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{{Short description|Chemical compound}} |
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| verifiedrevid = 400322477 |
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| verifiedrevid = 421771397 |
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| IUPAC_name = |
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| IUPAC_name = |
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| image = nargenicin structure.png |
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| image = Nargenicin.svg |
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| width = 250 |
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| width = 250 |
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| image2 = |
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| image2 = |
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| width2 = 250 |
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| width2 = 250 |
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<!--Clinical data--> |
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| tradename = |
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<!--Pharmacokinetic data--> |
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| bioavailability = |
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| protein_bound = |
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| metabolism = |
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| excretion = ~ |
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<!--Identifiers--> |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 70695-02-2 |
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| ATC_prefix = none |
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| PubChem = 6436286 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 4885360 |
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| ChemSpiderID = 4885360 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| InChI = 1/C28H37NO8/c1-13-11-14(2)28-17(12-20(34-5)27(33)35-23(13)16(4)30)8-9-18-21(28)22(31)15(3)24(25(18)37-28)36-26(32)19-7-6-10-29-19/h6-11,13,15-18,20-25,29-31H,12H2,1-5H3/b14-11+/t13-,15-,16-,17-,18-,20+,21+,22-,23+,24-,25+,28-/m1/s1 |
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| UNII = XP2QP458K4 |
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| InChIKey = YEUSSARNQQYBKH-KFIBIINQBT |
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| smiles = O=C2O((O)C)(\C=C(/C)51O4(\C=C/1C2OC)5(O)(4OC(=O)c3cccn3)C)C |
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<!--Chemical data--> |
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| C=28 | H=37 | N=1 | O=8 |
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| smiles = O=C2O((O)C)(\C=C(/C)51O4(\C=C/1C2OC)5(O)(4OC(=O)c3ccc3)C)C |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C28H37NO8/c1-13-11-14(2)28-17(12-20(34-5)27(33)35-23(13)16(4)30)8-9-18-21(28)22(31)15(3)24(25(18)37-28)36-26(32)19-7-6-10-29-19/h6-11,13,15-18,20-25,29-31H,12H2,1-5H3/b14-11+/t13-,15-,16-,17-,18-,20+,21+,22-,23+,24-,25+,28-/m1/s1 |
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| StdInChI = 1S/C28H37NO8/c1-13-11-14(2)28-17(12-20(34-5)27(33)35-23(13)16(4)30)8-9-18-21(28)22(31)15(3)24(25(18)37-28)36-26(32)19-7-6-10-29-19/h6-11,13,15-18,20-25,29-31H,12H2,1-5H3/b14-11+/t13-,15-,16-,17-,18-,20+,21+,22-,23+,24-,25+,28-/m1/s1 |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = YEUSSARNQQYBKH-KFIBIINQSA-N |
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| StdInChIKey = YEUSSARNQQYBKH-KFIBIINQSA-N |
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| Jmol = none |
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| CAS_number = 70695-02-2 |
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| ATC_prefix = none |
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| ATC_supplemental = |
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| PubChem = 6436286 |
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| DrugBank = |
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| C = 28 | H = 37 | N = 1 | O = 8 |
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| molecular_weight = 515.5953 g/mol |
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| bioavailability = |
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| protein_bound = |
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| metabolism = |
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| licence_EU = |
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| pregnancy_AU = |
