基于莪术醇胺氟化结构修饰的三维天然产物片段库的构建

doi:10.6023/cjoc202202006

有机化学 ›› 2022, Vol. 42 ›› Issue (7): 2124-2133.DOI: 10.6023/cjoc202202006 上一篇下一篇

所属专题：有机氟化学虚拟合辑

研究论文

基于莪术醇胺氟化结构修饰的三维天然产物片段库的构建

李响^a^,^b, 张依凡^a, 陆凯琳^b, 刘石惠^a^,^*(), 张永强^b^,^*()

^a嘉兴学院医学院浙江嘉兴 314001
^b华东理工大学药学院上海 200237

收稿日期:2022-02-06 修回日期:2022-03-26 发布日期:2022-08-09
通讯作者: 刘石惠, 张永强
作者简介:
^† 共同第一作者
基金资助:
国家自然科学基金(22001096); 国家自然科学基金(21871086); 浙江省自然科学基金(LQ21B020008); 嘉兴学院启动经费(CD70519040); 嘉兴学院“百青”培养人才(CD70621018)

Aminofluorination-Based Structural Modification of Curcumol for the Construction of 3D-Shaped Natural Product Fragment Library

Xiang Li^a^,^b, Yifan Zhang^a, Kailin Lu^b, Shihui Liu^a(), Yongqiang Zhang^b()

^aCollege of Medicine, Jiaxing University, Jiaxing, Zhejiang 314001
^bSchool of Pharmacy, East China University of Science and Technology, Shanghai 200237

Received:2022-02-06 Revised:2022-03-26 Published:2022-08-09
Contact: Shihui Liu, Yongqiang Zhang
About author:
^† These authors contributed equally to this work
Supported by:
National Natural Science Foundation of China(22001096); National Natural Science Foundation of China(21871086); Natural Science Foundation of Zhejiang Province(LQ21B020008); Start Up Funds of Jiaxing University(CD70519040); Jiaxing University "Hundred Youth" Training Talents(CD70621018)

文章分享

1. 基于莪术醇胺氟化结构修饰的三维天然产物片段库的构建.pdf(6688KB)

摘要/Abstract

富含sp³中心的三维天然产物结构由于其独特的生物活性, 在药物化学及生物化学方面越来越受到重视. 以天然产物莪术醇为基础, 通过光催化的胺氟化反应, 高效引入胺和氟两个潜在的结合或反应位点, 构建了以三维形状天然产物为核心的片段库. 通过这一策略, 合成了包含24个新型莪术醇衍生物的片段库, 进一步计算结果表明, 所获得的片段库具有高三维度、天然产物相似性和优质的片段属性, 在基于片段的药物发现中开辟了一个新的化学空间.

关键词: 莪术醇, 结构修饰, 胺氟化, 三维片段, 基于片段的药物发现

The biological significance of sp³-rich synthetic scaffolds with natural product like features yet distinct global frameworks is being increasingly recognized in medicinal chemistry and biochemistry. Herein, a fragment library consisting of 3D-shaped natural product fragments was assembled. Library construction was performed by photocatalytic amidofluorination of curcumol to incorporate amine and fluorine as potential binding groups and synthetic growth points. Through this strategy, a fragment library of 24 fragments was generated, which was demonstrate to have high three-dimensionality, natural product likeness and superior fragment-like properties, covering a novel chemical space in fragment based drug discovery.

Key words: curcumol, structural modification, aminofluorination, 3D-shaped fragments, fragment based drug discovery

引用此文

李响, 张依凡, 陆凯琳, 刘石惠, 张永强. 基于莪术醇胺氟化结构修饰的三维天然产物片段库的构建[J]. 有机化学, 2022, 42(7): 2124-2133.

