- Phenolic Lipids Derived from Cashew Nut Shell Liquid to Treat Metabolic Diseases
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Metabolic diseases are increasing at staggering rates globally. The peroxisome proliferator-activated receptors (PPARα/γ/δ) are fatty acid sensors that help mitigate imbalances between energy uptake and utilization. Herein, we report compounds derived from phenolic lipids present in cashew nut shell liquid (CNSL), an abundant waste byproduct, in an effort to create effective, accessible, and sustainable drugs. Derivatives of anacardic acid and cardanol were tested for PPAR activity in HEK293 cell co-transfection assays, primary hepatocytes, and 3T3-L1 adipocytes. In vivo studies using PPAR-expressing zebrafish embryos identified CNSL derivatives with varying tissue-specific activities. LDT409 (23) is an analogue of cardanol with partial agonist activity for PPARα and PPARγ. Pharmacokinetic profiling showed that 23 is orally bioavailable with a half-life of 4 h in mice. CNSL derivatives represent a sustainable source of selective PPAR modulators with balanced intermediate affinities (EC50 ~100 nM to 10 μM) that provide distinct and favorable gene activation profiles for the treatment of diabetes and obesity.
- Sahin, Cigdem,Magomedova, Lilia,Ferreira, Thais A. M.,Liu, Jiabao,Tiefenbach, Jens,Alves, Priscilla S.,Queiroz, Fellipe J. G.,Oliveira, Andressa S. De,Bhattacharyya, Mousumi,Grouleff, Julie,Nogueira, Patrícia C. N.,Silveira, Edilberto R.,Moreira, Daniel C.,Leite, José Roberto Souza De Almeida,Brand, Guilherme D.,Uehling, David,Poda, Gennady,Krause, Henry,Cummins, Carolyn L.,Romeiro, Luiz A. S.
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p. 1961 - 1978
(2022/02/14)
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- Synthesis and Evaluation of Ginkgolic Acid Derivatives as SUMOylation Inhibitors
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SUMOylation has emerged as an important post-translational modification that has been shown to modulate protein activity associated with various signaling pathways, and consequently, it has emerged as an important therapeutic target. While several natural products have been shown to inhibit enzymes involved in the SUMOylation process, there has been little progress toward the development of more selective and potent SUMOylation inhibitors. Ginkgolic acid was one of the first natural products discovered to inhibit the SUMO E1 enzyme. Despite its use to mechanistically investigate the SUMOylation process, ginkgolic acid also modulates other pathways as well. In this Letter, preliminary structure-activity relationships for ginkgolic acid as a SUMOylation inhibitor are presented.
- Brackett, Christopher M.,García-Casas, Ana,Castillo-Lluva, Sonia,Blagg, Brian S. J.
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p. 2221 - 2226
(2020/12/17)
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- Structure-inspired design of a sphingolipid mimic sphingosine-1-phosphate receptor agonist from a naturally occurring sphingomyelin synthase inhibitor
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Ginkgolic acid obtained as a sphingomyelin synthase inhibitor from a plant extract library inspired the concept of sphingolipid mimics. Ginkgolic acid-derived N-acyl anilines and ginkgolic acid 2-phosphate (GA2P) respectively mimic ceramide and sphingosine 1-phosphate (S1P) in structure and function. The GA2P-induced phosphorylation of ERK and internalization of S1P receptor 1 (S1P1) indicated potent agonist activity. Docking studies revealed that GA2P adopts a similar binding conformation to the bound ligand ML5, which is a strong antagonist of S1P1.
- Swamy, Mahadeva M. M.,Murai, Yuta,Ohno, Yusuke,Jojima, Keisuke,Kihara, Akio,Mitsutake, Susumu,Igarashi, Yasuyuki,Yu, Jian,Yao, Min,Suga, Yoshiko,Anetai, Masaki,Monde, Kenji
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supporting information
p. 12758 - 12761
(2018/12/01)
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- Synthesis, characterization and antimicrobial evaluation of (E)-N'-[(1-(2-methoxy-6-pentadecylbenzyl)-1H-1,2,3-triazol-4-yl]-methylene)benzohydrazide derivatives
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Anacardic acid (pentadecyl salicylic acid) is a phenolic constituent present in cashew nut shell liquid (Anacardium occidentale L.) and exhibits antimicrobial properties. The present paper describes the synthesis, characterization and antimicrobial evaluation of hydrazone derivatives of anacardic acid (9a-l) linked with 1,2,3-triazole ring. All the newly synthesized compounds were determined by 1H NMR, mass and IR spectroscopy. Compounds 9d, 9e, 9h, 9i and 9j exhibited strong antifungal activity against the tested fungal strains viz., A. Niger and C. albicans.
- Rambabu,Dubey,Ram,Balram
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p. 175 - 180
(2016/01/20)
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- Synthesis and antibacterial activity of anacardic acid derivatives
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New anacardic acid derivatives (6a -6u) were prepared from commercially available anacardic acid and tested for Gram positive and Gram negative activities. Most compounds were found to be active compared to ampicillin.
