2-氨基噻唑类小分子酪氨酸激酶抑制剂的合成和活性研究
摘要
抗肿瘤药物的研究一直是药物研发领域的重要课题,近年来随着对各类酪氨酸激酶在肿瘤细胞恶性增殖过程中作用的不断探索和认识,酪氨酸激酶已经成为了药物研发的重要靶点,许多有效的药物陆续上市,并且更多高活性药物分子正处于临床试验期。2-氨基噻唑类化合物对Src酪氨酸家族激酶有良好的抑制活性,其中Dasatinib(BMS-354825)已经作为治疗慢性粒细胞白血病(CML)的药物上市,2-氨基噻唑类化合物具有显著的研究价值。
实验中构建了一类新的2-氨基噻唑类化合物库,通过活性筛选研究,寻找到对肿瘤细胞具有高抑制活性的化合物。用溴乙酸乙酯作为起始原料,通过Wittig反应与甲酸乙酯形成双键,经过NBS加成和硫脲成环,制备2-氨基-5-噻唑甲酸乙酯。经过一系列反应在5-羧基端接上6种胺分子,在2-氨基端接上40种酸分子或异氰酸酯分子,构建116个2-氨基噻唑类化合物的库,经过CA数据库查询,都是新的化合物。最后,通过细胞模型对化合物库进行活性筛选,研究其可能的构效关系。
实验选取了其中具有代表性的45个化合物,测定其对K562细胞株的抑制活性,以预测这类化合物对治疗CML病的潜在药效,结果显示有25个化合物有一定的抑制活性。本文最后根据药理实验数据,对这类化合物的构效关系进行了讨论。
The research of anticancer drugs has always been an important task in the R&D of new drugs. During the past few years, the role of protein tyrosine kinases(PTKs) palying in the malignant proliferation of tumour cell has been studied and revealed, and consequently the PTKs has been an important target to find a new drug. Many effective drugs of PTKs inhibitor have appeared on market while much more kinds of PTKs inhibitor molecule are in the clinical trial. 2-aminthiazole has been proved novel Src family kinase inhibitor template and Dasatinib(BMS-354825 ) has been on sale as a significant Bcr-Able kinase inhibitor to treat Chronic Myeloid Leukemia(CML). So 2-aminthiazole compounds have great value in anticancer drugs research.
A new library of 2-aminthiazole-5-carboxylates was built, which would be screened in biochemical and cellular assays, in order to find a new high potent PTKs inhibitor. 6 kinds of amins and 40 kinds of carboxylic acids or isocyanates were bound to the template, so that a convenient rout was designed to build the library. About 116 compounds have been synthesised in this way, which are all new. On the basis of the cell-inhebition experiment, the QSAR of these compounds can be studied.
45 compounds have been chosen to detect the inhebition activity to K562 cell strain, with the purpose to find good compouds to treat CML desease. 25 of the compouds can inhebit the regular growth of the tumor cell. A preliminary discussion of the QSAR have been given at the last part of this article.
实验中构建了一类新的2-氨基噻唑类化合物库,通过活性筛选研究,寻找到对肿瘤细胞具有高抑制活性的化合物。用溴乙酸乙酯作为起始原料,通过Wittig反应与甲酸乙酯形成双键,经过NBS加成和硫脲成环,制备2-氨基-5-噻唑甲酸乙酯。经过一系列反应在5-羧基端接上6种胺分子,在2-氨基端接上40种酸分子或异氰酸酯分子,构建116个2-氨基噻唑类化合物的库,经过CA数据库查询,都是新的化合物。最后,通过细胞模型对化合物库进行活性筛选,研究其可能的构效关系。
实验选取了其中具有代表性的45个化合物,测定其对K562细胞株的抑制活性,以预测这类化合物对治疗CML病的潜在药效,结果显示有25个化合物有一定的抑制活性。本文最后根据药理实验数据,对这类化合物的构效关系进行了讨论。
The research of anticancer drugs has always been an important task in the R&D of new drugs. During the past few years, the role of protein tyrosine kinases(PTKs) palying in the malignant proliferation of tumour cell has been studied and revealed, and consequently the PTKs has been an important target to find a new drug. Many effective drugs of PTKs inhibitor have appeared on market while much more kinds of PTKs inhibitor molecule are in the clinical trial. 2-aminthiazole has been proved novel Src family kinase inhibitor template and Dasatinib(BMS-354825 ) has been on sale as a significant Bcr-Able kinase inhibitor to treat Chronic Myeloid Leukemia(CML). So 2-aminthiazole compounds have great value in anticancer drugs research.
A new library of 2-aminthiazole-5-carboxylates was built, which would be screened in biochemical and cellular assays, in order to find a new high potent PTKs inhibitor. 6 kinds of amins and 40 kinds of carboxylic acids or isocyanates were bound to the template, so that a convenient rout was designed to build the library. About 116 compounds have been synthesised in this way, which are all new. On the basis of the cell-inhebition experiment, the QSAR of these compounds can be studied.