Xiang Li, Yifan Zhang, Kailin Lu, Shihui Liu, Yongqiang Zhang. Aminofluorination-Based Structural Modification of Curcumol for the Construction of 3D-Shaped Natural Product Fragment Library[J]. Chinese Journal of Organic Chemistry, 2022, 42(7): 2124-2133.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

图/表 5

参考文献 16

[1]	(a) Jencks, W. P. Proc. Natl. Acad. Sci. 1981, 78, 4046. doi: 10.1073/pnas.78.7.4046 pmid: 21695633
	(b) Fattori, D. Drug Discovery Today 2004, 9, 229. doi: 10.1016/S1359-6446(03)03007-1 pmid: 21695633
	(c) Congreve, M.; Chessari, G.; Tisi, D.; Woodhead, A. J. J. Med. Chem. 2008, 51, 3661. doi: 10.1021/jm8000373 pmid: 21695633
	(d) Murray, C. W.; Rees, D. C. Nat. Chem. 2009, 1, 187. doi: 10.1038/nchem.217 pmid: 21695633
	(e) Scott, D. E.; Coyne, A. G.; Hudson, S. A.; Abell, C. Biochemistry 2012, 51, 4990. doi: 10.1021/bi3005126 pmid: 21695633
	(f) Erlanson, D. A. Top. Curr. Chem. 2012, 317, 1. doi: 10.1007/128_2011_180 pmid: 21695633
	(g) Baker, M. Nat. Rev. Drug Discovery 2013, 12, 5. doi: 10.1038/nrd3926 pmid: 21695633
	(h) Erlanson, D. A.; Fesik, S. W.; Hubbard, R. E.; Jahnke, W.; Jhoti, H. Nat. Rev. Drug Discovery 2016, 15, 605. doi: 10.1038/nrd.2016.109 pmid: 21695633
	(i) Bancet, A.; Raingeval, C.; Lomberget, T.; Le Borgne, M.; Guichou, J.-F.; Krimm, I. J. Med. Chem. 2020, 63, 11420. doi: 10.1021/acs.jmedchem.0c00242 pmid: 21695633
	(j) Vaidergorn, M. M.; da Silva Emery, F.; Ganesan, A. J. Med. Chem. 2021, 64, 13980. doi: 10.1021/acs.jmedchem.1c00787 pmid: 21695633
[2]	(a) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752. doi: 10.1021/jm901241e pmid: 19827778
	(b) Meanwell, N. A. Chem. Res. Toxicol. 2011, 24, 1420. doi: 10.1021/tx200211v pmid: 19827778
	(c) Shultz, M. D. J. Med. Chem. 2019, 62, 1701. doi: 10.1021/acs.jmedchem.8b00686 pmid: 19827778
[3]	(a) Morley, A. D.; Pugliese, A.; Birchall, K.; Bower, J.; Brennan, P.; Brown, N.; Chapman, T.; Drysdale, M.; Gilbert, I. H.; Hoelder, S.; Jordan, A.; Ley, S. V.; Merritt, A.; Miller, D.; Swarbrick, M. E.; Wyatt, P. G. Drug Discov. Today 2013, 18, 1221. doi: 10.1016/j.drudis.2013.07.011
	(b) Chen, H.; Zhou, X.; Wang, A.; Zheng, Y.; Gao, Y.; Zhou, J. Drug Discov. Today 2015, 20, 105. doi: 10.1016/j.drudis.2014.09.015
[4]	(a) Hung, A. W.; Ramek, A.; Wang, Y.; Kaya, T.; Wilson, J. A.; Clemons, P. A.; Young, D. W. Proc. Natl. Acad. Sci. 2011, 108, 6799. doi: 10.1073/pnas.1015271108 pmid: 33892142
	(b) Keserű, G. M.; Erlanson, D. A.; Ferenczy, G. G.; Hann, M. M.; Murray, C. W.; Pickett, S. D. J. Med. Chem. 2016, 59, 8189. doi: 10.1021/acs.jmedchem.6b00197 pmid: 33892142
	(c) Murray, C. W.; Rees, D. C. Angew. Chem. Int. Ed. 2016, 55, 488. doi: 10.1002/anie.201506783 pmid: 33892142
