Cytotoxic Amides from Fruits of Kawakawa, Macropiper excelsum

Abstract

Cytotoxic amides have been isolated from the fruits of the endemic New Zealand medicinal plant kawakawa, Macropiper excelsum (Piperaceae). The main amide was piperchabamide A and this is the first report of this rare compound outside the genus Piper. Eleven other amides were purified including two new compounds with the unusual 3,4-dihydro-1(2H)-pyridinyl group. The new compounds were fully characterized by 2D NMR spectroscopy, which showed a slow exchange between two rotamers about the amide bond, and they were chemically synthesized. In view of the antitumor activity of the related piperlongumine, all of these amides plus four synthetic analogs were tested for cytotoxicity. The most active was the piperine homolog piperdardine, with an IC50 of 14 µM against HT 29 colon cancer cells.

Exploring the Chemical Space of Kawakawa Leaf (Piper excelsum)

“…A further 262 features were annotated by spectral matching to reference spectra using MS-DIAL with scores >0.85. Compounds previously identified in P. excelsum and other Piper species were well represented, including phenylpropanoids, alkaloids, amides, flavonoids and lignans [ 4 , 5 , 19 , 20 , 21 ]. Examples include dihydropiperlonguminine 34 , myristicin 45 , vitexin 7 , vitexin-O-glucoside 4 , cinnamoyl piperidine 26 and cinnamoyl piperideine 16 [ 5 ], dimethoxycinnamoyl piperidine 22 [ 22 ] and piperanine 42 [ 19 ].…”

“…Compounds previously identified in P. excelsum and other Piper species were well represented, including phenylpropanoids, alkaloids, amides, flavonoids and lignans [ 4 , 5 , 19 , 20 , 21 ]. Examples include dihydropiperlonguminine 34 , myristicin 45 , vitexin 7 , vitexin-O-glucoside 4 , cinnamoyl piperidine 26 and cinnamoyl piperideine 16 [ 5 ], dimethoxycinnamoyl piperidine 22 [ 22 ] and piperanine 42 [ 19 ]. Features annotated as apiole and piperlongumine did not match the retention time and mass spectra of those standards.…”

Acute Effects of Kawakawa (Piper excelsum) Intake on Postprandial Glycemic and Insulinaemic Response in a Healthy Population

“…For example, isovitexin and vitexin present in mistletoe fig ( Ficus deltoidea) have been reported to affect glucose metabolism by enhancing GLUT 4 receptor activity [9]. A recent in vitro study observed that piperine-related compounds from kawakawa fruit increased glucose uptake and decreased fatty acid uptake in differentiated intestinal Caco-2 cells [7]. Additionally, kawakawa has a complex chemistry, and there is likely an additive or synergistic effect between these compounds.…”

“…Chemical profiling of kawakawa vegetative tissues and kawakawa tea extracts has identified a complex mixture of secondary metabolites, many of which are associated with biological activity [4,5]. Foremost amongst these are lignans including (+)-excelsin and (+) diayangambin [6]; several amides including piperine, dihydropiperlonguminine, pellitorin and fagaramide [7]; the phenylpropanoids myristicin and elemicin; the flavone glycoside vitexin; and terpenoids such as α-pinene and camphene [4].…”