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

doi:10.6023/cjoc202202006

Chinese Journal of Organic Chemistry ›› 2022, Vol. 42 ›› Issue (7): 2124-2133.DOI: 10.6023/cjoc202202006 Previous Articles Next Articles

Special Issue: 有机氟化学虚拟合辑

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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)

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Abstract

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

Cite this article

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.

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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

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