	(d) Kidd, S. L.; Osberger, T. J.; Mateu, N.; Sore, H. F.; Spring, D. R. Front. Chem. 2018, 6, 460. doi: 10.3389/fchem.2018.00460 pmid: 33892142
	(e) Talele, T. T. J. Med. Chem. 2020, 63, 13291. doi: 10.1021/acs.jmedchem.0c00829 pmid: 33892142
	(f) Hiesinger, K.; Dar'in, D.; Proschak, E.; Krasavin, M. J. Med. Chem. 2021, 64, 150. doi: 10.1021/acs.jmedchem.0c01473 pmid: 33892142
	(g) van Vlijmen, H.; Ortholand, J.-Y.; Li, V. M.; de Vlieger, J. S. B. Drug Discovery Today 2021, 26, 2406. doi: 10.1016/j.drudis.2021.04.019 pmid: 33892142
	(h) Konteatis, Z. Expert Opin. Drug Discovery 2021, 16, 723. doi: 10.1080/17460441.2021.1905629 pmid: 33892142
[5]	(a) Wetzel, S.; Schuffenhauer, A.; Roggo, S.; Ertl, P.; Waldmann, H. CHIMIA 2007, 61, 355. doi: 10.2533/chimia.2007.355 pmid: 32015480
	(b) Lachance, H.; Wetzel, S.; Kumar, K.; Waldmann, H. J. Med. Chem. 2012, 55, 5989-6001. doi: 10.1021/jm300288g pmid: 32015480
	(c) Over, B.; Wetzel, S.; Grütter, C.; Nakai, Y.; Renner, S.; Rauh, D.; Waldmann, H. Nat. Chem. 2013, 5, 21. doi: 10.1038/nchem.1506 pmid: 32015480
	(d) Stratton, C. F.; Newman, D. J.; Tan, D. S. Bioorg. Med. Chem. Lett. 2015, 25, 4802. doi: 10.1016/j.bmcl.2015.07.014 pmid: 32015480
	(e) Ntie-Kang, F.; Nyongbela, K. D.; Ayimele, G. A.; Shekfeh, S. Phys. Sci. Rev. 2019, 4, 20180169. pmid: 32015480
	(f) Chen, Y.; Kirchmair, J. Mol. Inform. 2020, 39, e2000171. pmid: 32015480
	(g) Hanby, A. R.; Troelsen, N. S.; Osberger, T. J.; Kidd, S. L.; Mortensen, K. T.; Spring, D. R. Chem. Commun. 2020, 56, 2280. doi: 10.1039/C9CC09796A pmid: 32015480
	(h) Stone, S.; Newman, D. J.; Colletti, S. L.; Tan, D. S. Nat. Prod. Rep. 2021, 10.1039/d1np00039j. doi: 10.1039/d1np00039j pmid: 32015480
	(i) Karageorgis, G.; Reckzeh, E. S.; Ceballos, J.; Schwalfenberg, M.; Sievers, S.; Ostermann, C.; Pahl, A.; Ziegler, S.; Waldmann, H. Nat. Chem. 2018, 10, 1103. doi: 10.1038/s41557-018-0132-6 pmid: 32015480
	(j) Grigalunas, M.; Burhop, A.; Christoforow, A.; Waldmann, H. Curr. Opin. Chem. Biol. 2020, 56, 111. doi: S1367-5931(19)30117-6 pmid: 32015480
	(k) Karageorgis, G.; Foley, D. J.; Laraia, L.; Waldmann, H. Nat. Chem. 2020, 12, 227. doi: 10.1038/s41557-019-0411-x pmid: 32015480
[6]	(a) Wei, W.; Rasul, A.; Sadiqa, A.; Sarfraz, I.; Hussain, G.; Nageen, B.; Liu, X.; Watanabe, N.; Selamoglu, Z.; Ali, M.; Li, X.; Li, J. Int. J. Biol. Sci. 2019, 15, 1600. doi: 10.7150/ijbs.34716 pmid: 31360103
	(b) Hashem, S.; Nisar, S.; Sageena, G.; Macha, M. A.; Yadav, S. K.; Krishnankutty, R.; Uddin, S.; Haris, M.; Bhat, A. A. Nutr. Cancer 2021, 73, 181. doi: 10.1080/01635581.2020.1749676 pmid: 31360103
