所述的一种小白菊内酯的Boc保护的胺类衍生物,其特征在于,所述R基团选自下列任意一种:
。
4.如权利要求1所述的一种小白菊内酯的Boc保护的胺类衍生物,其特征在于,所述带有氨基被保护的氨基酸选自天然的L构型的α-氨基酸、天然的D构型的α-氨基酸、非天然的L构型的α-氨基酸、非天然的D构型的α-氨基酸、非天然的β-氨基酸、非天然的γ-氨基酸或氨基与羧基相隔不超过10个碳原子的氨基酸中的一种。
5.如权利要求4所述的一种小白菊内酯的Boc保护的胺类衍生物,其特征在于,天然的L构型的α-氨基酸选自下列任意一种:
a、烷基类氨基酸:包括苯丙氨酸,丙氨酸,甘氨酸,亮氨酸,异亮氨酸,缬氨酸;
b、含有氨基的氨基酸,包括:组氨酸,精氨酸,谷氨酰胺,赖氨酸,脯氨酸,天冬酰胺,色氨酸;
c、含有两个羧基的氨基酸:包括天冬氨酸和谷氨酸;
d、含有巯基的氨基酸:包括半胱氨酸和蛋氨酸;
e、含有羟基的氨基酸:包括丝氨酸,酪氨酸和苏氨酸。
6.一种制备权利要求1-5所述的小白菊内酯Boc保护的胺类衍生物的方法,其特征在于,包括步骤:
称取小白菊内酯4.03 mmol,1.00g,1.00 eq,使用2eq的二氧化硒进行氧化,所得氧化产物与1eq的Boc保护的氨基酸或带有Boc保护的氨基酸衍生物或带有Boc保护的氨基酸肽链发生缩合,得到小白菊内酯的Boc保护的胺类衍生物,反应通式为:
。
7.一种药物组合物,其特征在于,包含权利要求1-5所述小白菊内酯Boc保护的胺类衍生物及药学上接受的助剂、稀释剂或载体。
8.如权利要求1-5所述的小白菊内酯Boc保护的胺类衍生物在制备抗肿瘤药物中的应用。
9.如权利要求8所述的小白菊内酯Boc保护的胺类衍生物在制备抗肿瘤药物中的应用,所述肿瘤包括白血病、前列腺癌、肺癌、乳腺癌、肝癌、胃癌、宫颈癌、结肠癌或上皮癌。
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