CN1152050C - 一种新的具有抗癌活性的环肽类化合物phakellistatin 12 - Google Patents

一种新的具有抗癌活性的环肽类化合物phakellistatin 12 Download PDF

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CN1152050C
CN1152050C CNB011133899A CN01113389A CN1152050C CN 1152050 C CN1152050 C CN 1152050C CN B011133899 A CNB011133899 A CN B011133899A CN 01113389 A CN01113389 A CN 01113389A CN 1152050 C CN1152050 C CN 1152050C
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易杨华
李文林
林厚文
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Second Military Medical University SMMU
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Abstract

本发明涉及医药技术领域，是从我国南海海域的棕色扁海绵中提取的一种新的抗癌化合物Phakellistatin 12。化学结构式为右式，体外抗癌活性试验证明该化合物对人肝癌细胞株BEL-7402具有很强的抑制作用，其半数有效浓度IC50小于1×10-8mol/l。本发明为研究开发新的抗癌药物提供了先导化合物，对开发利用中国的海洋药物资源具有重要价值。

Description

一种新的具有抗癌活性的环肽类化合物Phakellistatin 12
技术领域：本发明涉及医药技术领域，是指从海洋动物棕色扁海绵中提取的一种新的抗癌活性化合物Phakellistatin 12。
背景技术：棕色扁海绵(Phakellia fusa Thiele)为寻常海绵纲(Demospongea)小轴海绵目(Axinellide)小轴海绵科(Axinellidae)海绵动物。美国亚利桑那州立大学George R.Pettit教授于1993年从Phakellia costaata和Stylotellaaurantium两种不同的海绵中同时分得具有细胞生长抑制活性的环七肽化合物-Phakellistatin 1(G.R.Pettit，et al，J.Nat.Prod.1993，56(2)：260)。以后又相继报道了10种同类结构的此类成分即Phakellistatin 2-Phakellistatin 11，它们都具有抗癌活性。
发明内容：本发明是从生长于中国南海海域的棕色扁海绵中提取一种新的具有抗癌活性的环肽类化合物Phakellistatin 12。其提取的方法与上述的环肽类化合物基本相同，简略地举例表述如下：棕色扁海绵500g(干重)经80％乙醇室温浸提后，提取液减压浓缩除去乙醇，得浸膏状提取物。提取物溶于甲醇∶水(9∶1)的混合溶剂中，用石油醚萃取五遍，下层甲醇∶水部分加水稀释为3∶2，再用二氯甲烷萃取5次，合并二氯甲烷萃取液，减压浓缩，得二氯甲烷萃取物2g。该萃取物经硅胶柱层析，再经高效液相层析纯化，得纯的Phakellistatin 12单体。物理常数和光谱数据如下：
Phakellistatin 12：白色粉末，分子式C42H54O8N8。电喷雾离子质谱：799.7(M+1)+，821.4(M+Na)+，1620.9(2M+H+Na)+。1H和13C核磁共振见表1。
     表1 Phakellistatin 12的1H和13C核磁共振数据
                             1H ppm                              13C ppm
Leu             H-2          4.48，m，1H                C-1        169.90
                H-3          1.52，m，1H                C-2        51.68
Figure C0111338900041
               1.69，m，1H                C-3        40.02
                H-4          1.63，m，1H                C-4        24.52
                H-5，6       0.90，d，3H，6.6Hz         C-5，6     22.10，23.73
                             1.00，d，3H，6.6Hz
                NH           7.13，d，1H，6Hz
Thr             H-2          4.25，m，1H                C-1        172.06
                H-3          4.23，m，1H                C-2        58.99
                H-4          1.03，d，3H，6Hz           C-3        65.69
    OH           4.87，d，1H，5.4Hz         C-4        20.76
                NH           7.84，d，1H，9Hz
Pro I           H-2          4.26，m，1H                C-1        171.09
                H-3          1.82，m，1H                C-2        61.88
                 2.27，m，1H                C-3        30.11
                H-4          1.93，m，2H                C-4        24.53
                H-5          3.51，m，1H                C-5        46.27
                             3.69，m，1H
Gly             H-2          3.95，d，1H，18.6Hz        C-1        168.33
                             4.17，d，1H，18.6Hz        C-2        42.98
Figure C0111338900044
      NH           7.55，s，1H
Phe             H-2          4.15，m，1H                C-1        170.05
                H-3          2.95，t，1H，13.2Hz        C-2        56.60
                             3.17，m，1H                C-3        37.27
Figure C0111338900045
H-2’，6’         7.10，d，2H，6.6Hz         C-1’              137.80
                H-3’，5’         7.24，t，2H，6.6，7.2Hz    C-2’，6’    128.71
                H-4’                   7.19，t，1H，6，7.8Hz      C-3’，5’    128.49
                NH           8.29，d，1H，11.4Hz        C-4’              126.74
Pro II          H-2          3.44，d，1H，7.2Hz         C-1        170.69
                H-3          1.50，m，1H                C-2        60.00
                             1.04，m，1H                C-3        40.60
    H-4          0.19，m，1H                C-4        28.92
                             0.32，m，1H                C-5        45.68
                H-5          2.91，m，1H
                             2.37，t，1H，10Hz
Trp             H-2          4.43，m，1H                C-1        171.60
                H-3          3.10，m，2H                C-2        53.65
                H-2’                  7.34，s，1H                C-3        26.82
                H-4’，7’        7.32，d，2H，3.6Hz         C-2’               124.23
                H-5’                  6.91，t，1H，7.2Hz         C-3’               108.92
  H-6’                  7.04，t，1H，7.2Hz         C-4’，    124.29
                H-1’                  10.79，s，1H               C-7’               111.53
                NH           9.33，s，1H                C-5’              121.39
                                                        C-6’              118.27
                                                        C-9’              127.30
                                                        C-8’              136.24
采用600MHz的核磁共振仪测定，样品溶解于氘代二甲基亚砜。
同时，还测定了该化合物多种二维核磁共振谱(TOCSY，DQCOSY，HMQC和NOESY)，确定了该化合物所有的碳原子和氢原子的归属及该化合物的化学结构。结构式如下：
具体实施方式：体外抗癌活性试验：采用磺酰罗丹明B蛋白染色法，BEL-7402人肝癌细胞株，作用时间72小时，结果如表2：
         表2 Phakellistatin 12对肿瘤细胞生长抑制率
      浓度(M)     10-4 10-5 10-6 10-7 10-8
      抑制率(％)  80.1  78.5  79.8  74.4  66.0
该化合物在体外对人肝癌BEL-7402细胞株具有极强的抑制作用，其半数有效抑制浓度IC50小于1×10-8mol/L。
本发明化合物的体外抗癌活性试验表明其有很强的抗癌活性，因而为研究开发新的抗癌药物提供了先导化合物，对开发利用中国的海洋药物资源具有重要价值。

