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

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: 1 February 2015
Available Online: 20 May 2015
Fund Project: This work was supported by the National Natural Science Foundation of China (No. 81172914) (No. 81172914)

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.
- Synthesis,
- Isoxazolopyrimidine,
- PI3Kδ inhibitors,
- Cytotoxicity
1. [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.
2. [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.
3. [3]
  [3] L.C. Cantley, The phosphoinositide 3-kinase pathway, Science 296(2002) 1655-1657.
4. [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.
5. [5]
  [5] B.H. Jiang, L.Z. Liu, PI3K/PTEN signaling in angiogenesis and tumorigenesis, Adv. Cancer Res. 102(2009) 19-65.
6. [6]
  [6] B. Markman, R. Dienstmann, J. Tabernero, Targeting the PI3K/Akt/mTOR pathwaybeyond rapalogs, Oncotarget 1(2010) 530-543.
7. [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.
8. [8]
  [8] A. Carnero, Novel inhibitors of the PI3K family, Expert Opin. Investig. Drugs 18(2009) 1265-1277.
9. [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.
10. [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.
11. [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.
12. [12]
  [12] J.J. Hale, C.L. Lynch, C.G. Caldwell, et al., Pyrrolidine modulators of CCR5 chemokine receptor activity, US/2002/0094989.
13. [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.
14. [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.
15. [15]
  [15] U. Niewohner, H. Haning, T. Lampe, et al., Isoxazolo pyrimidinones and the use thereof, US/2003/149033.
16. [16]
  [16] M.P. Prasad, B. Laxminarayan, Compositions, synthesis, and methodes of using indanone based cholinesterase inhibitors, WO/2008/073452.
17. [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.
18. [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.
19. [19]
  [19] W. Shen, Palladium catalyzed coupling of aryl chlorides with arylboronic acids, Tetrahedron Lett. 38(1997) 5575-5578.
20. [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.
21. [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.
22. [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.
23. [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.
24. [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.
1. [1]
  Yulong Shi , Fenbei Chen , Mengyuan Wu , Xin Zhang , Runze Meng , Kun Wang , Yan Wang , Yuheng Mei , Qionglu Duan , Yinghong Li , Rongmei Gao , Yuhuan Li , Hongbin Deng , Jiandong Jiang , Yanxiang Wang , Danqing Song . Chemical construction and anti-HCoV-OC43 evaluation of novel 10,12-disubstituted aloperine derivatives as dual cofactor inhibitors of TMPRSS2 and SR-B1. Chinese Chemical Letters, 2024, 35(5): 108792-. doi: 10.1016/j.cclet.2023.108792
2. [2]
  Jin Wang , Xiaoyan Pan , Junyu Zhang , Qingqing Zhang , Yanchen Li , Weiwei Guo , Jie Zhang . Active molecule-based theranostic agents for tumor vasculature normalization and antitumor efficacy. Chinese Chemical Letters, 2024, 35(8): 109187-. doi: 10.1016/j.cclet.2023.109187
3. [3]
  Chuan Li , Yangyang Han , Yanan Zhai , Ke Li , Xingzhong Liu , Zhuan Zhang , Cai Jia , Yongsheng Che . Phomaketals A and B, pentacyclic meroterpenoids from a eupC overexpressed mutant strain of Phoma sp.. Chinese Chemical Letters, 2024, 35(7): 109019-. doi: 10.1016/j.cclet.2023.109019
4. [4]
  Huiju Cao , Lei Shi . sp¹-Hybridized linear and cyclic carbon chain. Chinese Chemical Letters, 2025, 36(4): 110466-. doi: 10.1016/j.cclet.2024.110466
5. [5]
  Zimo Yang , Yan Tong , Yongbo Liu , Qianlong Liu , Zhihao Ni , Yuna He , Yu Rao . Developing selective PI3K degraders to modulate both kinase and non-kinase functions. Chinese Chemical Letters, 2024, 35(11): 109577-. doi: 10.1016/j.cclet.2024.109577
6. [6]
  Xiongbo Song , Jinwen Xiao , Juan Wu , Li Sun , Long Chen . Decellularized amniotic membrane promotes the anti-inflammatory response of macrophages via PI3K/AKT/HIF-1α pathway. Chinese Chemical Letters, 2025, 36(1): 109844-. doi: 10.1016/j.cclet.2024.109844
