Basic & Clinical Pharmacology & Toxicology, 110, 122–132 Doi: 10.1111/j.1742-7843.2011.00833.x MiniReview Emerging Roles of Anacardic Acid and Its Derivatives: A Pharmacological Overview Mahadevappa Hemshekhar, Martin Sebastin Santhosh, Kempaiah Kemparaju and Kesturu S. Girish Department of Biochemistry, University of Mysore, Manasagangothri, Mysore, India (Received 1 July 2011; Accepted 9 November 2011) Abstract: Anacardic acid (AA) is a bioactive phytochemical found in nutshell of Anacardium occidentale. Chemically, it is a mixture of several closely related organic compounds, each consisting of salicylic acid substituted with an alkyl chain. The traditional Ayurveda depicts nutshell oil as a medicinal remedy for alexeritic, amebicidal, gingivitis, malaria and syphilitic ulcers. However, the enduring research and emerging evidence suggests that AA could be a potent target molecule with bactericide, fungicide, insecticide, anti-termite and molluscicide properties and as a therapeutic agent in the treatment of the most serious pathophysiological disorders like cancer, oxidative damage, inflammation and obesity. Furthermore, AA was found to be a common inhibitor of several clinically targeted enzymes such as NFjB kinase, his- tone acetyltransferase (HATs), lipoxygenase (LOX-1), xanthine oxidase, tyrosinase and ureases. In view of this, we have made an effort to summarize the ongoing research on the therapeutical role of AA and its derivatives. The current MiniReview sheds light on the pharmacological applications, toxicity and allergic responses associated with AA and its derivatives. Although the available records are promising, much more detailed investigations into the therapeutical prop- erties, particularly the anti-cancer and anti-inflammatory activities, are urgently needed. We hope the present MiniRe- view will attract and encourage further research on elucidating and appreciating the possible curative properties of AA and its derivatives in the management of multifactorial diseases. Plant medicines play a vital role in human health and consisting of a salicylic acid substituted with saturated or diseases. According to the WHO, in recent times, more than unsaturated alkyl chain that has 15–17 carbon. 80% of the world’s population in developing countries Outstandingly, AA claims a lion’s share in the medicinal depends primarily on herbal medicines for basic healthcare value of the nutshell as it offers a better protection against needs. The ancient ayurvedic preparations and usage have several pathophysiological disorders ranging from oxidative proven the healing abilities of plants, undoubtedly. Hence, a damage to cancer (Table 1). On the other hand, cardanol and large proportion of drugs used in modern medicine are either cardol are the phenolic components that are less effective in all directly isolated from plants or synthetically modified from a sorts of biological activity exhibited by AA. However, these are lead compound of natural origin. Medicinal plant extracts largely employed in the chemical industry in the preparation of and their isolated compounds are often used as an alterna- resins, coatings, frictional materials, surfactants and pigment tive for the drugs with associated complications in the treat- dispersants for water-based inks. Friction particles are made by ment of many disorders [1,2]. polymerizing the unsaturated side chain of cardanol, followed In the course, anacardic acid (AA) (fig. 1A) and its related by cross-polymerization with phenol to yield a cardanol- compounds from Anacardium occidentale (an angiosperm formaldehyde resin by a process analogous to the formation of belonging to the Anacardiaceae family) seed (Cashew nut- phenol-formaldehyde resin such as Bakelite. shell) have received great attention by the chemicobiology researchers and pharmaceutical companies. AA alone consti- Ethnopharmacology tutes about 90% of the cashew nutshell liquid (CNSL), and the remaining part is constituted by AA-related compounds Many parts of the Anacardium occidentale have been such as cardanol, cardol and 2-methyl cardol (fig. 1B–D) [3]. exploited for its medicinal value. The fruit juice and the nut- It is a yellow liquid partially miscible in alcohol and ether shell oil are both said to be folk remedies for cancerous but nearly immiscible in water [4,5]. Chemically, AA is a ulcers, elephantiasis and warts. The oily substance from peri- mixture of several closely related organic compounds each carp is used for cracks on the feet. Old leaves are applied to skin afflictions and burns. In the Gold Coast, the bark and leaves are used for sore gums and toothache. Decoction of the astringent bark is suggested for severe diarrhoea and Author for correspondence: K. S. Girish, Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysore-570 thrush. In India, bark is used in herbal tea for asthma, cold 006, India (fax 0821-2419622, e-mail [email protected]). and