Claims (2)

1.一种具有抗癌活性的环肽类化合物，其特征在于是具有如下结构的Phakellistatin 12：
Figure C0111338900021
2.权利要求1所述的环肽类化合物Phakellistatin 12的用途，其特征在于用于制备抗癌药物。
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101519438B (zh) * 2009-04-09 2011-05-04 中国人民解放军第二军医大学 西沙海绵中一种环肽类化合物及其用途

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* Cited by examiner, † Cited by third party
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CN100396696C (zh) * 2004-04-23 2008-06-25 中国科学院海洋研究所 一种海洋绿藻在提取抗肿瘤活性环肽组分中的应用
CN101519435B (zh) * 2009-04-09 2011-09-14 中国人民解放军第二军医大学 西沙海绵中一种环九肽类化合物及其用途
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CN108929371A (zh) * 2018-08-02 2018-12-04 哈尔滨师范大学 一种Phakellistatin13直链衍生物、其制备办法及用途
CN111606975B (zh) * 2019-02-26 2021-12-24 上海交通大学医学院附属仁济医院 从棕色扁海绵中提取的环肽类化合物及其制备方法与用途
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5130414A (en) * 1989-11-30 1992-07-14 Arizona Board Of Regents, A Body Corporate Of Arizona State University Isolation and structural elucidation of the cyclic peptide hymenistatin 1
EP0626383A1 (en) * 1993-04-20 1994-11-30 Pharma Mar, S.A. Palan'amine: a pharmacologically active compound from a sponge
US5646246A (en) * 1994-11-14 1997-07-08 Arizona Board Of Regents Acting On Behalf Of Arizona State University Isolation and structural elucidation of the human cancer cell growth inhibitory cyclic peptides phakellistatin 4, 5, 6, 7, 8 and 9
US5801222A (en) * 1994-12-20 1998-09-01 Arizona Board Of Regents Acting On Behalf Of Arizona State University Isolation and structure of the human cancer cell growth inhibitory cyclic octapeptides phakellistatin 10 and 11

