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GIOI THIEU ve COUMARIN
Introduction to Coumarins INTRODUCTION Coumarin is 5,6-benzo-2-pyrone and an important class of oxygen heterocycles The name comes from a French word “Coumarou” for the tonka been (Dipteryx odorata) It has a sweet odor, readily recognized as the scent of new-mown hay, and has been used in perfumes since 1882 Coumarin was first isolated in 1820 by Vogel1 in 1820 from the fruit of Dipteryx odorata Wild (Tonka been) of Munich; he mistook it for benzoic acid.1,2 Also in 1820, Nicholas Jean Baptiste Gaston Guibourt (1790-1867) of France independently isolated coumarin; he realized that it was not benzoic acid.3 In a subsequent essay that he read before the pharmacy section of the L'Académie royale de médecine, Guibourt named the new substance "coumarine".4 In 1835, the French pharmacist A Guillemette proved that Vogel and Guibourt had isolated the same substance.5 Coumarin was first synthesized in 1868 by the English chemist William Henry Perkin.6 More than 1350 coumarins have been isolated till 1997 The chemical structure of coumarin (2) can be looked upon as arising out of the fusion of a benzene ring to pyran-2-one (1), across the and th positions The systematic name is 2H-1-benzopyran-2-one.7 O O O O O O Figure-1 Structure of coumarin and atom numbering Introduction to Coumarins Many compounds containing coumarin moiety, exhibit useful and diverse biological activity and, in recent years, there has been a growing interest in their synthesis.8 Some of the coumarin derivatives have been found to be useful as dyes,9 CNS-stumulants,10 antibacterials,11,12 anticoagulants13,14 and in photochemotherapy, antitumor and anti-HIV therapy.15,16 Coumarins are widely distributed throughout the plant kingdom, with the vast majority carrying an oxygen substituent at the C-7 position 7-Hydroxycoumarin (umbelliferone) is often regarded as the parent (in a structural and biogenetic sense) of a large number of structurally more complex coumarins.17 Coumarins occur as secondary metabolites in the seeds, roots and leaves of many plant species such as coumarin along with its various derivatives occurs abundantly in plant kingdom such as Umbelliferae, Rutaceae, Leguminaceae, Otchidaceae, Asteraceae, Guttiferae, Melastomaceae, Thymelaceae and Solanaceae; their function is far from clear, although suggestions include plant growth regulators, fungistats, bacteriostats and , even, waste products.18 Synthetic coumarins are widely used as aroma chemicals because of their odour strength, tenacity, stability to alkali and relatively cheap price; applications include use as a sweetener and fixative (in perfume); fragrance enhancers (for natural essential oils); blenders (in soaps and detergents); aroma enhancers (in tobacco); and for imparting pleasant odours to industrial products.19 Introduction to Coumarins Classification Coumarins are classified based on the substitution in benzene and pyrone rings Natural coumarins are mainly classified into six types based on the chemical structure of the compounds A Simple coumarins with 5,6-benzene-2-pyrone skeleton with hydroxyl, alkoxy, alkyl substituents both in benzene ring and the pyrone ring ( Figure 2) O O H3CO O O HO Herniarin (7-Methoxycoumarin) Coumarin O O Umbelliferone (7-Hydroxycoumarin) OCH3 OCH3 HO H3CO O O Suberosin [6-(3-methylbut-2-enyl)-7-methoxy coumarins] H3CO O O O O Siderin (5-methyl-4,7-dimethoxycoumarin) (5-methyl-6-hydroxy-4-methoxycoumarin) OH HO O O O O Mammein O 2,3-dihydro-2-methylcyclopenta[c]chromen-4(1H)-one 4-n-propyl-5,7-dihydroxy-6-isopentenyl-8-isovalerylcoumarin Figure-2 Examples of Simple Coumarins B Furocoumarins containing linear or angular types with substituents on benzene nucleus or pyrone ring including dihydrofuranocoumarins are shown in Figure- 3 Introduction to Coumarins Linear furanocoumarins O O O O O O Psoralen Swietenocoumarin 2,3-dihydrofuro[3,2-g]chromen-7-one 2,3-dihydro-9-(2-methylprop-1-enyl)furo[3,2-g]chromen-7-one O O O Xylotenin 2,3-dihydro-6-(2-methylbut-3-en-2-yl)furo[3,2-g]chromen-7-one Linear Dihydro furanocoumarins HO O O O HO O O O Chapellin 2,3-dihydro-2-(2-hydroxypropan-2-yl) furo[3,2-g]chromen-7-one 2,3-dihydro-2-(2-hydroxypropan-2-yl)-6-(2-methyl but-3-en-2-yl)furo[3,2-g]chromen-7-one OH HO O O O Leptophyllin 