Synthesis and biological evaluation of 3-(piperidin-4-yl)isoxazolo[4,5-d]pyrimidine derivatives as novel PI3K<i>δ</i> inhibitors

Citation: Jia-Lin Guo, Yun-Yong Liu, Ya-Zhong Pei. Synthesis and biological evaluation of 3-(piperidin-4-yl)isoxazolo[4,5-d]pyrimidine derivatives as novel PI3Kδ inhibitors[J]. Chinese Chemical Letters, 2015, 26(10): 1283-1288. doi: 10.1016/j.cclet.2015.05.041 shu

Synthesis and biological evaluation of 3-(piperidin-4-yl)isoxazolo[4,5-d]pyrimidine derivatives as novel PI3Kδ inhibitors

通讯作者: Ya-Zhong Pei,

基金项目:
This work was supported by the National Natural Science Foundation of China (No. 81172914) (No. 81172914)

摘要: An efficient synthesis of novel 3-(piperidin-4-yl)isoxazolo[4, 5-d]pyrimidine scaffold has been designed and deveopled. A series of 5-phenylurea derivatives was synthesized using this method. Their cytotoxic activities against breast cancer cell line BT-474 were evaluated by CCK-8 assay. Most of them showed potent anti-proliferative activities, of which compound 20 and 21 exhibited IC₅₀s of 1.565 μmol/L and 1.311 μmol/L, respectively. Furthermore, compound 20 and 21 also showed potent inhibitory activities against PI3Kδ with IC₅₀s of 0.286 μmol/L and 0.452 μmol/L, respectively. These results indicate that these 3-(piperidin-4-yl)isoxazolo[4, 5-d] pyrimidine derivatives are novel antitumor agents through the inhibition of PI3Kδ.

关键词:

English

Synthesis and biological evaluation of 3-(piperidin-4-yl)isoxazolo[4,5-d]pyrimidine derivatives as novel PI3Kδ inhibitors

1.
1 The Center for Combinatorial Chemistry and Drug Discovery of Jilin University, School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China;
2.
2 Nanjing Gator MediTech Company, Ltd., Nanjing 211300, China

Corresponding author: Ya-Zhong Pei,

Received Date: 01 February 2015
Available Online: 02 June 2015
Fund Project:

Abstract: An efficient synthesis of novel 3-(piperidin-4-yl)isoxazolo[4, 5-d]pyrimidine scaffold has been designed and deveopled. A series of 5-phenylurea derivatives was synthesized using this method. Their cytotoxic activities against breast cancer cell line BT-474 were evaluated by CCK-8 assay. Most of them showed potent anti-proliferative activities, of which compound 20 and 21 exhibited IC₅₀s of 1.565 μmol/L and 1.311 μmol/L, respectively. Furthermore, compound 20 and 21 also showed potent inhibitory activities against PI3Kδ with IC₅₀s of 0.286 μmol/L and 0.452 μmol/L, respectively. These results indicate that these 3-(piperidin-4-yl)isoxazolo[4, 5-d] pyrimidine derivatives are novel antitumor agents through the inhibition of PI3Kδ.

Key words:

