Bergamottin

Bergamottin
IUPAC name (E)-4-[(3,7-Dimethyl-2,6-octadienyl)oxy]- 7H-furo[3,2-g][1]benzopyran-7-one
Other names Bergamotine 5-Geranoxypsoralen
Identifiers
CAS number	7380-40-7
PubChem	5471349
ChemSpider	4581520 Y
ChEMBL	CHEMBL1078442 Y
Jmol-3D images	Image 1
SMILES CC(=CCC/C(=C/COC1=C2C=CC(=O)OC2=CC3=C1C=CO3)/C)C
InChI InChI=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+ Y Key: DBMJZOMNXBSRED-OQLLNIDSSA-N Y 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+ Key: DBMJZOMNXBSRED-OQLLNIDSBR
Properties
Molecular formula	C21H22O4
Molar mass	338.397 g/mol
Exact mass	338.151809
Melting point	55-56 °C
Y (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Bergamottin is a natural furanocoumarin found principally in grapefruit juice. It is also found in the oil of bergamot, from which it was first isolated and from which its name is derived. To a lesser extent, bergamottin is also present in the essential oils of other citrus fruits. Along with the chemically related compound 6’,7’-dihydroxybergamottin, it is believed to be responsible for the grapefruit juice effect in which the consumption of the juice affects the metabolism of a variety of pharmaceutical drugs.^[1]

Chemistry

Chemically, bergamottin and dihydroxybergamottin are linear furanocoumarins functionalized with side chains derived from geraniol. They are inhibitors of some isoforms of the cytochrome P450 enzyme, particularly CYP3A4.^[2] 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.^[3] Bergamottin, dihydroxybergamottin, or synthetic analogs may be developed as drugs that are targeted to increase the oral bioavailability of other drugs. Drugs that may have limited use because they are metabolized by CYP3A4 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.^[4]

6',7'-Dihydroxybergamottin

Biosynthesis of bergamottin

Bergamottin is derived from components originating in the shikimate pathway.^[5] 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.^[6] The alkylation of the umbelliferone is initiated with the use of dimethylallyl pyrophosphate, 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.^[7] 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).^[8] Bergaptol (6) is next methylated with SAM, S-Adenosyl methionine, to form bergapten (7). The final step in this biosynthesis is the attachment of a GPP, or geranyl pyrophosphate, to the newly methylated bergapten (7) to form the target molecule bergamottin (8).

References

1. ^ David G. Bailey, J. Malcolm, O. Arnold, J. David Spence (1998). "Grapefruit juice-drug interactions". Br J Clin Pharmacol 46 (2): 101–110. doi:10.1046/j.1365-2125.1998.00764.x. PMC 1873672. PMID 9723817. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1873672. 
2. ^ Basavaraj Girennavar, Shibu M. Poulose, Guddadarangavvanahally K. Jayaprakasha, Narayan G. Bhat and Bhimanagouda S. Patila (2006). "Furocoumarins from grapefruit juice and their effect on human CYP 3A4 and CYP 1B1 isoenzymes". Bioorganic & Medicinal Chemistry 14 (8): 2606–2612. doi:10.1016/j.bmc.2005.11.039. PMID 16338240. 
3. ^ E. C. Row, S. A. Brown, A. V. Stachulski and M. S. Lennard (2006). "Design, synthesis and evaluation of furanocoumarin monomers as inhibitors of CYP3A4". Org. Biomol. Chem. 4 (8): 1604–1610. doi:10.1039/b601096b. PMID 16604230. 
4. ^ Christensen, Hege; Asberg, Anders; Holmboe, Aase-Britt; Berg, Knut Joachim (2002). "Coadministration of grapefruit juice increases systemic exposure of diltiazem in healthy volunteers". European Journal of Clinical Pharmacology 58 (8): 515–520. doi:10.1007/s00228-002-0516-8. PMID 12451428. 
5. ^ Dewick, P. Medicinal Natural Products:A Biosynthetic Approach, 2nd ed., Wiley&Sons: West Sussex, England, 2001, p 145.
6. ^ Bisagni, E. Synthesis of psoralens and analogues. J. Photochem. Photobiol. B. 1992, 14, 23-46.
7. ^ 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.
8. ^ 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.