2,3-dihydro-4-hydroxy-2-(2-hydroxypropan-2-yl)furo[3,2-g]chromen-7-one Angular furanocoumarins and their derivatives H3CO O O O O O O O O O Angelicin 2H-furo[2,3-h]chromen-2-one 4-methoxy-2H-furo[2,3-h] chromen-2-one 8-isopropyl-2H-furo[2,3-h]chromen-2-one Figure-3 Examples of Furanocoumarins C Pyranocoumarins containing linear or angular type with substituents on benzene and pyrone rings (Figure-4) Introduction to Coumarins Pyranocoumarins and their derivatives Linear pyranocoumarins: OCH3 OCH3 O O O O O O Clausarin Angular pyranocoumarins O O O O O O O O O O O Seselin Mesuangin Calophyllolide Figure-4 Examples of Pyranocoumarins D Bis- and Tri-coumarins (Figure-5) HO O O O O HO HO HO Edgeworoside Biscoumarin Figure-5 Examples of Bis-coumarins STRUCTURE AND REACTIVITY In coumarin, the aromatic nature of pyron-2-one ring system is disputable, because it shows some characteristic reactions of aliphatic compounds and also some reactions of aromatic compounds The complete aromatic nature of coumarin molecule can be only realized if O-CO functional group contributes Introduction to Coumarins two electrons to form 10π electron system This means that it should be a resonance hybrid, to which contribution from canonical form (4) is significant However, no evidence is found in the spectra of coumarin to suggest that contribution from betaine form (4) is considerable O O O O The IR absorption spectrum of coumarin shows an absorption band at 1710 cm-1 which is attributed to lactone carbonyl group but not a betaine form In the 1H NMR spectrum of coumarin,20 the signal due to protons of C3 and C4 appears in the region of 6.45 δ ppm and 7.80 δ ppm with coupling constant of 9.8 Hz These values are typical of cis-alkenes rather than any aryl ring 21 Finally the 13C NMR spectrum of coumarins22 are consistent with an essentially aliphatic heterocyclic ring The chemical shifts of C 2, C3, and C4 in coumarin are remarkably close to the values for the corresponding carbons in α-pyrone and are given as follows 13 C NMR DATA (∂ ppm) Compound α-Pyrone Coumarin C2 162.0 160.4 C3 116.7 116.4 C4 144.3 143.4 But coumarin does show aromatic character in its pattern of reactivity The carbonyl oxygen atom of coumarin can be alkylated by powerful agents to give stable pyrillium salts (5) Introduction to Coumarins Et3OBF4 O O O OEtBF4 Coumarin molecule is susceptible to electrophilic substitution 23 Sulphonation takes place initially in the benzene ring at C 6, to give (6), but under drastic conditions one more SO3H group can be introduced at C3 to give coumarin-3,6-disulphonic acid (7) HO3S HO3S Sulphonation O O O O SO3H Sulphonation O O As in case of simple pyrones the properties of heterocyclic ring of coumarin are greatly influenced by the presence of substituents In case of “Mills-Nixon effect”, Anantakrishanan24 discussed the reactivity of coumarin was rationalized based on the comparative studies of bromination and nitration of coumarin, naphthalene and benzene By considering the possible electron movement in coumarin molecule, Thakur and Shah25 predicted that in coumarin molecule C-6 and C-8 positions are the most reactive centers The electron movements in coumarin molecule at different positions are shown as follows Introduction to Coumarins O O A O O O O O O B D O O C Greater electron densities can be seen on C-6 and C-8 from the resonating structures B and C Out of these two C-6 seems to be more reactive position because of its proximity to the oxygen atom, similar to the reactivity of para-position of phenol Structure A though imparts more electron density to the C-3 position; the electrophilic substation at C-3 is less probable because of its closeness to the electron withdrawing carbonyl group In fact the π electron densities calculated by Song and Gorden 26 are quite close to the resonance picture of the molecule The structure (8) shows the distribution of π electron densities for the ground state of coumarin molecule 0.982 0.940 1.006 1.107 0.720 0.977 1.028 O O 1.801 1.955 By considering the structures B, C and D Bassingnan and Cogrossi27 have proposed structure (9) which is according to them represents the resonance hybrid structure of the coumarin molecule Introduction to Coumarins O O However the contributing structure of the type (D) does not have strong spectral evidences, the position of the carbonyl frequency in