1. [1] R. Williams, A. Berndt, S. Miller, W.C. Hon, X.X. Zhang, Form and flexibility in phosphoinositide 3-kinases, Biochem. Soc. Trans. 37(2009) 615-626.[1] R. Williams, A. Berndt, S. Miller, W.C. Hon, X.X. Zhang, Form and flexibility in phosphoinositide 3-kinases, Biochem. Soc. Trans. 37(2009) 615-626.
2. [2] P.X. Liu, H.X. Cheng, T.M. Roberts, J.J. Zhao, Targeting the phosphoinositide 3-kinase pathway in cancer, Nat. Rev. Drug Discov. 8(2009) 627-644.[2] P.X. Liu, H.X. Cheng, T.M. Roberts, J.J. Zhao, Targeting the phosphoinositide 3-kinase pathway in cancer, Nat. Rev. Drug Discov. 8(2009) 627-644.
3. [3] L.C. Cantley, The phosphoinositide 3-kinase pathway, Science 296(2002) 1655-1657.[3] L.C. Cantley, The phosphoinositide 3-kinase pathway, Science 296(2002) 1655-1657.
4. [4] E. Ciraolo, F. Morello, E. Hirsch, Present and future of PI3K pathway inhibition in cancer:perspectives and limitations, Curr. Med. Chem. 18(2011) 2674-2685.[4] E. Ciraolo, F. Morello, E. Hirsch, Present and future of PI3K pathway inhibition in cancer:perspectives and limitations, Curr. Med. Chem. 18(2011) 2674-2685.
5. [5] B.H. Jiang, L.Z. Liu, PI3K/PTEN signaling in angiogenesis and tumorigenesis, Adv. Cancer Res. 102(2009) 19-65.[5] B.H. Jiang, L.Z. Liu, PI3K/PTEN signaling in angiogenesis and tumorigenesis, Adv. Cancer Res. 102(2009) 19-65.
6. [6] B. Markman, R. Dienstmann, J. Tabernero, Targeting the PI3K/Akt/mTOR pathwaybeyond rapalogs, Oncotarget 1(2010) 530-543.[6] B. Markman, R. Dienstmann, J. Tabernero, Targeting the PI3K/Akt/mTOR pathwaybeyond rapalogs, Oncotarget 1(2010) 530-543.
7. [7] R. Marone, V. Cmiljanovic, B. Giese, M.P. Wymann, Targeting phosphoinositide 3-kinase-moving towards therapy, Biochim. Biophys. Acta 1784(2008) 159-185.[7] R. Marone, V. Cmiljanovic, B. Giese, M.P. Wymann, Targeting phosphoinositide 3-kinase-moving towards therapy, Biochim. Biophys. Acta 1784(2008) 159-185.
8. [8] A. Carnero, Novel inhibitors of the PI3K family, Expert Opin. Investig. Drugs 18(2009) 1265-1277.[8] A. Carnero, Novel inhibitors of the PI3K family, Expert Opin. Investig. Drugs 18(2009) 1265-1277.
9. [9] C.M. Dehnhardt, A.M. Venkatesan, E.D. Santos, et al., Lead optimization of N-3-substituted 7-morpholinotriazolopyrimidines as dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors:discovery of PKI-402, J. Med. Chem. 53(2010) 798-810.[9] C.M. Dehnhardt, A.M. Venkatesan, E.D. Santos, et al., Lead optimization of N-3-substituted 7-morpholinotriazolopyrimidines as dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors:discovery of PKI-402, J. Med. Chem. 53(2010) 798-810.
10. [10] A.J. Folkes, K. Ahmadi, W.K. Alderton, et al., The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[32-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer, J. Med. Chem. 51(2008) 5522-5532.[10] A.J. Folkes, K. Ahmadi, W.K. Alderton, et al., The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[32-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer, J. Med. Chem. 51(2008) 5522-5532.
11. [11] M.T. Burger, S. Pecchi, A. Wagman, et al., Identification of NVP-BKM120 as a potent, selective, orally bioavailable class I PI3 kinase inhibitor for treating cancer, ACS Med. Chem. Lett. 2(2011) 774-779.[11] M.T. Burger, S. Pecchi, A. Wagman, et al., Identification of NVP-BKM120 as a potent, selective, orally bioavailable class I PI3 kinase inhibitor for treating cancer, ACS Med. Chem. Lett. 2(2011) 774-779.
12. [12] J.J. Hale, C.L. Lynch, C.G. Caldwell, et al., Pyrrolidine modulators of CCR5 chemokine receptor activity, US/2002/0094989.[12] J.J. Hale, C.L. Lynch, C.G. Caldwell, et al., Pyrrolidine modulators of CCR5 chemokine receptor activity, US/2002/0094989.
13. [13] J.A. Deceuninck, D.K. Buffel, G.J. Hoornaert, A pathway to 3-(β-D-ribofuranosyl)-4-nitro-5-ethoxycarbonyl-isoxazoles, useful in the synthesis of pyrazofurin analogues, Tetrahedron Lett. 21(1980) 3613-3616.[13] J.A. Deceuninck, D.K. Buffel, G.J. Hoornaert, A pathway to 3-(β-D-ribofuranosyl)-4-nitro-5-ethoxycarbonyl-isoxazoles, useful in the synthesis of pyrazofurin analogues, Tetrahedron Lett. 21(1980) 3613-3616.
14. [14] H. Liu, X.H. He, H.S. Choi, et al., Compounds and compositions as inhibitors of cannabinoid receptor 1 activity, WO/2006/047516.[14] H. Liu, X.H. He, H.S. Choi, et al., Compounds and compositions as inhibitors of cannabinoid receptor 1 activity, WO/2006/047516.
15. [15] U. Niewohner, H. Haning, T. Lampe, et al., Isoxazolo pyrimidinones and the use thereof, US/2003/149033.[15] U. Niewohner, H. Haning, T. Lampe, et al., Isoxazolo pyrimidinones and the use thereof, US/2003/149033.
16. [16] M.P. Prasad, B. Laxminarayan, Compositions, synthesis, and methodes of using indanone based cholinesterase inhibitors, WO/2008/073452.[16] M.P. Prasad, B. Laxminarayan, Compositions, synthesis, and methodes of using indanone based cholinesterase inhibitors, WO/2008/073452.
17. [17] V.J. Cunera, Z. Arie, A.K. Semiramis, et al., Ureidoaryl- and carbamoylaryl-morpholino-pyrimidine compounds, their use as mTOR kinase and PI3 kinase inhibitors, and their synthesis, WO/2010/120994.[17] V.J. Cunera, Z. Arie, A.K. Semiramis, et al., Ureidoaryl- and carbamoylaryl-morpholino-pyrimidine compounds, their use as mTOR kinase and PI3 kinase inhibitors, and their synthesis, WO/2010/120994.
18. [18] T.P. Heffron, B.Q. Wei, A. Olivero, et al., Rational design of phosphoinositide 3-kinase α inhibitors that exhibit selectivity over the phosphoinositide 3-kinase β isoform, J. Med. Chem. 54(2011) 7815-7833.[18] T.P. Heffron, B.Q. Wei, A. Olivero, et al., Rational design of phosphoinositide 3-kinase α inhibitors that exhibit selectivity over the phosphoinositide 3-kinase β isoform, J. Med. Chem. 54(2011) 7815-7833.
19. [19] W. Shen, Palladium catalyzed coupling of aryl chlorides with arylboronic acids, Tetrahedron Lett. 38(1997) 5575-5578.[19] W. Shen, Palladium catalyzed coupling of aryl chlorides with arylboronic acids, Tetrahedron Lett. 38(1997) 5575-5578.
20. [20] A.M. Venkatesan, C.M. Dehnhardt, E.D. Santos, et al., Bis (morpholino-13, 5-triazine) derivatives:potent adenosine 50-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors:discovery of compound 26(PKI-587), a highly efficacious dual inhibitor, J. Med. Chem. 53(2010) 2636-2645.[20] A.M. Venkatesan, C.M. Dehnhardt, E.D. Santos, et al., Bis (morpholino-13, 5-triazine) derivatives:potent adenosine 50-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors:discovery of compound 26(PKI-587), a highly efficacious dual inhibitor, J. Med. Chem. 53(2010) 2636-2645.
21. [21] Q.Z. Zheng, K. Cheng, X.M. Zhang, et al., Synthesis of some N-alkyl substituted urea derivatives as antibacterial and antifungal agents, Eur. J. Med. Chem. 45(2010) 3207-3212.[21] Q.Z. Zheng, K. Cheng, X.M. Zhang, et al., Synthesis of some N-alkyl substituted urea derivatives as antibacterial and antifungal agents, Eur. J. Med. Chem. 45(2010) 3207-3212.
22. [22] B.V. Yang, D. O'Rourke, J.C. Li, Mild and selective debenzylation of tertiary amines using a-chloroethyl chloroformate, Synlett 3(1994) 195-196.[22] B.V. Yang, D. O'Rourke, J.C. Li, Mild and selective debenzylation of tertiary amines using a-chloroethyl chloroformate, Synlett 3(1994) 195-196.
23. [23] F. Pettersson, P. Svensson, S. Waters, N. Waters, C. Sonesson, Synthesis, pharmacological evaluation and QSAR modeling of mono-substituted 4-phenylpiperidines and 4-phenylpiperazines, Eur. J. Med. Chem. 62(2013) 241-255.[23] F. Pettersson, P. Svensson, S. Waters, N. Waters, C. Sonesson, Synthesis, pharmacological evaluation and QSAR modeling of mono-substituted 4-phenylpiperidines and 4-phenylpiperazines, Eur. J. Med. Chem. 62(2013) 241-255.
24. [24] B.J. Lannutti, S.A. Meadows, S.E.M. Herman, et al., CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability, Blood 117(2011) 591-594.[24] B.J. Lannutti, S.A. Meadows, S.E.M. Herman, et al., CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability, Blood 117(2011) 591-594.