[7]	(a) Nadin, A.; Hattotuwagama, C.; Churcher, I. Angew. Chem. Int. Ed. 2012, 51, 1114. doi: 10.1002/anie.201105840 pmid: 24239725
	(b) Doveston, R.; Marsden, S.; Nelson, A. Drug Discovery Today 2014, 19, 813. doi: 10.1016/j.drudis.2013.11.006 pmid: 24239725
[8]	Colomer, I.; Empson, C. J.; Craven, P.; Owen, Z.; Doveston, R. G.; Churcher, I.; Marsden, S. P.; Nelson, A. Chem. Commun. 2016, 52, 7209. doi: 10.1039/C6CC03244C
[9]	(a) Sun, H.-J.; Zou, Y.-P.; Nie, X.-F.; Yu, R.-H. Chin. J. Pharm. 1983, 14, 12. (in Chinese)
	( 孙汉杰, 邹亚平, 聂秀范, 于润海, 中国医药工业杂志, 1983, 14, 12.)
	(b) Zhao, J.-H. M.S. Thesis, Liaoning University, Shenyang, 2017. (in Chinese)
	( 赵京华, 硕士论文, 辽宁大学, 沈阳, 2017.)
	(c) Liu, J.; Zhao, J.; Zhang, J.; Cui, Q.; Wang, X.; Liang, X.; Liu, H.; Chen, L. J. Lat. Am. J. Pharm. 2017, 36, 955.
[10]	(a) Ma, X. M.S. Thesis, Dalian University of Technology, Dalian, 2010. (in Chinese)
	( 马旭, 硕士论文, 大连理工大学,大连, 2010.)
	(b) Guo, P.; Liu, J.-M.; Ye, F.-Q.; Li, X.-K.; Yao, Q.-Z. Chin. J. Org. Chem. 2012, 32, 2003. (in Chinese) doi: 10.6023/cjoc201204007
	( 郭平, 刘剑敏, 叶发青, 李校堃, 姚其正, 有机化学, 2012, 32, 2003.) doi: 10.6023/cjoc201204007
[11]	(a) Guo, P.; Wang, Y.-W.; Weng, B.-X.; Li, X.-K.; Yang, S.-L.; Ye, F.-Q. J. Asian Nat. Prod. Res. 2014, 16, 53. doi: 10.1080/10286020.2013.857660
	(b) Guo, P. Ph.D. Dissertation, Nanjing University Of Science And Technology, Nanjing, 2015. (in Chinese)
	( 郭平, 博士论文, 南京理工大学, 南京, 2015.)
	(c) Meng, X.-W.; Nie, T.-Q.; Zhang, X.-X. CN 111153912, 2020.
[12]	Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J. Med. Chem. 2015, 58, 8315. doi: 10.1021/acs.jmedchem.5b00258 pmid: 26200936
[13]	Jiang, H.; Studer, A. Angew. Chem., Int. Ed. 2018, 57, 10707. doi: 10.1002/anie.201804966
[14]	CCDC 2156806 (12a) contains the supplementary crystallographic data for this paper. These data are free of charge from The Cambridge Crystallographic Centre via. www.ccdc.cam.ac.uk/data_request/cif.
[15]	(a) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug Delivery Rev. 2001, 46, 3. doi: 10.1016/S0169-409X(00)00129-0
	(b) Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.; Ward, K. W.; Kopple, K. D. J. Med. Chem. 2002, 45, 2615. doi: 10.1021/jm020017n
[16]	(a) Firth, N. C.; Brown, N.; Blagg, J. J. Chem. Inf. Model. 2012, 52, 2516. doi: 10.1021/ci300293f
	(b) Bento, A. P.; Gaulton, A.; Hersey, A.; Bellis, L. J.; Chambers, J.; Davies, M.; Krüger, F. A.; Light, Y.; Mak, L.; McGlinchey, S.; Nowotka, M.; Papadatos, G.; Santos, R.; Overington, J. P. Nucleic Acids Res. 2014, 42, D1083. doi: 10.1093/nar/gkt1031
	(c) Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. Future Med. Chem. 2016, 8, 1753. doi: 10.4155/fmc-2016-0095