7. [7]
  Jing JIN , Zhuming GUO , Zhiyin XIAO , Xiujuan JIANG , Yi HE , Xiaoming LIU . Tuning the stability and cytotoxicity of fac-[Fe(CO)₃I₃]^- anion by its counter ions: From aminiums to inorganic cations. Chinese Journal of Inorganic Chemistry, 2024, 40(5): 991-1004. doi: 10.11862/CJIC.20230458
8. [8]
  Jiaming Xu , Yu Xiang , Weisheng Lin , Zhiwei Miao . Research Progress in the Synthesis of Cyclic Organic Compounds Using Bimetallic Relay Catalytic Strategies. University Chemistry, 2024, 39(3): 239-257. doi: 10.3866/PKU.DXHX202309093
9. [9]
  Mianling Yang , Meehyein Kim , Peng Zhan . Modular miniaturized synthesis and in situ biological evaluation facilitate rapid discovery of potent MraY inhibitors as antibacterial agents. Chinese Chemical Letters, 2025, 36(2): 110455-. doi: 10.1016/j.cclet.2024.110455
10. [10]
  Ruofan Yin , Zhaoxin Guo , Rui Liu , Xian-Sen Tao . Ultrafast synthesis of Na₃V₂(PO₄)₃ cathode for high performance sodium-ion batteries. Chinese Chemical Letters, 2025, 36(2): 109643-. doi: 10.1016/j.cclet.2024.109643
11. [11]
  Rong-Nan Yi , Wei-Min He . Photocatalytic Minisci-type multicomponent reaction for the synthesis of 1-(halo)alkyl-3-heteroaryl bicyclo[1.1.1]pentanes. Chinese Chemical Letters, 2024, 35(10): 110115-. doi: 10.1016/j.cclet.2024.110115
12. [12]
  Yuexiang Liu , Xiangqiao Yang , Tong Lin , Guantian Yang , Xiaoyong Xu , Bubing Zeng , Zhong Li , Weiping Zhu , Xuhong Qian . Efficient continuous synthesis of 2-[3-(trifluoromethyl)phenyl]malonic acid, a key intermediate of Triflumezopyrim, coupling with esterification-condensation-hydrolysis. Chinese Chemical Letters, 2025, 36(1): 109747-. doi: 10.1016/j.cclet.2024.109747
13. [13]
  Hong-Tao Ji , Yu-Han Lu , Yan-Ting Liu , Yu-Lin Huang , Jiang-Feng Tian , Feng Liu , Yan-Yan Zeng , Hai-Yan Yang , Yong-Hong Zhang , Wei-Min He . Nd@C₃N₄-photoredox/chlorine dual catalyzed synthesis and evaluation of antitumor activities of 4-alkylated sulfonyl ketimines. Chinese Chemical Letters, 2025, 36(2): 110568-. doi: 10.1016/j.cclet.2024.110568
14. [14]
  Huimin Luan , Qinming Wu , Jianping Wu , Xiangju Meng , Feng-Shou Xiao . Templates for the synthesis of zeolites. Chinese Journal of Structural Chemistry, 2024, 43(4): 100252-100252. doi: 10.1016/j.cjsc.2024.100252
15. [15]
  Hang Wang , Qi Wang , Chuan-De Wu . Continuous synthesis of ammonia. Chinese Journal of Structural Chemistry, 2025, 44(3): 100437-100437. doi: 10.1016/j.cjsc.2024.100437
16. [16]
  Ya-Nan Yang , Zi-Sheng Li , Sourav Mondal , Lei Qiao , Cui-Cui Wang , Wen-Juan Tian , Zhong-Ming Sun , John E. McGrady . Metal-metal bonds in Zintl clusters: Synthesis, structure and bonding in [Fe₂Sn₄Bi₈]^3– and [Cr₂Sb₁₂]^3–. Chinese Chemical Letters, 2024, 35(8): 109048-. doi: 10.1016/j.cclet.2023.109048
17. [17]
  Tao Zhou , Jing Zhou , Yunyun Liu , Jie-Ping Wan , Fen-Er Chen . Transition metal-free tunable synthesis of 3-(trifluoromethylthio) and 3-trifluoromethylsulfinyl chromones via domino C–H functionalization and chromone annulation of enaminones. Chinese Chemical Letters, 2024, 35(11): 109683-. doi: 10.1016/j.cclet.2024.109683
18. [18]
  Ao Sun , Zipeng Li , Shuchun Li , Xiangbao Meng , Zhongtang Li , Zhongjun Li . Stereoselective synthesis of α-3-deoxy-D-manno-oct-2-ulosonic acid (α-Kdo) derivatives using a C3-p-tolylthio-substituted Kdo fluoride donor. Chinese Chemical Letters, 2025, 36(3): 109972-. doi: 10.1016/j.cclet.2024.109972
19. [19]
  Zhaojun Liu , Zerui Mu , Chuanbo Gao . Alloy nanocrystals: Synthesis paradigms and implications. Chinese Journal of Structural Chemistry, 2023, 42(11): 100156-100156. doi: 10.1016/j.cjsc.2023.100156
20. [20]
  Zhenhao Wang , Yuliang Tang , Ruyu Li , Shuai Tian , Yu Tang , Dehai Li . Bioinspired synthesis of cochlearol B and ganocin A. Chinese Chemical Letters, 2024, 35(7): 109247-. doi: 10.1016/j.cclet.2023.109247

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(684)
HTML views(6)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142