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Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives.
Eur J Med Chem. 2016 Jun 10; 115:109-20.EJ

Abstract

In an ongoing investigation of 20-sulfonylamidine derivatives (9, YQL-9a) of camptothecin (1) as potential anticancer agents directly and selectively inhibiting topoisomerase (Topo) I, the sulfonylamidine pharmacophore was held constant, and a camptothecin derivatives with various substitution patterns were synthesized. The new compounds were evaluated for antiproliferative activity against three human tumor cell lines, A-549, KB, and multidrug resistant (MDR) KB subline (KBvin). Several analogs showed comparable or superior antiproliferative activity compared to the clinically prescribed 1 and irinotecan (3). Significantly, the 20-sulfonylamidine derivatives exhibited comparable cytotoxicity against KBvin, while 1 and 3 were less active against this cell line. Among them, compound 15c displayed much better cytotoxic activity than the controls 1, 3, and 9. Novel key structural features related to the antiproliferative activities were identified by structure-activity relationship (SAR) analysis. In a molecular docking model, compounds 9 and 15c interacted with Topo I-DNA through a different binding mode from 1 and 3. The sulfonylamidine side chains of 9 and 15c could likely form direct hydrogen bonds with Topo I, while hydrophobic interaction with Topo I and π-π stacking with double strand DNA were also confirmed as binding driving forces. The results from docking models were consistent with the SAR conclusions. The introduction of bulky substituents at the 20-position contributed to the altered binding mode of the compound by allowing them to form new interactions with Topo I residues. The information obtained in this study will be helpful for the design of new derivatives of 1 with most promising anticancer activity.

Authors+Show Affiliations

School of Pharmacy, Lanzhou University, Lanzhou 730000, China.School of Pharmacy, Lanzhou University, Lanzhou 730000, China.School of Pharmacy, Lanzhou University, Lanzhou 730000, China.School of Pharmacy, Lanzhou University, Lanzhou 730000, China.School of Medicine, Shandong University, Jinan 250012, China.School of Pharmacy, Lanzhou University, Lanzhou 730000, China.Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.School of Pharmacy, Lanzhou University, Lanzhou 730000, China. Electronic address: yqliu@lzu.edu.cn.School of Pharmacy, Lanzhou University, Lanzhou 730000, China.Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.School of Pharmacy, Lanzhou University, Lanzhou 730000, China. Electronic address: hxliu@lzu.edu.cn.Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.Gansu Corps Hospital of CAPF, Lanzhou 730050, China.Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, China. Electronic address: khlee@email.unc.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26994847

Citation

Song, Zi-Long, et al. "Design, Synthesis, Cytotoxic Activity and Molecular Docking Studies of New 20(S)-sulfonylamidine Camptothecin Derivatives." European Journal of Medicinal Chemistry, vol. 115, 2016, pp. 109-20.
Song ZL, Wang MJ, Li L, et al. Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives. Eur J Med Chem. 2016;115:109-20.
Song, Z. L., Wang, M. J., Li, L., Wu, D., Wang, Y. H., Yan, L. T., Morris-Natschke, S. L., Liu, Y. Q., Zhao, Y. L., Wang, C. Y., Liu, H., Goto, M., Liu, H., Zhu, G. X., & Lee, K. H. (2016). Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives. European Journal of Medicinal Chemistry, 115, 109-20. https://doi.org/10.1016/j.ejmech.2016.02.070
Song ZL, et al. Design, Synthesis, Cytotoxic Activity and Molecular Docking Studies of New 20(S)-sulfonylamidine Camptothecin Derivatives. Eur J Med Chem. 2016 Jun 10;115:109-20. PubMed PMID: 26994847.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives. AU - Song,Zi-Long, AU - Wang,Mei-Juan, AU - Li,Lanlan, AU - Wu,Dan, AU - Wang,Yu-Han, AU - Yan,Li-Ting, AU - Morris-Natschke,Susan L, AU - Liu,Ying-Qian, AU - Zhao,Yong-Long, AU - Wang,Chih-Ya, AU - Liu,Huanxiang, AU - Goto,Masuo, AU - Liu,Heng, AU - Zhu,Gao-Xiang, AU - Lee,Kuo-Hsiung, Y1 - 2016/03/03/ PY - 2014/12/16/received PY - 2015/03/20/revised PY - 2016/02/26/accepted PY - 2016/3/21/entrez PY - 2016/3/21/pubmed PY - 2016/12/15/medline KW - Camptothecin KW - Cytotoxic activity KW - Molecular docking KW - Sulfonylamidine KW - Synthesis SP - 109 EP - 20 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 115 N2 - In an ongoing investigation of 20-sulfonylamidine derivatives (9, YQL-9a) of camptothecin (1) as potential anticancer agents directly and selectively inhibiting topoisomerase (Topo) I, the sulfonylamidine pharmacophore was held constant, and a camptothecin derivatives with various substitution patterns were synthesized. The new compounds were evaluated for antiproliferative activity against three human tumor cell lines, A-549, KB, and multidrug resistant (MDR) KB subline (KBvin). Several analogs showed comparable or superior antiproliferative activity compared to the clinically prescribed 1 and irinotecan (3). Significantly, the 20-sulfonylamidine derivatives exhibited comparable cytotoxicity against KBvin, while 1 and 3 were less active against this cell line. Among them, compound 15c displayed much better cytotoxic activity than the controls 1, 3, and 9. Novel key structural features related to the antiproliferative activities were identified by structure-activity relationship (SAR) analysis. In a molecular docking model, compounds 9 and 15c interacted with Topo I-DNA through a different binding mode from 1 and 3. The sulfonylamidine side chains of 9 and 15c could likely form direct hydrogen bonds with Topo I, while hydrophobic interaction with Topo I and π-π stacking with double strand DNA were also confirmed as binding driving forces. The results from docking models were consistent with the SAR conclusions. The introduction of bulky substituents at the 20-position contributed to the altered binding mode of the compound by allowing them to form new interactions with Topo I residues. The information obtained in this study will be helpful for the design of new derivatives of 1 with most promising anticancer activity. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/26994847/Design_synthesis_cytotoxic_activity_and_molecular_docking_studies_of_new_20_S__sulfonylamidine_camptothecin_derivatives_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(16)30170-2 DB - PRIME DP - Unbound Medicine ER -