45 compounds have been chosen to detect the inhebition activity to K562 cell strain, with the purpose to find good compouds to treat CML desease. 25 of the compouds can inhebit the regular growth of the tumor cell. A preliminary discussion of the QSAR have been given at the last part of this article.
引文
1.Li S.,Gerald M.Drugs Discovery Today,2000,5(8),344-353.
2.茆勇军,李海泓,李剑峰,沈敬山。药学学报,2008,43(4),323-334.
3.孙忠实,朱珠,韩风英。中国药学杂志,2003,38(1),69-71.
4.Baselga J.,Averbuch S.D..Drugs 2000,60,33-40.
5.Wilhelm S.,Carter C.,Lynch M.,et al.Nat.Rev.Drug Discov.2006,5(10),835-844.
6.Moyer J.D.,Barbaeei E.G.,Iwata K.K.,et al.Cancer Res.1997,57(21),4838-48.
7.任晓岚,汪鑫,李志裕。中国新药杂志,2005,14(7),821-826.
8.Konecny G.E.,Pegram M.Do,Venkatesan N.,et al.Cancer Res.2006,66,1630-1639.
9.Nahta R.,Yuan L.X.,Du Y.,et al.Mol cancer ther.2007,6,667-674.
10.Geyer C.E.,Forster J.,Lindquist D.et al.N.Engl.J.Med.2006,355,2733-43.
11.Arora A.,Scholar E.M.J.Pharmacol.Exp.Ther.2005,315(3),971-979.
12.a)Motzer R.J.,Michaelson M.D.,Redman B.G.,et al.J Clin.Oncol.2006,24(1),16-24.
13.Casali P.G.,Garrett R.,Blackstein M.E.,et al.J.Clin.Oncol.2006,24(18),a9513.
14.Hochhaus A.,Kantarjian H.M.,Baccarani M.,et al.Blood 2007,109(6),2303-2309.
15.Druker B.J.,Talpaz M.,Resta D.J.,et al.N.Engl.J.Med.,2001,344,1031-7John S.T.,et al.Cancer Res.2006,66(11),5790-5797.
16.Manley P.W.,et al.Blood 2005,106,940.
17.Weisberg E.Manley P.W.,Breitenstein W.,et al.Cancer Cel.2005,7,129.
18.Masatern M.,Tamito S.,Souichirou Y.,et al.Biochemical and Biophysical Research Communications,2004,19(1),114-119.
19.Yokota A.,Kimura S.,Masuda S.,et al.Blood 2007,109(1),306-314.
20.Rixe O.,Bukowski R.M.,Michaelson M.D.,et al.Lancet Oncol.2007,8(11),975-984.
21.Liu Y.,Poon R.T.,Li Q.,et al.Cancer Res.2005,65(9),3691-3699.
22.Nakanmra K.,Tagn chi E.,Miura T.,et al.Cancer Res.2006,66(18),9134-9142.
23.Faded S.,Talpaz M.,Estrov Z.,et al.Ann.Intern.Med.1999,131(3),207-219.
24.Sawyers C.L.N.Engl.J.Med.1999,340(17),1330-1340.
25.Cortes J.E.,Talpaz M.,Kantarjian H.,Am.J.Med.1996,100(5),555-570.
26.Cuenco G.M.,Ren R.Oncogene 2001,20(57),8236-8248.
27.Dash A.B.,Williams I.R.,Kutok J.L.,et al.Proc.Natl.Acad.Sci.2002,99(11),7622-7627.
28.Feinstein E.,Cimino G.,Gale R.P.,et al.Proc.Natl.Acad.Sci.1991,88(14),6293-6297.
29.Sill H.,Goldman J.M.,Cross N.C.,Blood 1995,85(8),2013-2016.
30.Orkin S.H.,Blood,1992,80(3),575-581.
31.Bhushan Nagar,et al.Canceer Res.2002,62,4236-4243.
32.John S.T.,Cancer Res.2006,66(11),5790-5797.
33.Thomas O.H.,et al.Cancer Res.2005,65(11),4500-4505.
34.Molina,T.J.Nature,1992,357,161-164.
35.Jagabandhu Das,et al.J.Med.Chem.2006,49,(23),6819-6832.
36.Rudd C.E.Immunol.Today 1994,15(5),225.
37.(a) Straus D.B.,Weiss A.,Cell 1992,70,585.
(b) Chan A.C.,Desai D.M.,Weiss A.C.,Ann.Rev.Immunol.1994,12,555.
(c) Weiss A.,Littman D.,Cell 1994,76,263.
(d) Hanke J.H.,Gardner J.P.,Dow R.L.,Changelian P.S.,Brissette W.H.,Weringer E.J.,Pollok B.A.,Connelly P.A.,J.Biol.Chem.1996,271,695.
38.Das J.,et al.Bioorg.Med.Chem.Lett.2003,13,2145.
39.Das J.,et al.Bioorg.Med.Chem.Lett.2003,13,2587-90.
40.Das J.,et al.J.Med.Chem.2006,49,6819-6832.
41.Das J.,et al.J.Med.Chem.2006,49,6819-6832.