- Nallamillia, Subhakara Reddy,Kumara, V. Ravi,Himabindub,Rama,Aalapati, Srinivas Rao
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experimental part
p. 626 - 632
(2012/05/05)
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- Improved inhibition of the histone acetyltransferase PCAF by an anacardic acid derivative
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Several lines of evidence indicate that histone acetyltransferases (HATs) are novel drug targets for treatment of diseases like, for example, cancer and inflammation. The natural product anacardic acid is a starting point for development of small molecule inhibitors of the histone acetyltransferase (HAT) p300/CBP associated factor (PCAF). In order to optimize the inhibitory potency, a binding model for PCAF inhibition by anacardic acid was proposed and new anacardic acid derivatives were designed. Ten new derivatives were synthesized using a novel synthetic route. One compound showed a twofold improved inhibitory potency for the PCAF HAT activity and a twofold improved inhibition of histone acetylation in HEP G2 cells.
- Ghizzoni, Massimo,Boltjes, André,Graaf, Chris De,Haisma, Hidde J.,Dekker, Frank J.
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experimental part
p. 5826 - 5834
(2010/10/01)
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- COMPOUNDS CAPABLE OF ABSORBING ULTRAVIOLET RADIATION, COMPOSITIONS CONTAINING THEM AND PROCESSES FOR THEIR PREPARATION
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The molecules capable of absorbing ultraviolet radiation from the cashew nut shell liquid changes are the object of the present invention; it is also described the compositions responsible for protecting the surfaces and chemical processes for the referred molecules production.
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Page/Page column 28
(2008/06/13)
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- New application of triphosgene in a convenient synthesis of 3-aryl-1,3-benzoxazine-2,4-diones from anacardic acids
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In conjunction with a search program focused on utilization of cashew (Anacardium occidentale) nut shell liquid (CNSL) as starting material for the preparation of useful compounds, a convenient synthesis of novel series of 3-aryl-1, 3-benzoxazine-2, 4-diones was prepared from anacardic acids by using of the triphosgene.
- Sabioni Resck, Ines,dos Santos, Maria Lucilia,Soares Romeiro, Luiz Antonio
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p. 311 - 318
(2007/10/03)
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- SUBSTITUTED DIHYDROPYRIMIDINES, DIHYDROPYRIMIDONES AND DIHYDROPYRIMIDINETHIONES AS CALCIUM CHANNEL BLOCKERS
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The present invention is directed in part towards methods of modulating the function of calcium channels with pyrimidine-based compounds. In addition, the invention describes methods of preventing and treating calcium channel-related abnormal conditions in organisms with a compound identified by the invention. Furthermore, the invention pertains to pyrimidine-based compounds and pharmaceutical compositions comprising these compounds.
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- Synthesis and evaluation of a new class of nifedipine analogs with T-type calcium channel blocking activity
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We have synthesized a novel series of 18 dialkyl 1,4-dihydro-4-(2′alkoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5 pyddine dicarboxylates from anacardic acid, a natural compound found in cashew nut shells, and investigated their blocking action on L- and T-type calcium channels transiently expressed in tSA-201 cells. The IC50 values for L-type calcium channel block obtained with the series ranged from 1 to ~40 μM, with higher affinities being favored by increasing the size of the alkoxy group on the 4-phenyl ring and ester substituent in the 3,5 positions. A detailed analysis of the strongest L-type channel blocker of the series (PPK-12) revealed that block was poorly reversible and mediated an apparent speeding of the time course of inactivation. Moreover, in the presence of PPK-12, the midpoint of the steady state inactivation curve was shifted by 20 mV toward more hyperpolarized potentials, resulting in an increase in blocking efficacy at more depolarized holding potentials. Surprisingly, PPK-12 blocked T- and L-type calcium channels with similar affinities. One of the weakest L-type channel inhibitors (PPK-5) exhibited a T-type channel affinity that was similar to that seen with PPK-12, resulting in a 40-fold selectivity of PPK-5 for T- over L-type channels. Thus, dialkyl 1,4-dihydro-4-(2′alkoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5 pyridine dicarboxylates may serve as excellent candidates for the development of T-type calcium-channel specific blockers.
- Phani Kumar,Stotz, Stephanie C.,Paramashivappa,Beedle, Aaron M.,Zamponi, Gerald W.,Srinivasa Rao
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p. 649 - 658
(2007/10/03)
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- Synthesis of anacardic acids utilizing an annelation reaction of isoxazoles with ethyl acetoacetate
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Anacardic acids, 6-pentadecylsalicylic acid (1) and 6-[8(Z)- pentadecenyl]salicylic acid (2) were synthesized from isoxazoles by annelation reactions with ethyl acetoacetate.