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| pregnancy_US = |
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| legal_US = |
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| routes_of_administration = |
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| excretion = ~ |
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'''Nargenicin''' is a 28 carbon ] with a tricyclic ] containing a unique ether bridge. The ] antibiotic was isolated from ''Nocardia argentinensis''.<ref name=nargenicinorigin>{{cite journal | author=Celmer WD; Moppett CE; Ware, RS; Watts, PC; Whipple, EB |title=Structure of natural antibiotic CP-47,444 | journal=J. Am. Chem. Soc. | year=1980 | volume=102 | issue=12 | pages=4203–4209 | doi= 10.1021/ja00532a036}}</ref> Nargenicin is effective towards gram-positive bacteria and been shown to have strong antibacterial activity against '']'', a ] resistance bacterium.<ref name=nargenicinact>{{cite journal | author=Sohng, K; Yamaguchi, T; Seong, CN; Baik, KS; Park, SC; Lee, HJ |title=Production, isolation and biological activity of nargenicin from Nocardia sp. CS682 | journal=Arch Pharm Res | year=2008 | volume=31 | pages=1339–1345 | pmid=18958426 | issue=10 | doi=10.1007/s12272-001-2115-0}}</ref> It has also been shown to induce cell differentiation and be used as a possible treatment for neoplastic diseases.<ref name=nargenicinenhance>{{cite journal | author=Kim, SH; Yoo, JC; Kim, TS |title=Nargenicin enhances, dihydroxyvitamin D-3 and all-trans retinoic acid-induced leukemia cell differentiation via PKC beta I/MAPK pathways | journal=Biochemical Pharmacology | year=2009 | volume=77 | pages=1694–1701 | pmid=19428323 | issue=11 | doi=10.1016/j.bcp.2009.03.004}}</ref> |
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'''Nargenicin''' ('''CP-47,444''', '''CS-682''') is a 28 carbon ] with a fused ] core that has in addition a unique ] bridge. The ] antibiotic was isolated from ''] argentinensis''.<ref name=nargenicinorigin>{{cite journal | vauthors = Celmer WD, Chmurny GN, Moppett CE, Ware RS, Watts PT, Whipple EB |title=Structure of natural antibiotic CP-47,444 | journal=J. Am. Chem. Soc. | year=1980 | volume=102 | issue=12 | pages=4203–4209 | doi= 10.1021/ja00532a036}}</ref> Nargenicin is effective towards gram-positive bacteria and been shown to have strong antibacterial activity against '']'', including ].<ref name=nargenicinact>{{cite journal | vauthors = Sohng JK, Yamaguchi T, Seong CN, Baik KS, Park SC, Lee HJ, Jang SY, Simkhada JR, Yoo JC | s2cid = 20377463 | display-authors = 6 | title = Production, isolation and biological activity of nargenicin from Nocardia sp. CS682 | journal = Archives of Pharmacal Research | volume = 31 | issue = 10 | pages = 1339–45 | date = October 2008 | pmid = 18958426 | doi = 10.1007/s12272-001-2115-0 }}</ref> It has also been shown to induce ] and inhibit ] in a human ] cell line.<ref name=nargenicinenhance>{{cite journal | vauthors = Kim SH, Yoo JC, Kim TS | title = Nargenicin enhances 1,25-dihydroxyvitamin D(3)- and all-trans retinoic acid-induced leukemia cell differentiation via PKCbetaI/MAPK pathways | journal = Biochemical Pharmacology | volume = 77 | issue = 11 | pages = 1694–701 | date = June 2009 | pmid = 19428323 | doi = 10.1016/j.bcp.2009.03.004 }}</ref> |
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__TOC__ |
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==Biosynthesis== |
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==Biosynthesis== |
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The biosynthesis of nargenicin is believed to be closely related to fatty acid biosynthesis. David E. Cane and colleagues have shown, through feeding experiments, that nargenicin is derived from common precursors acetate and propionate, specifically 4 propionate and 5 acetate building blocks.<ref name=nargenicin1>{{cite journal | doi=10.1021/ja00315a052 | author=Cane, DE; Yang, CC |title=Biosynthetic Origin of the Carbon Skeleton and Oxygen Atoms of Nargenicin A1 | journal=J. Am. Chem. Soc. | year=1984 | volume=106 | pages=784–787}}</ref> Experiments using -, -, and acetate and - and propionate established the carbon skeleton of nargenicin. To determine origin of oxygen atoms, acetate and propionate where incorporated in the experimental feeding. It was then determined that oxygens located at C-1 and C-11 originate from carboxylate oxygens of the acetate precursors while oxygens at C-9 and C-17 positions originate from propoinate precursors.