Synthesis of 5-methyl phenanthridium derivatives: a new class of human DOPA decarboxylase inhibitors

Bioorg Med Chem Lett. 2014 Jun 15;24(12):2712-6. doi: 10.1016/j.bmcl.2014.04.047. Epub 2014 Apr 19.

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.

Keywords: Human DOPA decarboxylase; Inhibitor; Phenanthridium; Quaternary benzophenanthridine alkaloids; Synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aromatic Amino Acid Decarboxylase Inhibitors / chemical synthesis*
  • Aromatic Amino Acid Decarboxylase Inhibitors / chemistry
  • Aromatic Amino Acid Decarboxylase Inhibitors / pharmacology*
  • Enzyme Activation / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Phenanthridines / chemical synthesis*
  • Phenanthridines / chemistry
  • Phenanthridines / pharmacology*
  • Rats

Substances

  • Aromatic Amino Acid Decarboxylase Inhibitors
  • Phenanthridines