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Revision as of 08:00, 2 September 2011 editCheMoBot (talk | contribs)Bots141,565 edits Updating {{chembox}} (no changed fields - added verified revid - updated 'DrugBank_Ref', 'UNII_Ref', 'ChEMBL_Ref') per Chem/Drugbox validation (report errors or bugs)← Previous edit Latest revision as of 10:02, 9 December 2022 edit undoAlyInWikiWonderland (talk | contribs)Autopatrolled, Extended confirmed users81,771 editsNo edit summary 
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{{distinguish|bergamotene}}
{{chembox {{chembox
| Watchedfields = changed
| verifiedrevid = 448004797 | verifiedrevid = 448005625
| ImageFile = bergamottin.png | ImageFile = bergamottin.svg
| ImageSize = | ImageSize = 220
⚫ | IUPACName = (E)-4-- 7H-furobenzopyran-7-one
| ImageAlt = Skeletal formula of bergamottin
⚫ | OtherNames = Bergamotine<br>5-Geranoxypsoralen
| ImageFile1 = Bergamottin-3D-balls.png
⚫ | Section1 = {{Chembox Identifiers
| ImageSize1 = 240
| ImageAlt1 = Ball-and-stick model of the bergamottin molecule
⚫ | PIN = 4-{oxy}-7''H''-furobenzopyran-7-one
⚫ | OtherNames = Bergamotine<br />5-Geranoxypsoralen
⚫ |Section1={{Chembox Identifiers
| Abbreviations = | Abbreviations =
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 7380-40-7 | CASNo = 7380-40-7
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = JMU611YFRB
| EINECS = | EINECS =
| PubChem = 5471349 | PubChem = 5471349
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| ChEMBL = 1078442 | ChEMBL = 1078442
| SMILES = CC(=CCC/C(=C/COC1=C2C=CC(=O)OC2=CC3=C1C=CO3)/C)C | SMILES = CC(=CCC/C(=C/COC1=C2C=CC(=O)OC2=CC3=C1C=CO3)/C)C
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4581520 | ChemSpiderID = 4581520
| InChI = 1/C21H22O4/c1-14(2)5-4-6-15(3)9-11-24-21-16-7-8-20(22)25-19(16)13-18-17(21)10-12-23-18/h5,7-10,12-13H,4,6,11H2,1-3H3/b15-9+ | InChI = 1/C21H22O4/c1-14(2)5-4-6-15(3)9-11-24-21-16-7-8-20(22)25-19(16)13-18-17(21)10-12-23-18/h5,7-10,12-13H,4,6,11H2,1-3H3/b15-9+
| InChIKey = DBMJZOMNXBSRED-OQLLNIDSBR | InChIKey = DBMJZOMNXBSRED-OQLLNIDSBR
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C21H22O4/c1-14(2)5-4-6-15(3)9-11-24-21-16-7-8-20(22)25-19(16)13-18-17(21)10-12-23-18/h5,7-10,12-13H,4,6,11H2,1-3H3/b15-9+ | StdInChI = 1S/C21H22O4/c1-14(2)5-4-6-15(3)9-11-24-21-16-7-8-20(22)25-19(16)13-18-17(21)10-12-23-18/h5,7-10,12-13H,4,6,11H2,1-3H3/b15-9+
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = DBMJZOMNXBSRED-OQLLNIDSSA-N | StdInChIKey = DBMJZOMNXBSRED-OQLLNIDSSA-N
| RTECS = | RTECS =
Line 27: Line 36:
| KEGG_Ref = {{keggcite|correct|kegg}} | KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = | KEGG =
}}
| ATCCode_prefix =
⚫ |Section2={{Chembox Properties
| ATCCode_suffix =
| C=21 | H=22 | O=4
| ATC_Supplemental =}}
⚫ | Section2 = {{Chembox Properties
| Formula = C<sub>21</sub>H<sub>22</sub>O<sub>4</sub>
| MolarMass = 338.397 g/mol
| ExactMass = 338.151809
| Appearance = | Appearance =
| Density = | Density =
| MeltingPt = 55-56 °C | MeltingPtC = 55 to 56
| Melting_notes = | MeltingPt_notes =
| BoilingPt = | BoilingPt =
| Boiling_notes = | BoilingPt_notes =
| Solubility = | Solubility =
| SolubleOther = | SolubleOther =
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| pKa = | pKa =
| pKb = }} | pKb = }}
| Section7 = {{Chembox Hazards |Section7={{Chembox Hazards
| EUClass =
| EUIndex =
| MainHazards = | MainHazards =
| NFPA-H = | NFPA-H =
| NFPA-F = | NFPA-F =
| NFPA-R = | NFPA-R =
| NFPA-O = | NFPA-S =
| RPhrases =
| SPhrases =
| RSPhrases =
| FlashPt = | FlashPt =
| Autoignition = | AutoignitionPt =
| ExploLimits = | ExploLimits =
| PEL = }} | PEL = }}
}} }}


