No 6 刘诚等 : 大黄素衍生物的合成及抗癌活性 H Bruker Avance-400 /500 TMS Perkin Elmer Spectrum 2000 FTIR Thermofisher LCQ FLEET WRS-1B ~

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1 Vol 34 高等学校化学学报 No CHEMICAL JOURNAL OF CHINESE UNIVERSITIES 1408 ~ 1415 doi /cjcu 刘诚 1, 郑艳艳 1, 洪芳 1, 胡建达 2, 赵文娜 1, 袁耀锋 1, 邵敬伟 1 1, 王文峰 C H NMR Molt-4 CA46 8 9a + 9b 20a 20b 20c O R914 4 A DNA 5 6 DNA IC ~ 80 μmol /L 14 DNA DNA 1 DNA 15 2 DNA N7 DNA 16 3 DNA H DNA 17 DNA Graham C C6 caspase-3 caspase-9 Tan 22 π Lackner Y wangwf@ fzu edu cn

2 No 6 刘诚等 : 大黄素衍生物的合成及抗癌活性 H Bruker Avance-400 /500 TMS Perkin Elmer Spectrum 2000 FTIR Thermofisher LCQ FLEET WRS-1B ~ 7 2 m p 226 ~ ~ m p 246 ~ ~ m p 227 ~ ~ m p 233 ~ m p 217 ~ ~ 7 Scheme 1 Scheme 1 Synthetic routes of compounds ~ ~ Scheme 2 8 ~ mg 0 15 mmol 5 50 ml 24 mg 0 22 mmol 10 ml 5 ml 15 h 8 V V = a 9b 10 9a 9b % m p > 250 IR KBr ν珓 max /cm H NMR 500 MHz DMSO δ s 1H NH 8 50 d J = 1 5 Hz 1H Ar H 8 24 d J = 1 5 Hz 1H Ar H 7 67 m 1H Ar H 7 26 d J = 3 0 Hz 2H Ar H 7 23 d J = 2 5 Hz 1H Ar H 7 01 d J = 2 5 Hz 1H Ar H 4 04 s 3H OCH s 3H OCH s 3H OCH 3 ESI-MS m /z M + H +

3 1410 高等学校化学学报 Vol 34 Scheme 2 Synthetic routes of compounds a b 66 8% m p ~ IR KBr ν珓 max / cm H NMR 500 MHz DMSO δ s 1H OH s 1H OH s 1H NH s 1H NH 8 63 d J = 1 5 Hz 1H Ar H 8 47 d J = 1 5 Hz 1H Ar H 8 30 d J = 1 0 Hz 1H Ar H 8 05 d J = 2 0 Hz 1H Ar H 7 76 d J = 8 0 Hz 1H Ar H 7 73 d J = 8 0 Hz 1H Ar H 7 62 d J = 7 5 Hz 1H Ar H 7 58 d J = 8 0 Hz 1H Ar H 7 38 d J = 2 5 Hz 1H Ar H 7 33 ~ 7 28 m 2H Ar H 7 28 ~ 7 23 m 2H Ar H 7 20 d J = 2 5 Hz 1H Ar H 7 07 d J = 2 5 Hz 1H Ar H 6 88 d J = 2 5 Hz 1H Ar H 4 11 s 3H OCH s 3H OCH s 3H OCH s 3H OCH 3 ESI-MS m /z M + H % m p ~ IR KBr ν珓 max /cm H NMR 500 MHz DMSO δ s 1H NH s 1H Ar OH s 1H Ar OH 8 54 d J = 2 0 Hz 1H Ar H 8 10 d J = 2 0 Hz 1H Ar H 7 79 ~ 7 74 m 1H Ar H 7 63 ~ 7 59 m 1H Ar H 7 34 ~ 7 30 m 1H Ar H 7 29 d J = 3 0 Hz 1H Ar H 7 28 ~ 7 25 m 1H Ar H 6 94 d J = 3 0 Hz 1H Ar H 3 94 s 3H OCH 3 APCI-MS m /z M + H mg 0 12 mmol 8 50 ml 30 mg 0 12 mmol 0 03 ml 20 ml g NaOH 5 ml 12 h V V = % m p 49 7 ~ H NMR 500 MHz CDCl 3 δ 8 14 d J = 2 0 Hz 1H Ar H 7 94 ~ 7 88 m 2H Ar H 7 53 ~ 7 49 m 1H Ar H 7 43 ~ 7 49 m 2H Ar H 7 38 d J = 2 0 Hz 1H Ar H 6 84 d J = 2 5 Hz 1H Ar H 4 37 t J = 7 5 Hz 2H N CH s 3H OCH s 3H OCH s 3H OCH m 2H CH ~ 1 20 m 18H CH t J = 7 0 Hz 3H CH 3 ESI-MS m /z M + H ~ ~ 16 Scheme 3

