Anemonin

Anemonin is a tri-spirocyclic dibutenolide natural product found in members of the buttercup family (Ranunculaceae) such as Ranunculus bulbosus, R. ficaria, R. sardous, R. sceleratus, and Clematis hirsutissima. Originally isolated in 1792 by M. Heyer, It is the dimerization product of the toxin protoanemonin. One of the likely active agents in plants used in Chinese medicine as an anti-inflammatory and Native American medicine as a horse stimulant, its unique biological properties give it pharmaceutical potential as an anti-inflammatory and cosmetic agent.

Biosynthetic origins
Anemonin is a homodimer formed from two protoanemonin subunits. Protoanemonin is formed from the enzymatic cleavage of ranunculin upon crushing plant matter. When a plant from this family is injured, a β-glucosidase cleaves ranunculin, liberating protoanemonin from glucose as a defense mechanism. This butenolide readily dimerizes in aqueous media to form a single cyclodimer.

Chemical structure and proposed mechanism of formation
Despite multiple possibilities, X-ray crystallography of the solid anemonin has revealed that the two rings exclusively possess a trans relationship. The central cyclobutane ring was found to be bent to a dihedral angle of 152°. NMR spectroscopy reveals that the central ring is also twisted 9-11°.

The highly selective formation of the head-to-head dimer has been rationalized through the stability of a proposed diradical intermediate; the resulting radicals after an initial carbon-carbon bond forming step are delocalized through the α,β-unsaturated system. These proposed radicals could also be stabilized through the captodative effect, as they are situated between the enone and sp3-hybridized oxygen of the butenolides.

Destabilizing dipole-dipole interactions are proposed to disfavor the transition state where the two butenolide rings adopt a cis conformation, leading to selectivity of a trans relationship between the lactone rings.

The formation of anemonin from protoanemonin is most likely a photochemical process. When Kataoka et. al compared the dimerization of protoanemonin in the presence and absence of radiation from a mercury lamp, they found a 75% yield with radiation and a very poor yield without radiation. It is not mentioned whether light was excluded from this control reaction; the low yield of anemonin may arise from visible light-mediated dimerization of protoanemonin.

Pharmaceutical potential
Anemonin possesses anti-inflammatory properties rather than the vesicant properties of its parent monomer. Numerous studies have demonstrated anemonin’s potential in treating ulcerative colitis, cerebral ischemia, and arthritis. Its activity against LPS-related inflammation and nitric oxide production contribute to its pharmaceutical potential. Anemonin also displays inhibition of melanin production in human melanocytes with mild cytotoxicity.

Given its skin permeability in ethanolic solutions and its anti-inflammatory and anti-pigmentation properties, anemonin may be a good candidate for topical formulations as arthritis medications or cosmetics. An extraction method with the potential for industrial-scale preparations of anemonin may provide inroads to drug development.