the IR spectrum (1710 cm-1) is more in favour of an enol lactone.28 Hence, the contribution from such type of structures is negligible and the resonating state (9) appears to be less probable Coumarin has been used as a powerful model in elucidating the electronic structures and photo reactivity of psoralenes The configurational analysis of coumarin by Song et al.29 in the ground state indicates some charge transfer delocalization extending to the ethylenic region The dipole movements of coumarin (4.82x10 -8 e.s.u) determined earlier by Rao 30 also indicates the similar delocalization Alkali Degradation: Coumarin on treatment with hot dilute aqueous alkali hydrolyses to yield sodium coumarinate by lactone ring opening and retaining the cis configuration of the cinnamic acid salt This stereochemistry enables to re-lactonize to coumarin on acidification with mineral acid or even a mild acid like carbonic acid (H2CO3) However when coumarin is subjected to prolonged treatment with hot dilute aqueous alkali the cis-coumarinate converts to the more stable trans-coumarinate (Figure- 6) Introduction to Coumarins The compounds (19) and (20) isolated from ethyl acetate extracts of fruits and stem bark of calophyllum dispar have been reported to exhibit significant cytotoxicity against KB cell lines.61 5.7-Dimethoxy coumarin derivative (21) was extracted from the roots of the Kenyan plant toddalia asiatica was traditionally used for the treatment of malarial disorders and as a novel antispasmodic compound.62 Furanocoumarin derivative (22) isolated from the ethanol extracts from fruits of cnidium monneri (china) was found to exhibit anti-oxidative activity in both lipid peroxidation and haemolysis assays.63 O OH OH O O O HO O O HO O O O O O O O O O O O 19 OH 22 21 20 Further investigation led to the discovery of compounds containing a 3-substituted-4-hydroxycoumarin moiety, such as warfarin (4)68 and phenprocoumon (23).69 However, compound (4) is weakly active against HIV-PR The phenprocoumon (23) is more active against the protease enzyme with an inhibition potential of μM The hydroxyl group on phenprocoumon (23) has the potential to hydrogen-bond with the catalytic aspartic residues, while the carbonyl group of the coumarin nucleus hydrogen-bonds with the Ile-50 residue of protease enzyme 17 Introduction to Coumarins OH O O Phenprocoumon 23 List of some of the biologically active and naturally occurring coumarins: O HO O HO O O O O OH O O 24 25 Scopoletin60 Daphxetin62 O H 26 Paniculal63 R HO O O O 27 Angustifolin64 O O O 28 7-ethoxy-3,4-dimethyl coumarin65 O O 29 Piloselloidam66 OH HO O HO HO O O O O 31 30 Seretin67 Piloselloidam70 32 Hortiline71 O O O O 33 Alloxanthoxyletin72 18 Introduction to Coumarins METABOLISM OF COUMARINS IN THE BIOLOGICAL SYSTEMS: Coumarin is rapidly and extensively absorbed after topical or oral administration to human subjects It undergoes very extensive metabolism along two major pathways, 7-hydroxylation and ring-opening to ortho-hydroxy phenyl acetaldehyde There are numerous minor metabolites, many of which are secondary products from the primary metabolites The relative extent of these two major pathways is highly variable between species Ring-opening predominates in rodents, while 7-hydroxylation is particularly evident in humans The absorption, distribution, metabolism and excretion of coumarin in humans have been reviewed.77,78 Toxicokinetic studies in humans have demonstrated that coumarin is rapidly absorbed from the gastrointestinal tract after oral administration and extensively metabolized by the liver in the first pass, with only 2–6% reaching the systemic circulation intact.79, 80, 81 The elimination of coumarin from the systemic circulation is rapid, the half-lives following intravenous doses of 0.125, 0.2 and 0.25 mg/kg bw being 1.82, 1.46 and 1.49 h [109, 88 and 89 min], respectively82 Coumarin is also extensively absorbed after dermal application In one study with human subjects, some 60% of a 2.0-mg dose applied for h was absorbed 45 The percutaneous absorption of coumarin has also been demonstrated in vitro with human skin.83, 84 19 Introduction to Coumarins The rapid excretion of coumarin, primarily as 7-hydroxycoumarin conjugates, in the urine of human subjects given coumarin orally suggests that there is little or no biliary excretion of