<ref name="nargenicin1"/> The rest of the oxygens are believed to originate from molecular oxygen.<ref name=nargenicin5>{{cite journal | author=Cane, DE; Yang, CC |title=Nargenicin Biosynthesis: Late Stages Oxidations and Absolute Configuration | journal=J. Antibio. | year=1985 | volume=38 | pages=423–426}}</ref> In a later study, David E. Cane and colleagues incorporated the synthesized deutirated N-acetylcysteamine thioester (2S,3R)--2-methyl-3-hydroxypentanoic acid into nargenicin.<ref name=nargenicin6>{{cite journal | doi=10.1016/0040-4039(91)80057-D | author=Cane, DE; Prabhakaran, PC; Tan, W; Ott, WR |title=Macrolide Biosynthesis. 6 Mechanism of Polyketide Chain Elongation | journal=Tetrahedron Lett. | year=1991 | volume=32 | pages=5457–5460}}</ref> The feeding of the labeled intermediate, and other deuterinated ketide fragments, incorporated in nargenicin provide support of the proposed biosynthesis of the polyketide chain.<ref name=nargenicin7>{{cite journal | doi=10.1021/ja00055a024 | author=Cane, DE; Tan, W; Ott, WR |title=Nargenicin Biosynthesis. Incorporation of Polyketide Chain Elongation Intermediates and Support for a Proposed Intramolecular Diels-Alder Cyclization | journal=J. Am. Chem. Soc. | year=1993 | volume=115 | pages=527–535}}</ref> The following illustrates a proposed biosynthesis of nargenicin. |
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The ] of nargenicin is believed to be closely related to ] to produce a ] chain. ] and colleagues have used feeding experiments to determine that nargenicin is derived from common precursors ] and ].<ref name=nargenicin1>{{cite journal | vauthors = Cane DE, Yang CC | doi=10.1021/ja00315a052 |title=Biosynthetic Origin of the Carbon Skeleton and Oxygen Atoms of Nargenicin A<sub>1</sub> | journal=J. Am. Chem. Soc. | year=1984 | volume=106 | pages=784–787 | issue=3}}</ref><ref name=nargenicin6>{{cite journal | vauthors = Cane DE, Prabhakaran PC, Tan W, Ott WR | doi=10.1016/0040-4039(91)80057-D |title=Macrolide Biosynthesis. 6 Mechanism of Polyketide Chain Elongation | journal=Tetrahedron Lett. | year=1991 | volume=32 | pages=5457–5460 | issue=40}}</ref><ref name=nargenicin7>{{cite journal | vauthors = Cane DE, Tan W, Ott WR | doi=10.1021/ja00055a024 |title=Nargenicin Biosynthesis. Incorporation of Polyketide Chain Elongation Intermediates and Support for a Proposed Intramolecular Diels-Alder Cyclization | journal=J. Am. Chem. Soc. | year=1993 | volume=115 | pages=527–535 | issue=2}}</ref> |
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The polyketide chain produced then undergoes a ring closure to form the large ] ring and a ] to form the fused ]/] rings. The oxygen atoms attached to carbons in positions that do not correspond to polyketides—carbons 8 and 13 (the ether bridge), carbon 2 (the ] substituent), and carbon 18 (on the hydroxyethyl chain attached to the lactone ring) are derived from molecular oxygen.<ref name=nargenicin5>{{cite journal | vauthors = Cane DE, Yang CC | title = Nargenicin biosynthesis: late stage oxidations and absolute configuration | journal = The Journal of Antibiotics | volume = 38 | issue = 3 | pages = 423–6 | date = March 1985 | pmid = 4008333 | doi = 10.7164/antibiotics.38.423 | doi-access = free }}</ref> |
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The polyketide chain produced is electronically capable to go through a lactonization and a diels alder cyclization, as shown below. Experiments have shown the incorporation a complex intermediate of a synthesized pentaketide substrate containing four stereocenters and an E,E-diene into the biosynthesis of nargenicin to result in the labeled macrolide nargenicin.<ref name=nargenicin8>{{cite journal | doi=10.1021/ja00129a044 | author=Cane, DE; Luo, G |title=Biosynthesis of Polyketide Antibiotics. Incorporation of a Pentaketide Chain Elongation Intermediate into Nargenicin | journal=J. Am. Chem. Soc. | year=1995 | volume=117 | pages=6633–6634}}</ref> The study provides support for the biosynthetic route of nargenicin and absolute configuration. The last biosynthesis stages include the oxidations at C-2, C-8, C-13 and C-18 positions as well as the attachment of the pyrrole carboxylate.<ref name="nargenicin5"/> |
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==References== |
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== References == |
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{{reflist}} |
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{{reflist|30em}} |
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