- Satoh, Mitsuru,Takeuchi, Naoki,Fujita, Takeshi,Yamazaki, Katsuya,Tobinaga, Seisho
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p. 1501 - 1505
(2007/10/03)
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- Shortcut syntheses of naturally occurring 5-alkylresorcinols with DNA-cleaving properties
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Resorcinols such as 1-5 bearing long alkyl- or alkenyl substituents at the C-5 position, including bola-formed bis-resorcinol derivatives, have recently been isolated from natural sources and were shown to exhibit exceptional DNA-cleaving properties under oxidative conditions. Previous synthetic approaches to such compounds seem inappropriately lengthy with regard to their structural simplicity. Disclosed is a very flexible synthesis which assembles these targets from triflate 7 and well accessible alkenes, dienes, enynes, or dienynes, respectively, by means of a boron-mediated reaction manifold. As a typical example, hexadeca-1,15-dien-8-yne 11 is hydroborated with 9-H-9-BBN at all possible sites, the alkenyl borane entity of the resulting tris-borane 12 is selectively cleaved off to afford the desired (Z)-alkene group in a stereoselective manner, the remaining two terminal alkylboranes are treated with NaOMe, and the bis-borate complex 13 thus formed is finally used as the nucleophile for a palladium-catalyzed Suzuki cross-coupling reaction with triflate 7. This sequence is carried out in one pot and provides product 14 in 62% overall yield. Demethylation of 14 (and analogues) can be conveniently achieved by means of 9-iodo-9-BBN to afford the natural product 5. The efficiency and flexibility of this unprecedented approach which combines different features of classical and modern boron chemistry is further demonstrated by the synthesis of anacardic and ginkgolic acid derivatives.
- Fuerstner,Seidel
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p. 2332 - 2336
(2007/10/03)
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- Synthesis of Saturated Anacardic Acids, and Alkenyl and Alkynyl Analogues
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The C-alkylation of esters of 2-methoxy-6-methylbenzoic acid and of the 4-methyl isomers affords a route to homologous compounds including in the former case members of the natural anacardic acids from Anacardium occidentale and ω-alkynyl compounds suitable for synthesising other natural phenolic lipids or for structure/activity studies.
- Tyman, John H. P.,Visani, Naina
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p. 228 - 240
(2007/10/03)
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- Synthesis of Anacardic Acids
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The anacardic acids 1-11, isolated from various plants, were synthesized by a new general method.Reaction of the methyl alkynoates 12-18 with 1-methoxy-1,4-cyclohexadiene at 200 deg C afforded directly the methyl 2-methoxybenzoates 19-25 with long chain substituents in 6-position in 74-85percent yield.The dienophiles 12-16 were prepared by pyrolysis of the corresponding acylphosphoranes 26-30, the dienophiles 17 and 18 by methoxycarbonylation of the corresponding alkynes 31 and 32 via the hydroxy esters 33 and 34.Demethylation of 19-23 with AlI3 gave the methyl salicylates 35-39 which could be hydrolized to the anacardic acids 1-4 and 7.Hydrolysis of 24 and 25 provided the hydroxy acids 40 and 41, which were converted by treatment with CBr4/PPh3 into the acids 42 and 43 bearing bromoalkyl side chains.These were transformed into 44-47 by reaction with 1-hexynyllithium and 1-octynyllithium.Stereoselective hydrogenation of 44-47 gave 48-51 with (Z)-alkene side chains.In a similar approach 42 was converted into 52 and then into 53, which gave upon treatment with 1-pentynylmagnesium bromide or 1-heptynylmagnesium bromide the acids 54 and 55 with alkadiyne side chains.Stereoselective hydrogenation provided 56 and 57 with (Z,Z)-alkadiene side chains.The 2-methoxy group in 48-51, 56, 57 was demethylated by treatment with AlI3 to give the anacardic acids 5, 6, 8-11. - Keywords: Anacardic acids; Benzoates, methyl 6-alkyl-2-methoxy-; 2-Alkynoates, methyl; Aluminium triiodide, demethylation by treatment with
- Zehnter, Reinhard,Gerlach, Hans
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p. 2209 - 2220
(2007/10/03)
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- METHOD OF INHIBITING ALDOSE REDUCTASE IN DIABETIC HOSTS USING PHENOL DERIVATIVES
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The use of alkyl or alkenyl phenols or pharmaceutical acceptable salts thereof as aldose reductase inhibitors, and hence, as an agent for preventing or alleviating chronic diabetic complications.
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- Prostaglandin Synthetase Inhibitors from the African Medicinal Plant
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Two prostaglandin synthetase inhibitory anacardic acids were isolated from O. mucronata.The structures of these inhibitors were established by spectroscopic means.Efficient syntheses of these two via directive metallation were reported.
- Kubo, Isao,Kim, Mujo,Komatsu, Sakae,Yamagiwa, Yoshiro,Ohashi, Kinji,et al.
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p. 1101 - 1104
(2007/10/02)
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- SYNTHESES OF ANACARDIC ACIDS AND GINKGOIC ACID
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Syntheses of two anacardic acids , inhibitors of prostaglandin synthetase and of the growth of certain insects, and ginkgoic acid via directive metallation is reported.
- Yamagiwa, Yoshiro,Ohashi, Kinji,Sakamoto, Yoshitaka,Hirakawa, Shinji,Kamikawa, Tadao,Kubo, Isao
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p. 3387 - 3394
(2007/10/02)
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