'''Bergamottin''' ('''5-geranoxypsoralen''') is a natural ] found in the pulp of ]s and ]s.<ref name="Dugrand-Judek et al. 2015">{{cite journal |last1=Dugrand-Judek |first1=Audray |last2=Olry |first2=Alexandre |last3=Hehn |first3=Alain |last4=Costantino |first4=Gilles |last5=Ollitrault |first5=Patrick |last6=Froelicher |first6=Yann |last7=Bourgaud |first7=Frédéric |title=The Distribution of Coumarins and Furanocoumarins in ''Citrus'' Species Closely Matches ''Citrus'' Phylogeny and Reflects the Organization of Biosynthetic Pathways |journal=PLOS ONE |date=November 2015 |volume=10 |issue=11 |page=e0142757 |doi=10.1371/journal.pone.0142757 |pmid=26558757 |pmc=4641707|bibcode=2015PLoSO..1042757D |doi-access=free }}</ref> It is also found in the peel and pulp of the ], from which it was first isolated and from which its name is derived.
'''Bergamottin''' is a natural ] found principally in ]. It is also found in the oil of ], from which it was first isolated and from which its name is derived. To a lesser extent, bergamottin is also present in the ]s of other ] fruits. Along with the chemically related compound 6’,7’-dihydroxybergamottin, it is believed to be responsible for the ] in which the consumption of the juice affects the metabolism of a variety of pharmaceutical drugs.<ref>{{cite journal | author = David G. Bailey, J. Malcolm, O. Arnold, J. David Spence | title = Grapefruit juice-drug interactions| journal = Br J Clin Pharmacol | year = 1998| volume = 46 | pages = 101–110 | doi = 10.1046/j.1365-2125.1998.00764.x | pmid = 9723817 | issue = 2 | pmc = 1873672}}</ref>


==Chemistry== ==Chemistry==
Chemically, bergamottin and dihydroxybergamottin are linear furanocoumarins functionalized with side chains derived from ]. They are ] of some ] of the ] enzyme, particularly ].<ref>{{cite journal | author = Basavaraj Girennavar, Shibu M. Poulose, Guddadarangavvanahally K. Jayaprakasha, Narayan G. Bhat and Bhimanagouda S. Patila | title = Furocoumarins from grapefruit juice and their effect on human CYP 3A4 and CYP 1B1 isoenzymes | journal = Bioorganic & Medicinal Chemistry | volume = 14 | year = 2006 | pages = 2606–2612 | doi=10.1016/j.bmc.2005.11.039 | pmid = 16338240 | issue = 8}}</ref> This prevents oxidative metabolism of certain drugs by the enzyme, resulting in an elevated concentration of drug in the bloodstream. Bergamottin and dihydroxybergamottin are linear furanocoumarins functionalized with side chains derived from ]. They are ] of some ] of the ] enzyme, in particular ].<ref>{{cite journal | author = Basavaraj Girennavar | author2 = Shibu M. Poulose | author3 = Guddadarangavvanahally K. Jayaprakasha| author4 = Narayan G. Bhat | author5 = Bhimanagouda S. Patila | name-list-style = amp | title = Furocoumarins from grapefruit juice and their effect on human CYP 3A4 and CYP 1B1 isoenzymes | journal = Bioorganic & Medicinal Chemistry | volume = 14 | year = 2006 | pages = 2606–2612 | doi=10.1016/j.bmc.2005.11.039 | pmid = 16338240 | issue = 8}}</ref> This prevents oxidative metabolism of certain drugs by the enzyme, resulting in an elevated concentration of drug in the bloodstream.


Normally, the grapefruit juice effect is considered to be a negative interaction, and patients are often warned not to consume grapefruit or its juice when taking medication. However, some current research is focused on the potential benefits of cytochrome P450 inhibition.<ref>{{cite journal | author = E. C. Row, S. A. Brown, A. V. Stachulski and M. S. Lennard | title = Design, synthesis and evaluation of furanocoumarin monomers as inhibitors of CYP3A4 | journal = Org. Biomol. Chem. | year = 2006 | volume =4 | pages = 1604–1610 | doi = 10.1039/b601096b | pmid = 16604230 | issue = 8 }}</ref> Bergamottin, dihydroxybergamottin, or synthetic analogs may be developed as drugs that are targeted to increase the oral ] of other drugs. Drugs that may have limited use because they are metabolized by ] may become viable medications when taken with a CYP3A4 inhibitor because the dose required to achieve a necessary concentration in the blood would be lowered.<ref>{{cite journal | author=Christensen, Hege; Asberg, Anders; Holmboe, Aase-Britt; Berg, Knut Joachim| title=Coadministration of grapefruit juice increases systemic exposure of diltiazem in healthy volunteers| journal=European Journal of Clinical Pharmacology | year=2002| volume =58| issue=8 | pages=515–520| doi=10.1007/s00228-002-0516-8 | pmid=12451428}}</ref> Under normal circumstances, the grapefruit juice effect is considered to be a negative interaction, and patients are often warned not to consume grapefruit or its juice when taking medication. However, some current research is focused on the potential benefits of cytochrome P450 inhibition.<ref>{{cite journal | author = E. C. Row | author2 = S. A. Brown | author3 = A. V. Stachulski | author4 = M. S. Lennard | name-list-style = amp | title = Design, synthesis and evaluation of furanocoumarin monomers as inhibitors of CYP3A4 | journal = Org. Biomol. Chem. | year = 2006 | volume =4 | pages = 1604–1610 | doi = 10.1039/b601096b | pmid = 16604230 | issue = 8 }}</ref> Bergamottin, dihydroxybergamottin, or synthetic analogs may be developed as drugs that are targeted to increase the oral ] of other drugs. Drugs that may have limited use because they are metabolized by ] may become viable medications when taken with a CYP3A4 inhibitor because the dose required to achieve a necessary concentration in the blood would be lowered.<ref>{{cite journal |author1=Christensen, Hege |author2=Asberg, Anders |author3=Holmboe, Aase-Britt |author4=Berg, Knut Joachim | title=Coadministration of grapefruit juice increases systemic exposure of diltiazem in healthy volunteers| journal=European Journal of Clinical Pharmacology | year=2002| volume =58| issue=8 | pages=515–520| doi=10.1007/s00228-002-0516-8 | pmid=12451428|s2cid=7167359 }}</ref>


