title: Synthesis of 5-methyl phenanthridium derivatives: a new class of human DOPA decarboxylase inhibitors.
abstract: DOPA decarboxylase (DDC) is responsible for the decarboxylation of l-DOPA and related aromatic amino acids and correlates closely with a number of clinical disorders. Sanguinarine, a natural quaternary benzophenanthridine alkaloid (QBA), was reported to be inhibitor of rat DDC and possessed a different inhibitory mechanism. In this study, several natural QBAs were assayed as human DDC inhibitors for the first time. A series of 5-methyl phenanthridium derivatives that contain the basic core structure of QBAs were also synthesized and evaluated as human DDC inhibitors. The title compounds still possessed DDC inhibitory potential. Among the synthesized compounds, 2-hydroxyl-8-methoxy-5-methylphenanthridinium chloride (11k) showed good inhibitory activity with an IC50 value of 0.12mM. Preliminary structure-activity relationship indicated that DDC inhibitory potential of 5-methyl phenanthridium derivatives correlated with the π-electro densities on CN double bond of iminium cation. The hydroxyl group on compound 11k possibly contributed to the formation of hydrogen bond between DDC and the inhibitor.
authors.affiliation: Pre-State Key Laboratory for Germplasm Innovation and Utilization of Crop, Hunan Agricultural University, Changsha, Hunan 410128, China; National Research Center of Engineering Technology for Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University, Changsha, Hunan 410128, China.
authors.forename: Pi
authors.initials: P
authors.lastname: Cheng
authors.affiliation: School of Pharmaceutical, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: School of Pharmaceutical, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China.
authors.forename: Zhixing
authors.initials: Z
authors.lastname: Qing
authors.affiliation: School of Pharmaceutical, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China.
authors.forename: Weisong
authors.initials: W
authors.lastname: Kang
authors.affiliation: National Research Center of Engineering Technology for Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University, Changsha, Hunan 410128, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Liu
authors.affiliation: Pre-State Key Laboratory for Germplasm Innovation and Utilization of Crop, Hunan Agricultural University, Changsha, Hunan 410128, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Pre-State Key Laboratory for Germplasm Innovation and Utilization of Crop, Hunan Agricultural University, Changsha, Hunan 410128, China. Electronic address: xiehongqi2006@126.com.
authors.forename: Hongqi
authors.initials: H
authors.lastname: Xie
authors.affiliation: Pre-State Key Laboratory for Germplasm Innovation and Utilization of Crop, Hunan Agricultural University, Changsha, Hunan 410128, China; National Research Center of Engineering Technology for Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University, Changsha, Hunan 410128, China; School of Pharmaceutical, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China. Electronic address: ginkgo@world-way.net.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zeng
mesh_terms: D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010617:Phenanthridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
chemical_list: D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D010617:Phenanthridines
keywords: Human DOPA decarboxylase; Inhibitor; Phenanthridium; Quaternary benzophenanthridine alkaloids; Synthesis