congestion and as an antidote for snake envenomations. Ó 2011 The Authors Basic & Clinical Pharmacology & Toxicology Ó 2011 Nordic Pharmacological Society MiniReview PHARMACOLOGICAL ROLES OF AA AND ITS DERIVATIVES 123 ABCDOH OH OH OH COOH H3C HO HO Anacardic acid Cardol Cardanol 2-methyl cardol E OHFG OH OH HOH COOH COOH COOH COOH C15:3 C15:2 C15:1 C12:0 IJKOH OH COOH COOH CF3 H H N O N O Cl N N OO H NO2 N H N N Hydrazone derivative Hydrazone derivative CTPB CF L 3 MNCOOH OH Cl O O HO COOH N H CH3CH2(CH2)15CH2CH(CH2)4CH3 CTB C12:1 C24:1 O PQ R EtOO N OH i-OO N EtOO C COOH NNO N 2 H CH2CH2(CH2)17CH3 Synthones Synthones Synthones C20:0 STUVO O CH3 CH3 MeO HN N EtO HN N N N O N N OH CH CH CH CH CH CH CH 2 2 3 3 2 2 3 CH CH (CH ) CH N CH2CH2(CH2)12CH3 2 2 2 12 3 EtO HN COOH S S O O OO N N N N N N CH2CH2CH3 CH CH (CH ) CH CH CH 2 2 2 14 3 3 3 CH2CH2(CH2)12CH3 C17:0 Benzamide derivative Benzamide derivative Benzamide derivative Fig. 1. Structures of anacardic acid and its derivatives. The seed oil is believed to be alexeritic and amebicidal and is Pharmacology and Medicine used to treat gingivitis, malaria and syphilitic ulcers. Tradi- tional Ayurveda recommends the fruit for cancer, oxidative Antioxidant activity. stress, anti-helminthic, aphrodisiac, ascites, haemoptysis, Cellular injury from ROS (reactive oxygen species) has been dysentery, fever, inappetence, leucoderma, piles and obsti- implicated in the development and progression of several dis- nate ulcers and hyperglycaemia. Sap from young leaves eases [6]. AA (fig. 1A) effectively prevents cell damage and budding fruits is considered fungicidal and insect induced by H2O2 because this can be converted to ROS, repellent [3,5]. hydroxyl radicals, in the presence of metal ions. AA acts as Ó 2011 The Authors Basic & Clinical Pharmacology & Toxicology Ó 2011 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 110, 122–132 124 M. HEMSHEKHAR ET AL. MiniReview Table 1. Pharmacological roles of AA and its derivatives. Compounds Pharmacological role Model used to test Dose Anacardic acid (C15:0) ROS generation inhibition 0.053 € 0.005 mM Xanthine oxidase inhibition 0.0043 € 0.0005 mM Anti-bacterial Propionibacterium acnes 0.0015 mg ⁄ mL Corynebacterium xerosis 0.0062 mg ⁄ mL S. aureus 0.025 mg ⁄ mL MSSA ATCC12598 0.0031–0.0062 mg ⁄ mL MRSA B. subtilis Zoosporicidal activity Aphanomyces cochlioides Anti-parasitic activity Colorado potato beetle larvae HATs inhibition 0.0085 mM p300 PCAF 0.005 mM Cytotoxicity 0.008 mM PfGCN5 HATs inhibition NFjB inhibition Anti-cancer activity Pituitary adenoma cells, melanoma cells Aurora kinase A activation Anti-obase activity Wistar rats Tyrosinase inhibition Mashroom tyrosinase 0.18 mg ⁄ mL Urease inhibition 0.12 mg ⁄ mL Selective metal ion chelation Anacardic acid (C15:1) LOX-15 inhibition Soybean lipoxygenase 0.05 mM Cytotoxicity HeLa cells 0.01 mM Anacardic acid (C15:2) Anti-bacterial Helicobacter pylori 0.2 mg ⁄ mL Anacardic acid (C15:3) Anti-bacterial, Molluscidal H. pylori, Snails 0.2 mg ⁄ mL activity Anacardic acid (C24:1) Anti-proliferation of ERa MCF-10A, MCF-7, MDA-MB-231 breast cancer cells Cardol (C12:0) Anti-bacterial H. pylori 0.2 mg ⁄ mL LOX-15 inhibition Soybean lipoxygenase 0.06 mM Cytotoxicity HeLa cells 0.01 mM N-isonicotinoyl-N’-8-[(2-carbohydroxy- Anti-bacterial Mycobacterium 4mg⁄ mL 3-hydroxy) phenyl] octanal hydrazone. smegmatis N-isonicotinoyl- N’-8-[(2-carbohydroxy- 5mg⁄ mL 3-hydroxy-6-nitro) phenyl] octanal hydrazone N-(4-chloro-3-trifluoromethyl-phenyl)- p300 activation 2-ethoxy-6-pentadecyl-benzamide N-(4-chloro-3-trifluoromethyl-phenyl) – 2-ethoxy-benzamide 2-isopropoxy-6-pentadecyl-N-pyridin-4- Cytotoxicity HeLa cells 11.02 mM ylbenzamide. 2-ethoxy-N-(3-nitrophenyl)-6- 13.55 mM pentadecylbenzamide. 2-ethoxy-6-pentadecyl-N-pyridin- 15.29 mM 4-ylbenzamide 6-n-pentadecyl salicylic acid Amidolytic activity sTF ⁄ VIIa 0.3–0.4 mmol ⁄ L GAPDH inhibition 0.028 mM 6-n-dodecylsalicylic acid 0.055 mM 6-n-heptadecylsalicylic acid Amidolytic activity sTF ⁄ VIIa 0.3–0.4 mmol ⁄ L 5-[2-Ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)- PDE5 inhibition 0.145 mM 6-pentadecylphenyl]-1,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one 5-[2-Methoxy-5-(4-methylpiperazin-1-ylsulfonyl)- 0.125 mM 6-pentadecylphenyl]-1,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7- one AA, anacardic acid; HATs, histone acetyltransferase. Ó 2011 The Authors Basic & Clinical Pharmacology & Toxicology Ó 2011 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 110, 122–132 MiniReview PHARMACOLOGICAL ROLES OF AA AND ITS DERIVATIVES 125 an antioxidant in multiple ways including inhibition of vari- AA also showed anti-bacterial activity against the strains of ous pro-oxidant enzymes involved in the production of ROS MSSA ATCC 12598 and MRSA with minimal inhibitory and by chelating the divalent metal ions. The high selectivity concentrations ranging from 0.0031 to 0.0062 mg ⁄ mL [14].