Synthesis and Structure-Activity Relationships of a Series of Aporphine Derivatives with Antiarrhythmic Activities and Acute Toxicity
Some aporphine alkaloids, such as crebanine, were found to present arrhythmic activity and also higher toxicity. A series of derivatives were synthesized by using three kinds of aporphine alkaloids (crebanine, isocorydine, and stephanine) as lead compounds. Chemical methods, including ring-opening r...
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MDPI AG
2016-11-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/21/12/1555 |
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| author | Hui Wang Xin Cheng Shujun Kong Zixian Yang Hongmei Wang Qiuyan Huang Jingyu Li Cheng Chen Yunshu Ma |
| author_facet | Hui Wang Xin Cheng Shujun Kong Zixian Yang Hongmei Wang Qiuyan Huang Jingyu Li Cheng Chen Yunshu Ma |
| author_sort | Hui Wang |
| collection | DOAJ |
| description | Some aporphine alkaloids, such as crebanine, were found to present arrhythmic activity and also higher toxicity. A series of derivatives were synthesized by using three kinds of aporphine alkaloids (crebanine, isocorydine, and stephanine) as lead compounds. Chemical methods, including ring-opening reaction, bromination, methylation, acetylation, quaternization, and dehydrogenation, were adopted. Nineteen target derivatives were evaluated for their antiarrhythmic potential in the mouse model of ventricular fibrillation (VF), induced by CHCl3, and five of the derivatives were investigated further in the rat model of arrhythmia, induced by BaCl2. Meanwhile, preliminary structure-activity/toxicity relationship analyses were carried out. Significantly, N-acetamidesecocrebanine (1d), three bromo-substituted products of crebanine (2a, 2b, 2c), N-methylcrebanine (2d), and dehydrostephanine (4a) displayed antiarrhythmic effects in the CHCl3-induced model. Among them, 7.5 mg/kg of 2b was able to significantly reduce the incidence of VF induced by CHCl3 (p < 0.05), increase the number of rats that resumed sinus rhythm from arrhythmia, induced by BaCl2 (p < 0.01), and the number of rats that maintained sinus rhythm for more than 20 min (p < 0.01). Therefore, 2b showed remarkably higher antiarrhythmic activity and a lower toxicity (LD50 = 59.62 mg/kg, mice), simultaneously, indicating that 2b could be considered as a promising candidate in the treatment of arrhythmia. Structural-activity analysis suggested that variationsin antiarrhythmic efficacy and toxicity of aporphines were related to the C-1,C-2-methylenedioxy group on ring A, restricted ring B structural conformation, N-quaternization of ring B, levoduction of 6a in ring C, and the 8-, 9-, 10-methoxy groups on ring D on the skeleton. |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-12T05:31:48Z |
| publishDate | 2016-11-01 |
| publisher | MDPI AG |
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| series | Molecules |
| spelling | doaj.art-eb7b2db10477435ea894104bef37104b2022-12-22T03:46:04ZengMDPI AGMolecules1420-30492016-11-012112155510.3390/molecules21121555molecules21121555Synthesis and Structure-Activity Relationships of a Series of Aporphine Derivatives with Antiarrhythmic Activities and Acute ToxicityHui Wang0Xin Cheng1Shujun Kong2Zixian Yang3Hongmei Wang4Qiuyan Huang5Jingyu Li6Cheng Chen7Yunshu Ma8Department of Pharmaceutics Science, School of Chinese Materia Medica, Yunnan University of Traditional Chinese Medicine, 1076#, Yuhua road, Chenggong, Kunming 650000, ChinaDepartment of Pharmaceutics Science, School of Chinese Materia Medica, Yunnan University of Traditional Chinese Medicine, 1076#, Yuhua road, Chenggong, Kunming 650000, ChinaDepartment of Pharmaceutics Science, School of Chinese Materia Medica, Yunnan University of Traditional Chinese Medicine, 1076#, Yuhua road, Chenggong, Kunming 650000, ChinaDepartment of Pharmaceutics Science, School of Chinese Materia Medica, Yunnan University of Traditional Chinese Medicine, 1076#, Yuhua road, Chenggong, Kunming 650000, ChinaDepartment of Pharmaceutics Science, School of Chinese Materia Medica, Yunnan University of Traditional Chinese Medicine, 1076#, Yuhua