4 No 6 刘诚等 : 大黄素衍生物的合成及抗癌活性 1411 Scheme 3 Synthetic routes of compounds 16a 16c TBAP mg 0 46 mmol ml ml 1 5 ml 90 4 h 135 mg mmol % m p ~ H NMR 400 MHz DMSO δ 8 17 ~ H Ar H 4 42 ~ 4 38 q J = Hz 2H OCH ~ 3 91 s 9H 3 OCH ~ 1 35 t J = 5 6 Hz 3H CH 3 APCI-MS m /z M + H mg mmol ml 70 5 ml 80% 90 6 h 14 15a ~ 15c 14 3 h TLC V V = a ~ 15c 16a ~ 16c 20 2 mg mmol 15a 44 0 mg -T 4 h TLC V V = % NaOH ph = 6 CHCl a / 16a 16b 16c a 5 98 mg mmol 30 0% m p > H NMR 400 MHz CDCl 3 δ 8 48 d J = 1 2 Hz 1H Ar H 8 22 ~ 8 20 m 2H Ar H 8 12 d J = 1 2 Hz 1H Ar H 7 61 ~ 7 56 m 3H Ar H 7 37 d J = 2 0 Hz 1H Ar H 6 81 d J = 2 0 Hz 1H Ar H 4 13 s 3H OCH s 3H OCH s 3H OCH 3 APCI-MS m /z M + H b 52 2% m p > H NMR 400 MHz CDCl 3 δ 8 50 d J = 1 2 Hz 1H Ar H 8 15 dd J = Hz 1H Ar H 8 11 d J = 1 2 Hz 1H Ar H 7 60 dd J = Hz 1H Ar H 7 37 d J = 2 0 Hz 1H Ar H 7 53 m 1H Ar H 7 48 m 1H Ar H 6 81 d J = 2 0 Hz 1H Ar H 4 13 s 3H OCH s 3H OCH s 3H OCH 3 APCI-MS

5 1412 高等学校化学学报 Vol 34 m /z M + H c 49 8% m p > H NMR 400 MHz CDCl 3 δ 8 46 d J = 1 6 Hz 1H Ar H 8 23 m 2H Ar H 8 10 d J = 1 2 Hz 1H Ar H 7 37 d J = 2 0 Hz 1H Ar H H Ar H H Ar H 6 82 d J = 2 0 Hz 1H Ar H 4 13 s 3H OCH s 3H OCH s 3H OCH 3 APCI-MS m /z M + H ~ ~ 20 Scheme 4 Scheme 4 Synthetic routes of target compounds 20a 20c mg mmol mg K 2 CO ml 5 ml 24 h TLC V V = 60 1 V V = mg mmol 89 9% m p ~ H NMR 400 MHz CDCl 3 δ 7 66 s 1H Ar H 7 32 d J = 2 0 Hz 1H Ar H 7 12 s 1H Ar H 6 87 d J = 1 6 Hz 1H Ar H 4 48 dd J = Hz 1H OCHH 4 09 dd J = Hz 1H OCHH 4 01 s 3H OCH s 3H OCH m 1H 2 99 t 1H J = 3 6 Hz 2 84 dd 1H J = Hz 2 49 s 3H Ar CH 3 ESI-MS m /z M + H mg 0 96 mmol 18 CCl mg 0 96 mmol N- NBS 85 BPO 24 h TLC V V = 60 1 V V = mg mmol 51 0% m p ~ H NMR 400 MHz CDCl 3 δ 7 85 d J = 1 6 Hz 1H Ar H 7 33 s 2H Ar H 6 88 d J = 2 0 Hz 1H Ar H 4 55 s 2H Ar CH dd J = Hz 1H OCHH 4 09 dd J = Hz 1H OCHH 4 05 s 3H OCH s 3H OCH m 1H 2 99 t 1H J = 3 6 Hz 2 84 dd 1H J = Hz APCI-MS m /z M + 20a 100 mg mmol ml 19 N- 24 h TLC V V = 20 1 / 20a 20b 20c N ' 3' N- -N a 47 7 mg mmol 30 0% m p ~ H NMR 400 MHz CDCl 3 δ H Ar H H Ar H H Ar H H Ar H