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Synthesis and biological evaluation of 3-(piperidin-4-yl)isoxazolo[4,5-d]pyrimidine derivatives as novel PI3Kδ inhibitors

通讯作者: Ya-Zhong Pei,

English

Synthesis and biological evaluation of 3-(piperidin-4-yl)isoxazolo[4,5-d]pyrimidine derivatives as novel PI3Kδ inhibitors

Corresponding author: Ya-Zhong Pei,

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通讯作者: 陈斌, bchen63@163.com

中国化学会秘书处

Synthesis and biological evaluation of 3-(piperidin-4-yl)isoxazolo[4,5-d]pyrimidine derivatives as novel PI3Kδ inhibitors

通讯作者: Ya-Zhong Pei,

English

Synthesis and biological evaluation of 3-(piperidin-4-yl)isoxazolo[4,5-d]pyrimidine derivatives as novel PI3Kδ inhibitors

Corresponding author: Ya-Zhong Pei,

CCS Chemistry：嵌段共聚物自组装成 “三明治”二维有机材料，实现纳米级压力传感功能

CCS Chemistry：颜徐州、鲍哲南： 你的皮肤可能是一片SPMs

CCS Chemistry：工作高效不疲劳，只须让催化剂动起来

CCS Chemistry：静电组装导向聚合- 聚电解质纳米凝胶量化制备新策略

CCS Chemistry：金黄色葡萄球菌醛基脱氢酶是如何识别特异性底物的？

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