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Revision as of 13:35, 6 December 2010 editBeetstra (talk | contribs)Edit filter managers, Administrators172,142 edits Script assisted update of identifiers from ChemSpider, CommonChemistry and FDA for the Chem/Drugbox validation project - Updated: InChI1->InChI StdInChI StdInChIKey.← Previous edit		Latest revision as of 03:32, 10 December 2024 edit undoCitation bot (talk | contribs)Bots5,461,427 edits Added bibcode. | Use this bot. Report bugs. | Suggested by Dominic3203 | Linked from User:Marbletan/sandbox | #UCB_webform_linked 1138/2664
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			{{Short description|Chemical compound}}
	{{Unreferenced stub|auto=yes|date=December 2009}}
	{{Drugbox |		{{Drugbox
			| Verifiedfields = changed
			| Watchedfields = changed
			| verifiedrevid = 464405926
	| IUPAC_name = (7α,9α)-sparteine		| IUPAC_name = (7α,9α)-sparteine
	|synonyms = <small>(6''R'',8''S'',10''R'',12''S'')- 7,15-diazatetracyclo heptadecane</small>
	| image = (−)-Sparteine.svg		| image = (−)-Sparteine.svg
	| ChemSpiderID = 559096
			<!--Clinical data-->
	| InChI = 1/C15H26N2/c1-3-7-16-11-13-9-12(14(16)5-1)10-17-8-4-2-6-15(13)17/h12-15H,1-11H2/t12-,13-,14-,15+/m0/s1
			| tradename =
	| InChIKey = SLRCCWJSBJZJBV-ZQDZILKHBW
			| Drugs.com = {{drugs.com|international|sparteine}}
	| smiles = C1CCN2C3C(2C1)CN43CCCC4
			| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
	| StdInChI = 1S/C15H26N2/c1-3-7-16-11-13-9-12(14(16)5-1)10-17-8-4-2-6-15(13)17/h12-15H,1-11H2/t12-,13-,14-,15+/m0/s1
			| pregnancy_US = <!-- A / B / C / D / X -->
	| StdInChIKey = SLRCCWJSBJZJBV-ZQDZILKHSA-N
			| pregnancy_category =
			| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 -->
			| legal_UK = <!-- GSL / P / POM / CD -->
			| legal_US = <!-- OTC / Rx-only -->
			| legal_status =
			| routes_of_administration =
			<!--Pharmacokinetic data-->
			| bioavailability =
			| protein_bound =
			| metabolism =
			| elimination_half-life =
			| excretion =
			<!--Identifiers-->
			| CAS_number_Ref = {{cascite|correct|??}}
	| CAS_number = 90-39-1		| CAS_number = 90-39-1
	| ATC_prefix = C01		| ATC_prefix = C01
	| ATC_suffix = BA04		| ATC_suffix = BA04
	| PubChem = 644020		| PubChem = 644020
			| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
	| DrugBank =
			| DrugBank = DB06727
	| C = 15 | H = 26 | N = 2
			| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| molecular_weight = 234.380 g/mol
			| ChemSpiderID = 559096
	| bioavailability =
			| UNII_Ref = {{fdacite|correct|FDA}}
	| protein_bound =
			| UNII = 298897D62S
	| metabolism =
			| KEGG_Ref = {{keggcite|correct|kegg}}
	| elimination_half-life =
	| excretion =		| KEGG = D01041
			| ChEBI_Ref = {{ebicite|correct|EBI}}
	| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
			| ChEBI = 28827
	| pregnancy_US = <!-- A / B / C / D / X -->
			| ChEMBL_Ref = {{ebicite|changed|EBI}}
	| pregnancy_category =
			| ChEMBL = 44625
	| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 -->
	| legal_UK = <!-- GSL / P / POM / CD -->
	| legal_US = <!-- OTC / Rx-only -->
	| legal_status =
	| routes_of_administration =
	}}
	'''Sparteine''' is a class 1a ]; a sodium channel blocker. It is an ] and can be extracted from ]. It is the predominant alkaloid in '']'', and is thought to ] the bivalents ] and ]. It is not FDA approved for human use as an antiarrhythmic agent, and it is not included in the ].
			<!--Chemical data-->
	It is also used as a ] ] in ], and as a ] in organic ].
			| C=15 | H=26 | N=2
			| smiles = C1CCN2C3C(2C1)CN43CCCC4
			| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
			| StdInChI = 1S/C15H26N2/c1-3-7-16-11-13-9-12(14(16)5-1)10-17-8-4-2-6-15(13)17/h12-15H,1-11H2/t12-,13-,14-,15+/m0/s1
			| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
			| StdInChIKey = SLRCCWJSBJZJBV-ZQDZILKHSA-N
			| synonyms = (6''R'',8''S'',10''R'',12''S'')-7,15-diazatetracycloheptadecane
			<!--Physical data -->
	==Biosynthesis==
			| density = 1.02
			| melting_point = 30
			| boiling_point = 325
			| solubility = 3.04
			}}
			'''Sparteine''' is a class 1a ] and sodium channel blocker. It is an ] and can be extracted from ]. It is the predominant alkaloid in '']'', and is thought to ] the bivalent metals ] and ]. It is not FDA approved for human use as an antiarrhythmic agent, and it is not included in the ].