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5130414A (en) * 1989-11-30 1992-07-14 Arizona Board Of Regents, A Body Corporate Of Arizona State University Isolation and structural elucidation of the cyclic peptide hymenistatin 1
EP0626383A1 (en) * 1993-04-20 1994-11-30 Pharma Mar, S.A. Palan'amine: a pharmacologically active compound from a sponge
US5646246A (en) * 1994-11-14 1997-07-08 Arizona Board Of Regents Acting On Behalf Of Arizona State University Isolation and structural elucidation of the human cancer cell growth inhibitory cyclic peptides phakellistatin 4, 5, 6, 7, 8 and 9
US5801222A (en) * 1994-12-20 1998-09-01 Arizona Board Of Regents Acting On Behalf Of Arizona State University Isolation and structure of the human cancer cell growth inhibitory cyclic octapeptides phakellistatin 10 and 11

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
J Mol Graph Model. 17(1) 1999-02-28 Galzitskaya, O, Caflisch, A. Solution conformation of Galzitskaya, O, caflisch, A. Solution conformation ofphakellistatin 8 investigated by molecular dynamicssimulations. *
J Nat Prod. 58(6) 1995-06-30 Pettit, GR ,et al. Antineoplastic agents,325. Isolation andstructure of the human cancer cell growth inhibitory cyclicoctapeptides phakellistatin 10 and 11 from phakellia sp. *
J Nat Prod. 62(3) 1999-03-31 Pettit, GR ,et al. Antineoplastic agents. 400. synthesis of the pettit, GR, et al. Antineoplastic agents. 400. Synthesis ofthe Indian Ocean marine sponge cyclic heptapeptidephakellistatin 2. *
J Nat Prod.56(2) 1993-02-28 Pettit, GR ,et al. Isolation and structure of the marine spongecell growth inhibitory cyclic peptide phakellistation 1. *
J Nat Prod.63(1) 2000-01-31 Pettit, GR ,et al. Synthesis of the marine spongecycloheptapeptide phakellistatin 5(1). *
J Nat Prod.63(1) 2000-01-31 Pettit, GR ,et al. Synthesis of the marine spongecycloheptapeptide phakellistatin 5(1).;J Nat Prod.56(2) 1993-02-28 Pettit, GR ,et al. Isolation and structure of the marine spongecell growth inhibitory cyclic peptide phakellistation 1.;J Nat Prod. 58(6) 1995-06-30 Pettit, GR ,et al. Antineoplastic agents,325. Isolation andstructure of the human cancer cell growth inhibitory cyclicoctapeptides phakellistatin 10 and 11 from phakellia sp.;J Mol Graph Model. 17(1) 1999-02-28 Galzitskaya, O, Caflisch, A. Solution conformation of Galzitskaya, O, caflisch, A. Solution conformation ofphakellistatin 8 investigated by molecular dynamicssimulations.;J Nat Prod. 62(3) 1999-03-31 Pettit, GR ,et al. Antineoplastic agents. 400. synthesis of the pettit, GR, et al. Antineoplastic agents. 400. Synthesis ofthe Indian Ocean marine sponge cyclic heptapeptidephakellistatin 2. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101519438B (zh) * 2009-04-09 2011-05-04 中国人民解放军第二军医大学 西沙海绵中一种环肽类化合物及其用途

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