6 No 6 刘诚等 : 大黄素衍生物的合成及抗癌活性 s 2H Ar CH dd J = Hz 1H OCHH 4 08 dd J = Hz 1H OCHH 4 15 s 3H OCH s 3H OCH m 4H 2 NCH s 3H NCH t 1H J = 3 6 Hz 2 84 dd 1H J = Hz 1 85 ~ 1 75 m 4H 2 NCH 2 CH ~ 1 30 m 20H 2 CH t J = 7 2 Hz 6H 2 CH 3 APCI-MS m /z M - Br + N ' 3' N- -N b 73 9 mg mmol 42 0% m p ~ H NMR 400 MHz CDCl 3 δ H Ar H H Ar H H Ar H H Ar H 5 16 s 2H Ar CH dd J = Hz 1H OCHH 4 08 dd J = Hz 1H OCHH 4 16 s 3H OCH s 3H OCH m 1H CH 2 CHCH m 4H 2 NCH s 3H NCH t 1H J = 3 6 Hz 2 84 dd 1H J = Hz 1 83 ~ 1 75 m 36H 2 CH t J = 7 2 Hz 6H 2 CH 3 ESI-MS m / z M - Br + N ' 3' N- -N c 62 2 mg mmol 33 0% m p 77 2 ~ H NMR 400 MHz CDCl 3 δ H Ar H H Ar H H Ar H 5 22 s 2H Ar CH m 2H OCH m 3H 4 19 s 3H OCH s 3H OCH m 4H 2 NCH s 3H NCH ~ 1 75 m 4H 2 NCH 2 CH ~ 1 30 m 28H 2 CH t J = 7 2 Hz 6H 2 CH 3 ESI- MS m /z M - Br Molt-4 CA46 HELF Table 1 Anticancer activity IC 50 of emodin in vivio MTT cells /ml μl Compd 37 5% CO 2 24 h DMSO DMSO 1% 48 h 100 μl μl MTT 4 h μl DM- SO 10 min OD nm IC 50 against cancer line cells * IC 50 / μmol L - 1 CA46 Molt-4 HELF Emodin > > 50 9a + 9b > > 30 > 30 NT 11 > 30 > 30 NT 16a > 30 > 30 NT 16b > 30 > 30 NT 16c > 30 > 30 NT 20a b c * NT Not tested a + 9b a ~ 15c 16a ~ 16c 20a ~ 20c 6a 6b 9a 9b ~ PPA 180

7 1414 高等学校化学学报 Vol Scheme a ~ 21c 20a ~ 20c nm π-π * 2 3 Fig 1 MTT Molt-4 UV absorption spectra of compounds 1 a 5 b 8 c 9 d 10 e and 11 f CA C6 16a ~ 16c C a 9b 9 CA46 IC μmol /L 20a 20b 20c Molt-4 CA Dong L H Mechanistic Study of Emodin's Anti Cancer Effects on Human Liver Cancer HCCLM3 Cdl Line Sichuan University Chengdu 2007 HCCLM Wang X H Zhen Y S Chin J Cancer Li J Emodin Reverse Paclitaxel Resistance and Inhibits Invasive Activity of Paclitaxel Resistant Ovarian Cancer cells Shandong University Jinan Yan Z J Chen Y Jiang J H Xie G H Hu J S Chin J Urol Lown J W Sim S K Majumdar K C Chang R Y Biochem Biophys Res Commun Ross W A Glaubiger D L Kohn K W Biochim Biophys Acta Huang Q Lu G Shen H M Chung M C M Ong C N Med Res Rev Cha T L Qiu L Chen C T Wen Y Huang M C Cancer Res Deane N G Parker M A Beauchamp R D Surgery Fischer U Schulze-Osthoff K Cell Death Differ Wang C Wu X Chen M Duan W Sun L Yan M Zhang L Toxicology Huang Q Shen H M Ong C N Biochem Pharmacol

