Anemonin is a tri-spirocyclic di
butenolidenatural product found in members of the buttercup family (
Ranunculaceae) such as R. bulbosus, R. ficaria, R. sardous, R. sceleratus,[2] and C. hirsutissima.[3] Originally isolated in 1792 by M. Heyer,[4] It is the
dimerization product of the
toxinprotoanemonin.[5] One of the likely active agents in plants used in Chinese medicine as an anti-inflammatory[6] and Native American medicine as a horse stimulant,[3] its unique biological properties give it pharmaceutical potential as an anti-inflammatory and cosmetic agent.
Biosynthetic Origins
Protoanemonin
Ranunculin
Anemonin is a
homodimer formed from two protoanemonin subunits. Protoanemonin is formed from the enzymatic cleavage of
ranunculin upon crushing plant matter.[4] When a plant from this family is injured, a β-glucosidase cleaves ranunculin, liberating protoanemonin from glucose as a defense mechanism.[7] This butenolide readily dimerizes in aqueous media to form a single cyclodimer.[4]
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.[8] 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°.[9]
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.[4] 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.[4]
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.[10]
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,[11]cerebral ischemia,[12] and
arthritis.[13][14] Its activity against
LPS-related inflammation[13][15] and
nitric oxide production[16][6] contribute to its pharmaceutical potential. Anemonin also displays inhibition of
melanin production in human
melanocytes with mild cytotoxicity.[17]
Given its skin permeability in ethanolic solutions[18] 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.[19]
^
abKern JR, Cardellina JH (July 1983). "Native American medicinal plants. Anemonin from the horse stimulant Clematis hirsutissima". Journal of Ethnopharmacology. 8 (1): 121–123.
doi:
10.1016/0378-8741(83)90093-4.
PMID6632934.
^
abcdeMoriarty RM, Romain CR, Karle IL, Karle J (July 1965). "The Structure of Anemonin". Journal of the American Chemical Society. 87 (14): 3251–3252.
doi:
10.1021/ja01092a047.
ISSN0002-7863.
^
abDuan H, Zhang Y, Xu J, Qiao J, Suo Z, Hu G, Mu X (April 2006). "Effect of anemonin on NO, ET-1 and ICAM-1 production in rat intestinal microvascular endothelial cells". Journal of Ethnopharmacology. 104 (3): 362–366.
doi:
10.1016/j.jep.2005.09.034.
PMID16257161.
^Lustig E, Moriarty RM (July 1965). "The Estimation of the Angle of Twist for a Cyclobutane Derivative by Nuclear Magnetic Resonance". Journal of the American Chemical Society. 87 (14): 3252–3253.
doi:
10.1021/ja01092a048.
ISSN0002-7863.
^Lee TH, Huang NK, Lai TC, Yang AT, Wang GJ (March 2008). "Anemonin, from Clematis crassifolia, potent and selective inducible nitric oxide synthase inhibitor". Journal of Ethnopharmacology. 116 (3): 518–527.
doi:
10.1016/j.jep.2007.12.019.
PMID18281171.
^Huang YH, Lee TH, Chan KJ, Hsu FL, Wu YC, Lee MH (February 2008). "Anemonin is a natural bioactive compound that can regulate tyrosinase-related proteins and mRNA in human melanocytes". Journal of Dermatological Science. 49 (2): 115–123.
doi:
10.1016/j.jdermsci.2007.07.008.
PMID17766092.