	Sparteine is a lupin ] containing a tetracyclic bis-quinolizidine ring system derived from three C<sub>5</sub> chains of ], or more specifically, L-lysine.<ref name="NatProdBook">{{cite book |author=Dewick, P.M. |title= Medicinal Natural Products, 3rd. Ed. |publisher=Wiley |pages=311 |year=2009}}</ref> The first intermediate in the biosynthesis is ], the decarboxylation product of lysine catalyzed by the enzyme lysine decarboxylase (LDC).<ref name="Spenser">{{cite journal |doi=10.1139/v88-280 |author=Golebiewski, W.M., Spenser |title=Biosynthesis of the lupine alkaloids. II. Sparteine and lupanine |journal=Can. J. Chem. |volume=66 |pages=1734 |year=1988}}</ref>. Three units of cadaverine are used to form the quinolizidine skeleton. The mechanism of formation has been studied enzymatically, as well as with tracer experiments, but the exact route of synthesis still remains unclear.
			It is also used as a ] ] in ], especially in syntheses involving ]s.
	Tracer studies using <sup>13</sup>C-<sup>15</sup>N-doubly labeled cadaverine have shown three units of cadaverine are incorporated into sparteine and two of the C-N bonds from two of the cadaverine units remain intact.<ref name="Rana">{{cite journal |author=Rana, J., Robins, D.J. |title=Quinolizidine alkaloid biosynthesis: incorporation of cadaverine into sparteine. |journal=J. Chem. Soc., Chem. Comm.|volume=22 |pages=1335–6 |year=1983}}</ref> The observations have also been confirmed using <sup>2</sup>H NMR labeling experiments.<ref name="Fraser">{{cite journal |author=Fraser, A.M., Robins, D.J. |journal=J. Chem. Soc., Chem. Comm. |pages=11477 |year=1984}}</ref>
			==Biosynthesis==
	Enzymatic evidence then showed that the three molecules of cadaverine are transformed to the quinolizidine ring via enzyme bound intermediates, without the generation of any free intermediates. Originally, it was thought that conversion of cadaverine to the corresponding aldehyde, 5-aminopentanal, was catalyzed by the enzyme diamine oxidase.<ref name="SecretLife">{{cite book |author=Aniszewski, T. |title= Alkaloids - Secrets of Life, 1st Ed. |publisher=Elseview |pages=98–101 |year=2007}}</ref> The aldehyde then spontaneously converts to the corresponding Schiff base, Δ<sup>1</sup>-piperideine. Coupling of two molecules occurs between the two tautomers of Δ<sup>1</sup>-piperideine in an aldol-type reaction. The imine is then hydrolyzed to the corresponding aldehyde/amine. The primary amine is then oxidized to an aldehyde followed by formation of the imine to yield the quinolizidine ring.<ref name="SecretLife" /> The breakdown of this mechanism is shown in figure 1; however, the intermediates, as mentioned before, were not isolated.
	]		]
			Sparteine is a lupin ] containing a tetracyclic bis-quinolizidine ring system derived from three C<sub>5</sub> chains of ], or more specifically, {{small|L}}-lysine.<ref name="NatProdBook">{{cite book |vauthors=Dewick PM |date=2009 |title=Medicinal Natural Products: A Biosynthetic Approach |edition=3rd |publisher=Wiley |pages=328–329 |doi=10.1002/9780470742761 |isbn=978-0-470-74276-1}}</ref> The first intermediate in the biosynthesis is ], the decarboxylation product of lysine catalyzed by the enzyme lysine decarboxylase (LDC).<ref name="Spenser">{{cite journal |vauthors=Golebiewski WM, Spenser ID |date=1988 |title=Biosynthesis of the lupine alkaloids. II. Sparteine and lupanine |journal=Canadian Journal of Chemistry |volume=66 |issue=7 |pages=1734–1748 |doi=10.1139/v88-280 |doi-access=free}}</ref> Three units of cadaverine are used to form the quinolizidine skeleton. The mechanism of formation has been studied enzymatically, as well as with tracer experiments, but the exact route of synthesis still remains unclear.