coumarin metabolites in humans 85-90 Coumarin exhibits marked species differences in its metabolism 44, 77 The major primary pathways of coumarin metabolism are 7-hydroxylation or metabolism of the lactone ring by ring opening and cleavage at carbon atom to yield carbon dioxide The first step in the latter pathway is the formation of the unstable coumarin 3,4-epoxide which degrades spontaneously to form ortho-hydroxy phenyl acetaldehyde and may be subsequently converted to ortho-hydroxy phenyl ethanol and ortho-hydroxy phenyl acetic acid Coumarin may also be metabolized by hydroxylation to yield 3-, 4-, 5-, 6- or 8-hydroxycoumarin and 6,7-dihydroxycoumarin and, by opening of the lactone ring, to yield ortho-coumaric acid (ortho- hydroxyphenylcinnamic acid) and ortho-hydroxyphenylpropionic acid 90-94 The pathways of coumarin metabolism are shown in Figure 20 Introduction to Coumarins CH2CH2COOH OH o-hydroxyphenyl propionicacid OH CH2CHOHCOOH CHCOOH O O 3-Hydroxycoumarin OH o-coumaricacid OH o-hydroxyphenyl lacticacid CO2 O OH O Coumarin O O 4-Hydroxycoumarin O OH CH2CHO CH2COOH OH O CO O coumarin-3,4-epoxide o-hydroxyphenyl acetaldehyde GSH OH o-hydroxyphenyl aceticacid OH HO CH2CH2OH SG O O OHO 7-Hydroxycoumarin OH 5,6,8-Hydroxycoumarin O Glicuronic acid and sulfate conjugates HO OH O O o-hydroxyphenyl 4-hidroxydihydroethan-1-ol coumarin glutathione conjugate coumarin-3-mercapturic acid HO O O 6,7-Hydroxycoumarin Figure The major pathway of coumarin metabolism in most human subjects is 7-hydroxylation to form 7-hydroxycoumarin, which is excreted in the urine as both glucuronic acid and sulfate conjugates Coumarin 7-hydroxylation activity exhibits a Gaussian distribution in Caucasian populations86, 88 , but some individuals are deficient in this activity Hadidi et al.88 gave members of a family mg coumarin orally and collected their urine for h One subject excreted 41% of dose) and 4–10% as ortho-hydroxyphenylacetic acid Oscarson et al.96 refer to two individuals (among a population of two hundred) who were totally deficient in 7-hydroxycoumarin excretion after an oral dose of mg coumarin CYP2A6 (cytochrome P450 2A6) has been purified from human liver and CYP2A6 cDNA expression systems are 21 Introduction to Coumarins available Many studies have demonstrated marked interindividual variation in the levels of hepatic CYP2A6 protein, mRNA and associated microsomal coumarin 7-hydroxylase activity.44, 78 The role of CYP2A6 in the metabolism of coumarin by human liver microsomes has been confirmed by Sai et al,.97 who found that a monoclonal antibody to CYP2A6 inhibited coumarin 7-hydroxylation by more than 94% The marked interindividual variation in coumarin metabolism to 7-hydroxycoumarin has led to studies to evaluate whether a genetic polymorphism exists in human CYP2A6 The occurrence of variant alleles in the human CYP2A6 gene was shown by Fernandez-Salguero et al.98, these were designated CYP2A6*1 (wild type), CYP2A6*2 and CYP2A6*3 CYP2A6*2 has a point mutation in codon 160 and the resulting protein product is unable to 7-hydroxylate coumarin.95, 98 The functional significance of the rare CYP2A6*3 allele is uncertain The population frequency of these mutant alleles is uncertain at present; initial claims that the incidence of the CYP2A6*2 allele is 4–17% of European populations98 have been challenged by Oscarson et al.96 who found the incidence to be 1–3% These authors highlighted methodological uncertainties in polymerase chain reaction based genotyping procedures Establishment of the significance of the genetic polymorphism in CYP2A6 must await definitive genotyping and phenotyping procedures While 7-hydroxylation is the major metabolic pathway of coumarin in most subjects, humans also convert coumarin to ortho-hydroxy phenyl acetic acid Shilling et al (1969) reported that after an oral dose of 200 mg coumarin per subject, while 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trans-coumarinate... to Coumarins METABOLISM OF COUMARINS IN THE BIOLOGICAL SYSTEMS: Coumarin is rapidly and extensively absorbed after topical or oral administration to human subjects It undergoes very extensive... Furanocoumarins C Pyranocoumarins containing linear or angular type with substituents on benzene and pyrone rings (Figure-4) Introduction to Coumarins Pyranocoumarins and their derivatives Linear