An example of the use of this effect in current medicines is the co-administration of ], a potent inhibitor of the ] and ] isoforms of ], with other ] drugs. Although ] inhibits HIV replication in its own right, its use in these treatment regimens is to enhance the bioavailability of other agents through inhibition of the enzymes that metabolize them.
]<br style="clear:left;"/>


== Biosynthesis of bergamottin == == Biosynthesis ==
Bergamottin is derived from components originating in the ] pathway.<ref>Dewick, P. Medicinal Natural Products:A Biosynthetic Approach, 2nd ed., Wiley&Sons: West Sussex, England, 2001, p 145.</ref> The biosynthesis of this compound starts with the formation of the demethylsuberosin (3) product which is formed via the alkylation of the umbelliferone (2) compound.<ref>Bisagni, E. Synthesis of psoralens and analogues. J. Photochem. Photobiol. B. 1992, 14, 23-46.</ref> The alkylation of the umbelliferone is initiated with the use of ], more commonly known as DMAPP. The cyclization of an alkyl group occurs to form marmesin (4), which is done in the presence of NADPH and oxygen along with a cytochrome P450 monooxygenase catalyst.<ref>Voznesensky, A. I.; Schenkman, J. B. The cytochrome P450 2B4-NADPH cytochrome P450 reductase electron transfer complex is not formed by charge-pairing. J. Biol. Chem. 1992, 267, 14669-14676.</ref> This process is then repeated twice more, first to remove the hydroxyisopropyl substituent from marmesin (4) to form psoralen (5), and then to add a hydroxyl group to form bergaptol (6).<ref>Kent, U. M.; Lin, H. L.; Noon, K. R.; Harris, D. L.; Hollenberg, P. F. Metabolism of bergamottin by cytochromes P450 2B6 and 3A5. J. Pharmacol. Exp. Ther. 2006, 318, 992-1005.</ref> Bergaptol (6) is next methylated with SAM, ], to form bergapten (7). The final step in this biosynthesis is the attachment of a GPP, or ], to the newly methylated bergapten (7) to form the target molecule bergamottin (8). Bergamottin is derived from components originating in the ].<ref>Dewick, P. Medicinal Natural Products:A Biosynthetic Approach, 2nd ed., Wiley&Sons: West Sussex, England, 2001, p 145.</ref> The biosynthesis of this compound starts with the formation of the demethylsuberosin (3) product, which is formed via the alkylation of the umbelliferone (2) compound.<ref>Bisagni, E. Synthesis of psoralens and analogues. J. Photochem. Photobiol. B. 1992, 14, 23-46.</ref> The alkylation of the umbelliferone is initiated with the use of ], more commonly known as DMAPP. The cyclization of an alkyl group occurs to form ] (4), which is done in the presence of NADPH and oxygen along with a cytochrome P450 monooxygenase catalyst.<ref>Voznesensky, A. I.; Schenkman, J. B. The cytochrome P450 2B4-NADPH cytochrome P450 reductase electron transfer complex is not formed by charge-pairing. ''J. Biol. Chem''. 1992, 267, 14669-14676.</ref> This process is then repeated twice more, first to remove the hydroxyisopropyl substituent from marmesin (4) to form psoralen (5), and then to add a hydroxyl group to form bergaptol (6).<ref>Kent, U. M.; Lin, H. L.; Noon, K. R.; Harris, D. L.; Hollenberg, P. F. Metabolism of bergamottin by cytochromes P450 2B6 and 3A5. ''J. Pharmacol. Exp. Ther''. 2006, 318, 992-1005.</ref> Bergaptol (6) is next methylated with ] (SAM) to form bergapten (7). The final step in this biosynthesis is the attachment of a GPP, or ], to the newly methylated bergapten (7) to form the target molecule bergamottin (8).


] ]


==References== == References ==
{{Reflist}} {{Reflist}}


{{coumarin}} {{Coumarin}}


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