42.Zhao R.L.,Gove S.,Sundeen J.E.,et al.Tetrahedron Lett.2001,42(11),2101-2102.
2.茆勇军,李海泓,李剑峰,沈敬山。药学学报,2008,43(4),323-334.
3.孙忠实,朱珠,韩风英。中国药学杂志,2003,38(1),69-71.
4.Baselga J.,Averbuch S.D..Drugs 2000,60,33-40.
5.Wilhelm S.,Carter C.,Lynch M.,et al.Nat.Rev.Drug Discov.2006,5(10),835-844.
6.Moyer J.D.,Barbaeei E.G.,Iwata K.K.,et al.Cancer Res.1997,57(21),4838-48.
7.任晓岚,汪鑫,李志裕。中国新药杂志,2005,14(7),821-826.
8.Konecny G.E.,Pegram M.Do,Venkatesan N.,et al.Cancer Res.2006,66,1630-1639.
9.Nahta R.,Yuan L.X.,Du Y.,et al.Mol cancer ther.2007,6,667-674.
10.Geyer C.E.,Forster J.,Lindquist D.et al.N.Engl.J.Med.2006,355,2733-43.
11.Arora A.,Scholar E.M.J.Pharmacol.Exp.Ther.2005,315(3),971-979.
12.a)Motzer R.J.,Michaelson M.D.,Redman B.G.,et al.J Clin.Oncol.2006,24(1),16-24.
13.Casali P.G.,Garrett R.,Blackstein M.E.,et al.J.Clin.Oncol.2006,24(18),a9513.
14.Hochhaus A.,Kantarjian H.M.,Baccarani M.,et al.Blood 2007,109(6),2303-2309.
15.Druker B.J.,Talpaz M.,Resta D.J.,et al.N.Engl.J.Med.,2001,344,1031-7John S.T.,et al.Cancer Res.2006,66(11),5790-5797.
16.Manley P.W.,et al.Blood 2005,106,940.
17.Weisberg E.Manley P.W.,Breitenstein W.,et al.Cancer Cel.2005,7,129.
18.Masatern M.,Tamito S.,Souichirou Y.,et al.Biochemical and Biophysical Research Communications,2004,19(1),114-119.
19.Yokota A.,Kimura S.,Masuda S.,et al.Blood 2007,109(1),306-314.
20.Rixe O.,Bukowski R.M.,Michaelson M.D.,et al.Lancet Oncol.2007,8(11),975-984.
21.Liu Y.,Poon R.T.,Li Q.,et al.Cancer Res.2005,65(9),3691-3699.
22.Nakanmra K.,Tagn chi E.,Miura T.,et al.Cancer Res.2006,66(18),9134-9142.
23.Faded S.,Talpaz M.,Estrov Z.,et al.Ann.Intern.Med.1999,131(3),207-219.
24.Sawyers C.L.N.Engl.J.Med.1999,340(17),1330-1340.
25.Cortes J.E.,Talpaz M.,Kantarjian H.,Am.J.Med.1996,100(5),555-570.
26.Cuenco G.M.,Ren R.Oncogene 2001,20(57),8236-8248.
27.Dash A.B.,Williams I.R.,Kutok J.L.,et al.Proc.Natl.Acad.Sci.2002,99(11),7622-7627.
28.Feinstein E.,Cimino G.,Gale R.P.,et al.Proc.Natl.Acad.Sci.1991,88(14),6293-6297.
29.Sill H.,Goldman J.M.,Cross N.C.,Blood 1995,85(8),2013-2016.
30.Orkin S.H.,Blood,1992,80(3),575-581.
31.Bhushan Nagar,et al.Canceer Res.2002,62,4236-4243.
32.John S.T.,Cancer Res.2006,66(11),5790-5797.
33.Thomas O.H.,et al.Cancer Res.2005,65(11),4500-4505.
34.Molina,T.J.Nature,1992,357,161-164.
35.Jagabandhu Das,et al.J.Med.Chem.2006,49,(23),6819-6832.
36.Rudd C.E.Immunol.Today 1994,15(5),225.
37.(a) Straus D.B.,Weiss A.,Cell 1992,70,585.
(b) Chan A.C.,Desai D.M.,Weiss A.C.,Ann.Rev.Immunol.1994,12,555.
(c) Weiss A.,Littman D.,Cell 1994,76,263.
(d) Hanke J.H.,Gardner J.P.,Dow R.L.,Changelian P.S.,Brissette W.H.,Weringer E.J.,Pollok B.A.,Connelly P.A.,J.Biol.Chem.1996,271,695.
38.Das J.,et al.Bioorg.Med.Chem.Lett.2003,13,2145.
39.Das J.,et al.Bioorg.Med.Chem.Lett.2003,13,2587-90.
40.Das J.,et al.J.Med.Chem.2006,49,6819-6832.
41.Das J.,et al.J.Med.Chem.2006,49,6819-6832.
42.Zhao R.L.,Gove S.,Sundeen J.E.,et al.Tetrahedron Lett.2001,42(11),2101-2102.