Property	Ideal Range^b	Curcumol
MW	≤300	236.35
Alog P	0~2	2.63
Heavy atom count	10-16	17
Hydrogen-bond acceptors	≤3	2
Hydrogen-bond donors	≤3	1
Rotatable bond count	≤3	1
Carbon sp³fraction	—	0.866667
Plane of best fit/nm	—	0.1003
Polar surface area/nm²	≤0.60	0.2946

Property	Ideal Range^b	Curcumol
MW	≤300	236.35
Alog P	0~2	2.63
Heavy atom count	10-16	17
Hydrogen-bond acceptors	≤3	2
Hydrogen-bond donors	≤3	1
Rotatable bond count	≤3	1
Carbon sp³fraction	—	0.866667
Plane of best fit/nm	—	0.1003
Polar surface area/nm²	≤0.60	0.2946

Compd.	M_r	Alog P	Carbon sp³fraction	Plane of Best Fit/nm	Polar Surface Area/nm²
9	446.769	3.84	0.944	0.0989	0.67.79
10	271.371	1.70	1.000	0.0993	0.5548
12a	375.477	3.33	0.682	0.1056	0.5856
12b	389.503	3.35	0.696	0.0851	0.5856
12c	389.503	3.33	0.696	0.0979	0.5856
12d	389.503	3.34	0.696	0.1233	0.5856
12e	405.503	3.24	0.696	0.1254	0.67.79
12f	431.583	4.76	0.731	0.1071	0.5856
12g	393.467	3.25	0.682	0.0925	0.5856
12h	409.922	3.92	0.682	0.0931	0.5856
12i	454.373	3.89	0.682	0.1061	0.5856
12j	433.513	3.28	0.667	0.1294	0.8486
12k	400.486	3.02	0.652	0.1042	0.8235
12l	389.503	3.27	0.696	0.0940	0.5856
12m	401.514	3.75	0.625	0.1048	0.5856
12n	403.530	3.63	0.708	0.1356	0.5856
12o	435.529	3.33	0.708	0.1087	0.7702
12p	425.536	4.22	0.577	0.1168	0.5856
12q	365.439	2.77	0.750	0.0997	0.7170
12r	415.950	3.85	0.750	0.1076	0.5856
12s	455.361	3.03	0.714	0.1166	0.7145
12t	377.453	1.50	0.750	0.1005	0.8434
12u	425.557	2.52	0.727	0.1176	0.7563
12v	490.427	3.00	0.714	0.1071	0.7563
Average	407.366	3.30	0.718	0.1074	0.6564

Compd.	M_r	Alog P	Carbon sp³fraction	Plane of Best Fit/nm	Polar Surface Area/nm²
9	446.769	3.84	0.944	0.0989	0.67.79
10	271.371	1.70	1.000	0.0993	0.5548
12a	375.477	3.33	0.682	0.1056	0.5856
12b	389.503	3.35	0.696	0.0851	0.5856
12c	389.503	3.33	0.696	0.0979	0.5856
12d	389.503	3.34	0.696	0.1233	0.5856
12e	405.503	3.24	0.696	0.1254	0.67.79
12f	431.583	4.76	0.731	0.1071	0.5856
12g	393.467	3.25	0.682	0.0925	0.5856
12h	409.922	3.92	0.682	0.0931	0.5856
12i	454.373	3.89	0.682	0.1061	0.5856
12j	433.513	3.28	0.667	0.1294	0.8486
12k	400.486	3.02	0.652	0.1042	0.8235
12l	389.503	3.27	0.696	0.0940	0.5856
12m	401.514	3.75	0.625	0.1048	0.5856
12n	403.530	3.63	0.708	0.1356	0.5856
12o	435.529	3.33	0.708	0.1087	0.7702
12p	425.536	4.22	0.577	0.1168	0.5856
12q	365.439	2.77	0.750	0.0997	0.7170
12r	415.950	3.85	0.750	0.1076	0.5856
12s	455.361	3.03	0.714	0.1166	0.7145
12t	377.453	1.50	0.750	0.1005	0.8434
12u	425.557	2.52	0.727	0.1176	0.7563
12v	490.427	3.00	0.714	0.1071	0.7563
Average	407.366	3.30	0.718	0.1074	0.6564