	More recent enzymatic evidence has indicated the presence of 17-oxosparteine synthase (OS), a transaminase enzyme.<ref name="Wink84">{{cite book |author=Wink, M., Hartmann, T. |title=Enzymology of Quinolizidine Alkaloid Biosynthesis; Natural Products Chemistry: Zalewski and Skolik (Eds.) |pages=511–520 |year=1984}}</ref>, <ref name="Wink87">{{cite journal |author=Wink, M. |title=Quinolizidine Alkaloids: Biochemistry, Metabolism, and Function in Plants and Cell Suspension Cultures. |journal=Plant Medica |pages=509–514 |year=1987}}</ref>, <ref name="Wink79">{{cite journal |doi=10.1016/0014-5793(79)81040-6 |author=Wink, M., Hartmann, T. |title=Cadaverine--pyruvate transamination: the principal step of enzymatic quinolizidine alkaloid biosynthesis in Lupinus polyphyllus cell suspension cultures. |journal=FEBS Letters |volume= 101 |issue=2 |pages=343–346 |year=1979 |pmid=446758}}</ref>, <ref name="Perrey">{{cite journal |author=Perrey, R., Wink, M. |journal=Z. Naturfrosh |volume= 43 |pages=363–369 |year=1988}}</ref>, <ref name="Atta">{{cite book |author=Atta-ur-Rahman (Ed.) |title=Natural Products Chemistry |volume= 15 |publisher=Elsevier |pages=537 |year=1995 |isbn=0444426914}}</ref>, <ref name="Roberts">{{cite book |author=Roberts, M., Wink, M. (Eds.) |title=Alkaloids: Biochemistry, Ecology, and Medicinal Applications. |publisher=Plenum Press |pages=112–114 |year=1998}}</ref> The deaminated cadaverine is not released from the enzyme, thus is can be assumed that the enzyme catalyzes the formation of the quinolizidine skeleton in a channeled fashion (Figure 2).<ref name="Perrey" />, <ref name="Atta" />, <ref name="Roberts" /> 7-oxosparteine requires four units of pyruvate as the NH<sub>2</sub> acceptors and produces four molecules of alanine (Figure 3). Both lysine decarboxylase and the quinolizidine skeleton-forming enzyme are localized in chloroplasts.<ref name="Wink80">{{cite journal |author=Wink, M., Hartmann, T. |journal=Z. Naturforsh |volume= 35 |pages=93–97 |year=1980}}</ref>
			Tracer studies using <sup>13</sup>C-<sup>15</sup>N-doubly labeled cadaverine have shown three units of cadaverine are incorporated into sparteine and two of the C-N bonds from two of the cadaverine units remain intact.<ref name="Rana">{{cite journal |vauthors=Rana J, Robins DJ |date=1983 |title=Quinolizidine alkaloid biosynthesis: Incorporation of cadaverine into sparteine |journal=Journal of the Chemical Society, Chemical Communications |volume=1983 |issue=22 |pages=1335–1336 |doi=10.1039/C39830001335}}</ref> The observations have also been confirmed using <sup>2</sup>H NMR labeling experiments.<ref name="Fraser">{{cite journal |vauthors=Fraser AM, Robins DJ |date=1984 |title=Incorporation of chiral cadaverines into the quinolizidine alkaloids sparteine, lupanine, and angustifoline |journal=Journal of the Chemical Society, Chemical Communications |volume=1984 |issue=22 |pages=1477–1479 |doi=10.1039/C39840001477}}</ref>
	]
			Enzymatic evidence then showed that the three molecules of cadaverine are transformed to the quinolizidine ring via enzyme bound intermediates, without the generation of any free intermediates. Originally, it was thought that conversion of cadaverine to the corresponding aldehyde, 5-aminopentanal, was catalyzed by the enzyme diamine oxidase.<ref name="SecretLife">{{cite book |vauthors=Aniszewski T |date=2007 |title=Alkaloids – Secrets of Life: Alkaloid Chemistry, Biological Significance, Applications and Ecological Role |url=https://books.google.com/books?id=a1Z6oJL-dgMC&pg=PA98 |publisher=Elsevier |pages=98–101 |doi=10.1016/B978-0-444-52736-3.X5000-4 |isbn=978-0-444-52736-3}}</ref> The aldehyde then spontaneously converts to the corresponding Schiff base, Δ<sup>1</sup>-piperideine. Coupling of two molecules occurs between the two tautomers of Δ<sup>1</sup>-piperideine in an aldol-type reaction. The imine is then hydrolyzed to the corresponding aldehyde/amine. The primary amine is then oxidized to an aldehyde followed by formation of the imine to yield the quinolizidine ring.<ref name="SecretLife" />
	]