8 No 6 刘诚等 : 大黄素衍生物的合成及抗癌活性 Guo H C Bu H Q Luo J Wei W T Liu D L Chen H Tong H F Wang Z H Wu H Y Li H H Zuo M M Li W Lin S Z Int J Oncol Qiu B L Li J Chen C Chen Y Y Hu J D Yuan Y F Wang W F Chin J Med Chem Hsin L W Wang H P Kao P H Lee O Chen W R Chen H W Guh J H Chan Y L His C P Yang M S Li T K Lee C H Bioorg Med Chem Greenberg M M Hantosi Z Wiederholt C J Rithner C D Biochem Kotandeniya D Ganley B Gates K S Bioorg Med Chem Lett Graham J A Bruce F C Bruce C B Graeme J F William A D J Med Chem Lu Y Huang Z S Tan J H Ding Y Bu X Z An L K Ma L Fu L W Gu L Q Chin J Org Chem Wang W F Bai Z D Zhang F S Wang C H Yuan Y F Shao J W Eur J Med Chem Shao J W Zhang F S Bai Z D Wang C H Yuan Y F Wang W F Eur J Med Chem Tan J H Zhang Q X Huang Z S Chen Y Wang X D Gu L Q Wu J Y Eur J Med Chem Lackner B Popova Y Etzlstorfer C Smelcerovic A A Klampfl C W Falk H Monatsh Chem Chang J J Wang Y Zhang H Z Zhou C H Geng R X Ji Q G Chem J Chinese Universities Masao K Klgobumi T Chou T C Zbigniew D Jan K T Ross K Kyoichi A W J Med Chem Salama T A Lackner B Falk H Monatsh Chem Wang W F Zhang F S Zhao W N Bai Z D Yang H J Shao J W Yuan Y F Med Chem Lin S N Yang L H Tetrahedron Lett Lackner B Bretterbauer K Falk H Monatsh Chem Gaonkar S L Rai K M L Prabhuswamy B Eur J Med Chem Hisano T Ichikawa M Tsumoto K Tasaki M Chem Pharm Bull Czarny A Wilson W D Boykin D W J Heterocyclic Chem Bhatnagar I George M V Tetrahedron Synthesis and Anticancer Activity Evaluation of Derivatives of Emodin LIU Cheng 1 ZHENG Yan-Yan 1 HONG Fang 1 HU Jian-Da 2 ZHAO Wen-Na 1 YUAN Yao-Feng 1 SHAO Jing-Wei 1 WANG Wen-Feng 1* 1 College of Chemistry and Chemical Engineering Fuzhou University Fuzhou China 2 Union Xiehe Hospital of Fujian Medical University Fuzhou China Abstract In order to improve the anticancer activity of emodin seven emodin derivatives containing nitrogen heterocycle and three emodin derivatives containing quaternary ammonium salt were designed and synthesized by suitable modification at C6 position of emodin their structures were characterized by IR 1 H NMR and MS and their activities against leukemia cell line Molt-4 and lymphoma cell line CA46 in vitro were tested by MTT method Thereinto compounds 8 9a + 9b 20a 20b and 20c show higher anticancer activities than emodin which indicates that benzimidazole and quaternary ammonium salt are good pharmacophores for the anticancer activity of emodin We propose to introduce many such pharmacophores into emodin to improve the anticancer activity of emodin in further Keywords Emodin derivative Nitrogen heterocyclic Quaternary ammonium salt Anticancer activity ( Ed : P,H,N,K)

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