基于莪术醇胺氟化结构修饰的三维天然产物片段库的构建

Aminofluorination-Based Structural Modification of Curcumol for the Construction of 3D-Shaped Natural Product Fragment Library

RichHTML

PDF

补充材料

可视化

摘要/Abstract

引用此文

分享此文

图/表 5

参考文献 16

相关文章 14

编辑推荐

相关统计

本文评价

[1]	刘改枝, 李金鑫, 史礼君, 刘萌芽, 蔡邦荣. 熊果酸的结构修饰与生物活性研究进展[J]. 有机化学, 2021, 41(8): 2974-2989.
[2]	周汇源, 吴堰霖, 黄典红, 张铭婷, 陈欢明, 钱明成, 赵帅, 张辛燕, 陈新. 山竹醇新类似物的合成及其抗肿瘤活性研究[J]. 有机化学, 2020, 40(6): 1578-1587.
[3]	董子阳, 杨占会, 许家喜. 马钱子碱的结构修饰和手性应用[J]. 有机化学, 2020, 40(12): 4101-4121.
[4]	戴一, 仲飞. 冬凌草甲素的结构修饰与生物活性研究进展[J]. 有机化学, 2017, 37(7): 1701-1713.
[5]	刘颖杰, 丁泽洋, 谭冲, 袁洪亮, 季宇彬. 石蒜碱的全合成及结构修饰研究进展[J]. 有机化学, 2015, 35(5): 1009-1021.
[6]	唐初, 陈玉, 柏舜, 杨光忠. 齐墩果酸的结构修饰与生物活性研究进展[J]. 有机化学, 2013, 33(01): 46-65.
[7]	郭平, 刘剑敏, 叶发青, 李校堃, 姚其正. 莪术醇在Woodward-Prévost反应条件下的产物研究[J]. 有机化学, 2012, 32(10): 2003-2006.
[8]	王欢欢, 吴平, 康宏, 许亮, 朱瑞新, 康廷国. 嘧啶衍生物对牛蒡子苷元片段修饰的研究[J]. 有机化学, 2012, 32(10): 1894-1898.
[9]	梁英, 喻大昭. 大黄素的化学合成及结构修饰研究进展[J]. 有机化学, 2011, 31(08): 1324-1333.
[10]	樊会丹^a ; 张从海^a ; 严胜骄^a ; 林军^*,a,b. 印楝素的合成、结构修饰及生物活性研究进展[J]. 有机化学, 2009, 29(01): 20-33.
[11]	战佩英^a; 李东风^b ; 王进军^*,c. 环稠卟啉合成的研究进展[J]. 有机化学, 2008, 28(12): 2039-2056.
[12]	赵圣印*; 邵志宇; 钦维民; 张灯青. 吲哚马来酰亚胺类蛋白激酶C抑制剂的研究进展[J]. 有机化学, 2008, 28(10): 1676-1684.
[13]	王进军. 叶绿素-a衍生物的化学反应和多取代卟吩(啉)合成的研究进展[J]. 有机化学, 2005, 25(11): 1353-1371.
[14]	周冰, 许新华, 张秋林, 陈茹玉. 磷脂核苷缀合物甘油结构修饰新方法及应用[J]. 有机化学, 2004, 24(1): 88-92.