Identification of Novel 4′-<i>O</i>-Demethyl-epipodophyllotoxin Derivatives as Antitumor Agents Targeting Topoisomerase II
C4 variation of 4′-<i>O</i>-demethyl-epipodophyllotoxin (DMEP) is an effective approach to optimize the antitumor spectra of this compound class. Accordingly, two series of novel DMEP derivatives were synthesized, and as expected, the antitumor spectra of these derivatives varied with di...
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| Format: | Article |
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MDPI AG
2022-08-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/15/5029 |
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| author | Wenli Xi Hua Sun Kenneth F. Bastow Zhiyan Xiao Kuo-Hsiung Lee |
| author_facet | Wenli Xi Hua Sun Kenneth F. Bastow Zhiyan Xiao Kuo-Hsiung Lee |
| author_sort | Wenli Xi |
| collection | DOAJ |
| description | C4 variation of 4′-<i>O</i>-demethyl-epipodophyllotoxin (DMEP) is an effective approach to optimize the antitumor spectra of this compound class. Accordingly, two series of novel DMEP derivatives were synthesized, and as expected, the antitumor spectra of these derivatives varied with different C4 substituents. Notably, most compounds showed significant inhibition against the etoposide (2)-resistant KBvin cells. Four of the compounds (<b>11</b>, <b>18</b>, <b>27</b> and <b>28</b>) induced protein-linked DNA break (PLDB) levels higher than those of GL-331 (<b>6</b>) and <b>2</b>, and are assumed to be topoisomerase II (topo II) poisons more potent than <b>6</b> and <b>2</b>. Compound <b>28</b>, a potent topo II poison highly effective against KBvin cells, was further evaluated with a panel of tumor cells and was most active against HepG2. This compound also exhibited apparent in vivo antitumor efficacy in hepatoma 22 (H22) mouse model. The results indicated that C4 derivation of DMEP is a feasible approach to identify potent topo II inhibitors with optimized antitumor profiles. |
| first_indexed | 2024-03-09T05:09:07Z |
| format | Article |
| id | doaj.art-77d5561467a94d99889d02b91d0ecf27 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T05:09:07Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-77d5561467a94d99889d02b91d0ecf272023-12-03T12:51:11ZengMDPI AGMolecules1420-30492022-08-012715502910.3390/molecules27155029Identification of Novel 4′-<i>O</i>-Demethyl-epipodophyllotoxin Derivatives as Antitumor Agents Targeting Topoisomerase IIWenli Xi0Hua Sun1Kenneth F. Bastow2Zhiyan Xiao3Kuo-Hsiung Lee4Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaThe State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Material Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaNatural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USABeijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaNatural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USAC4 variation of 4′-<i>O</i>-demethyl-epipodophyllotoxin (DMEP) is an effective approach to optimize the antitumor spectra of this compound class. Accordingly, two series of novel DMEP derivatives were synthesized, and as expected, the antitumor spectra of these derivatives varied with different C4 substituents. Notably, most compounds showed significant inhibition against the etoposide (2)-resistant KBvin cells. Four of the compounds (<b>11</b>, <b>18</b>, <b>27</b> and <b>28</b>) induced protein-linked DNA break (PLDB) levels higher than those of GL-331 (<b>6</b>) and <b>2</b>, and are assumed to be topoisomerase II (topo II) poisons more potent than <b>6</b> and <b>2</b>. Compound <b>28</b>, a potent topo II poison highly effective against KBvin cells, was further evaluated with a panel of tumor cells and was most active against HepG2. This compound also exhibited apparent in vivo antitumor efficacy in hepatoma 22 (H22) mouse model. The results indicated that C4 derivation of DMEP is a feasible approach to identify potent topo II inhibitors with optimized antitumor profiles.https://www.mdpi.com/1420-3049/27/15/50294′-<i>O</i>-demethyl-epipodophyllotoxintopoisomerase IIantitumor agent |
| spellingShingle | Wenli Xi Hua Sun Kenneth F. Bastow Zhiyan Xiao Kuo-Hsiung Lee Identification of Novel 4′-<i>O</i>-Demethyl-epipodophyllotoxin Derivatives as Antitumor Agents Targeting Topoisomerase II Molecules 4′-<i>O</i>-demethyl-epipodophyllotoxin topoisomerase II antitumor agent |
| title | Identification of Novel 4′-<i>O</i>-Demethyl-epipodophyllotoxin Derivatives as Antitumor Agents Targeting Topoisomerase II |
| title_full | Identification of Novel 4′-<i>O</i>-Demethyl-epipodophyllotoxin Derivatives as Antitumor Agents Targeting Topoisomerase II |
| title_fullStr | Identification of Novel 4′-<i>O</i>-Demethyl-epipodophyllotoxin Derivatives as Antitumor Agents Targeting Topoisomerase II |
| title_full_unstemmed | Identification of Novel 4′-<i>O</i>-Demethyl-epipodophyllotoxin Derivatives as Antitumor Agents Targeting Topoisomerase II |
| title_short | Identification of Novel 4′-<i>O</i>-Demethyl-epipodophyllotoxin Derivatives as Antitumor Agents Targeting Topoisomerase II |
| title_sort | identification of novel 4 i o i demethyl epipodophyllotoxin derivatives as antitumor agents targeting topoisomerase ii |
| topic | 4′-<i>O</i>-demethyl-epipodophyllotoxin topoisomerase II antitumor agent |
| url | https://www.mdpi.com/1420-3049/27/15/5029 |
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