			=== Via 17-oxosparteine synthase ===
	==See also==
			More recent enzymatic evidence has indicated the presence of ] (OS), a transaminase enzyme.<ref name="Wink85">{{cite book |vauthors=Wink M, Hartmann T |veditors=Zalewski RI, Skolik JJ |date=1985 |chapter=Enzymology of quinolizidine alkaloid biosynthesis |chapter-url=https://archive.org/details/naturalproductsc0000inte/page/511/mode/1up |chapter-url-access=registration |title=Natural Products Chemistry 1984: A Collection of Invited Section and Colloquium Lectures Presented at the 14th IUPAC International Symposium on the Chemistry of Natural Products, Poznań, Poland, 9–14 July 1984 |url=https://archive.org/details/naturalproductsc0000inte |url-access=registration |series=Studies in Organic Chemistry |volume=20 |publisher=Elsevier |pages=511–520 |isbn=978-0-444-42457-0}}</ref><ref>{{cite journal |vauthors=Wink M |date=1987 |title=Quinolizidine alkaloids: Biochemistry, metabolism, and function in plants and cell suspension cultures |journal=Planta Medica |volume=53 |issue=6 |pages=509–514 |doi=10.1055/s-2006-962797 |doi-access=free |pmid=17269092}}</ref><ref name="Wink79">{{cite journal |vauthors=Wink M, Hartmann T |date=1979 |title=Cadaverine–pyruvate transamination: The principal step of enzymatic quinolizidine alkaloid biosynthesis in ''Lupinus polyphyllus'' cell suspension cultures |journal=FEBS Letters |volume=101 |issue=2 |pages=343–346 |doi=10.1016/0014-5793(79)81040-6 |doi-access=free |pmid=446758|bibcode=1979FEBSL.101..343W }}</ref><ref name="Perrey">{{cite journal |vauthors=Perrey R, Wink M |date=1988 |title=On the role of Δ1-piperideine and tripiperideine in the biosynthesis of quinolizidine alkaloids |journal=Zeitschrift für Naturforschung |volume=43c |issue=5–6 |pages=363–369 |doi=10.1515/znc-1988-5-607 |doi-access=free}}</ref><ref name="Saito">{{cite book |vauthors=Saito K, Murakoshi I |veditors=Atta-ur-Rahman |date=1995 |chapter=Chemistry, biochemistry and chemotaxonomy of lupine alkaloids in the Leguminosae |title=Structure and Chemistry (Part C) |series=Studies in Natural Products Chemistry |volume=15 |publisher=Elsevier |page=537 |doi=10.1016/S1572-5995(06)80142-0 |isbn=978-0-444-82083-9}}</ref><ref name="Roberts">{{cite book |vauthors=Roberts MF |veditors=Roberts MF, Wink M |date=1998 |chapter=Enzymology of alkaloid biosynthesis |chapter-url=https://archive.org/details/alkaloidsbiochem0000unse |url-access=registration |title=Alkaloids: Biochemistry, Ecology, and Medicinal Applications |url=https://archive.org/details/alkaloidsbiochem0000unse/page/112/mode/1up |chapter-url-access=registration |publisher=Plenum Press |pages=112–114 |doi=10.1007/978-1-4757-2905-4_5 |isbn=978-1-4757-2905-4}}</ref> The deaminated cadaverine is not released from the enzyme, thus is can be assumed that the enzyme catalyzes the formation of the quinolizidine skeleton in a channeled fashion .<ref name="Perrey" /><ref name="Saito" /><ref name="Roberts" /> 7-oxosparteine requires four units of pyruvate as the NH<sub>2</sub> acceptors and produces four molecules of alanine. Both lysine decarboxylase and the quinolizidine skeleton-forming enzyme are localized in chloroplasts.<ref name="Wink80">{{cite journal |vauthors=Wink M, Hartmann T |date=1980 |title=Enzymatic synthesis of quinolizidine alkaloids in lupin chloroplasts |journal=Zeitschrift für Naturforschung |volume=35c |issue=1–2 |pages=93–97 |doi=10.1515/znc-1980-1-218 |doi-access=free}}</ref>
	* ]
			{{Multiple image
	* ]
			| align =
			| direction = vertical
			| total_width = 400px
			| image1 = BiosynthesisSparteine2.png
			| alt1 =
			| caption1 = Proposed ring cyclization steps
			| image2 = GeneralbiosynthesisSparteine.gif
			| caption2 = Overall schematic
			| header = Biosynthesis of sparteine by 17-oxosparteine synthase
			}}
			== See also ==
			* ]
	* ]		* ]
	== References ==		== References ==
	<references />		<references />
			== External links ==
			{{NIE Poster|Sparteine}}
			*{{Commonscat-inline}}
	{{Antiarrhythmic agents}}		{{Antiarrhythmic agents}}
	]		]
	]		]
	]		]
	{{cardiovascular-drug-stub}}
	]
	]
	]
	]
	]
	]
	]