road, Chenggong, Kunming 650000, ChinaDepartment of Pharmaceutics Science, School of Chinese Materia Medica, Yunnan University of Traditional Chinese Medicine, 1076#, Yuhua road, Chenggong, Kunming 650000, ChinaDepartment of Pharmaceutics Science, School of Chinese Materia Medica, Yunnan University of Traditional Chinese Medicine, 1076#, Yuhua road, Chenggong, Kunming 650000, ChinaDepartment of Pharmaceutics Science, School of Chinese Materia Medica, Yunnan University of Traditional Chinese Medicine, 1076#, Yuhua road, Chenggong, Kunming 650000, ChinaDepartment of Pharmaceutics Science, School of Chinese Materia Medica, Yunnan University of Traditional Chinese Medicine, 1076#, Yuhua road, Chenggong, Kunming 650000, ChinaSome aporphine alkaloids, such as crebanine, were found to present arrhythmic activity and also higher toxicity. A series of derivatives were synthesized by using three kinds of aporphine alkaloids (crebanine, isocorydine, and stephanine) as lead compounds. Chemical methods, including ring-opening reaction, bromination, methylation, acetylation, quaternization, and dehydrogenation, were adopted. Nineteen target derivatives were evaluated for their antiarrhythmic potential in the mouse model of ventricular fibrillation (VF), induced by CHCl3, and five of the derivatives were investigated further in the rat model of arrhythmia, induced by BaCl2. Meanwhile, preliminary structure-activity/toxicity relationship analyses were carried out. Significantly, N-acetamidesecocrebanine (1d), three bromo-substituted products of crebanine (2a, 2b, 2c), N-methylcrebanine (2d), and dehydrostephanine (4a) displayed antiarrhythmic effects in the CHCl3-induced model. Among them, 7.5 mg/kg of 2b was able to significantly reduce the incidence of VF induced by CHCl3 (p < 0.05), increase the number of rats that resumed sinus rhythm from arrhythmia, induced by BaCl2 (p < 0.01), and the number of rats that maintained sinus rhythm for more than 20 min (p < 0.01). Therefore, 2b showed remarkably higher antiarrhythmic activity and a lower toxicity (LD50 = 59.62 mg/kg, mice), simultaneously, indicating that 2b could be considered as a promising candidate in the treatment of arrhythmia. Structural-activity analysis suggested that variationsin antiarrhythmic efficacy and toxicity of aporphines were related to the C-1,C-2-methylenedioxy group on ring A, restricted ring B structural conformation, N-quaternization of ring B, levoduction of 6a in ring C, and the 8-, 9-, 10-methoxy groups on ring D on the skeleton.http://www.mdpi.com/1420-3049/21/12/1555aporphine derivativesantiarrhythmia10,11-dibromocrebanine3-bromocrebaninecrebaninestephanine |
| spellingShingle | Hui Wang Xin Cheng Shujun Kong Zixian Yang Hongmei Wang Qiuyan Huang Jingyu Li Cheng Chen Yunshu Ma Synthesis and Structure-Activity Relationships of a Series of Aporphine Derivatives with Antiarrhythmic Activities and Acute Toxicity Molecules aporphine derivatives antiarrhythmia 10,11-dibromocrebanine 3-bromocrebanine crebanine stephanine |
| title | Synthesis and Structure-Activity Relationships of a Series of Aporphine Derivatives with Antiarrhythmic Activities and Acute Toxicity |
| title_full | Synthesis and Structure-Activity Relationships of a Series of Aporphine Derivatives with Antiarrhythmic Activities and Acute Toxicity |
| title_fullStr | Synthesis and Structure-Activity Relationships of a Series of Aporphine Derivatives with Antiarrhythmic Activities and Acute Toxicity |
| title_full_unstemmed | Synthesis and Structure-Activity Relationships of a Series of Aporphine Derivatives with Antiarrhythmic Activities and Acute Toxicity |
| title_short | Synthesis and Structure-Activity Relationships of a Series of Aporphine Derivatives with Antiarrhythmic Activities and Acute Toxicity |
| title_sort | synthesis and structure activity relationships of a series of aporphine derivatives with antiarrhythmic activities and acute toxicity |
| topic | aporphine derivatives antiarrhythmia 10,11-dibromocrebanine 3-bromocrebanine crebanine stephanine |
| url | http://www.mdpi.com/1420-3049/21/12/1555 |
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