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{{Chembox |
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{{Chembox |
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| Watchedfields = changed |
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| verifiedrevid = 445841740 |
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| verifiedrevid = 446035918 |
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| ImageFileL1 = Divicine.svg |
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| ImageFileL1 = Divicine.svg |
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| ImageSizeL1 = 110px |
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| ImageSizeL1 = 110px |
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| ImageSizeR1 = 95px |
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| ImageSizeR1 = 95px |
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| ImageCaptionR1 = pyrimidinone tautomer |
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| ImageCaptionR1 = pyrimidinone tautomer |
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| IUPACName = 2,6-diamino-4,5-dihydroxypyrimidine |
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| IUPACName = 2,6-Diamino-4,5-dihydroxypyrimidine |
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| OtherNames = 2,6-diamino-4,5-pyrimidinediol; 2,6-diamine-5-hydroxy-4(3''H'')-pyrimidinone; 2,4-diamino-5,6-dihydroxypyrimidine |
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| OtherNames = 2,6-Diamino-4,5-pyrimidinediol; 2,6-diamine-5-hydroxy-4(3''H'')-pyrimidinone; 2,4-diamino-5,6-dihydroxypyrimidine |
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| Section1 = {{Chembox Identifiers |
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|Section1={{Chembox Identifiers |
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| CASNo_Ref = {{cascite|correct|??}} |
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| CASNo = 32267-39-3 |
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| CASNo = 32267-39-3 |
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| CASNo_Comment=<ref name=ChemboxRef>http://www.druglead.com/cds/divicine.html</ref> |
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| CASNo_Comment= |
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| PubChem = 91606 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| SMILES = OC1=C(O)C(N)=NC(N)=N1 |
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| UNII = 1I0JQQ440Q |
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| SMILES_Comment = (pyrimidine tautomer) |
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| PubChem = 91606 |
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| SMILES1 = O=C1C(O)=C(N)NC(N)=N1 |
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| SMILES = OC1=C(O)C(N)=NC(N)=N1 |
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| SMILES1_Comment = (pyrimidinone tautomer) |
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| SMILES_Comment = (pyrimidine tautomer) |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| SMILES1 = O=C1C(O)=C(N)NC(N)=N1 |
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| SMILES1_Comment = (pyrimidinone tautomer) |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 2971290 |
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| ChemSpiderID = 2971290 |
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| InChI = 1/C4H6N4O2/c5-2-1(9)3(10)8-4(6)7-2/h9H,(H5,5,6,7,8,10) |
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| InChI = 1/C4H6N4O2/c5-2-1(9)3(10)8-4(6)7-2/h9H,(H5,5,6,7,8,10) |
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| InChIKey = ZMWZGZSARWJATP-UHFFFAOYAO |
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| InChIKey = ZMWZGZSARWJATP-UHFFFAOYAO |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C4H6N4O2/c5-2-1(9)3(10)8-4(6)7-2/h9H,(H5,5,6,7,8,10) |
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| StdInChI = 1S/C4H6N4O2/c5-2-1(9)3(10)8-4(6)7-2/h9H,(H5,5,6,7,8,10) |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = ZMWZGZSARWJATP-UHFFFAOYSA-N |
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| StdInChIKey = ZMWZGZSARWJATP-UHFFFAOYSA-N |
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| Section2 = {{Chembox Properties |
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|Section2={{Chembox Properties |
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| C=4|H=6|N=4|O=2 |
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| C=4 | H=6 | N=4 | O=2 |
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| Appearance = Brownish needles |
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| Appearance = Brownish needles |
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| Density = |
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| Density = |
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| MeltingPt = |
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| Solubility = Soluble in 10% KOH }} |
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| Solubility = |
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| SolubleOther = Soluble{{vague|date=September 2015}} |
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| Section3 = {{Chembox Hazards |
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| Solvent = 10% KOH }} |
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| MainHazards = |
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|Section3={{Chembox Hazards |
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| FlashPt = |
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| Autoignition = }} |
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| FlashPt = |
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'''Divicine''' (2,6-diamino-4,5-dihydroxypyrimidine) is an oxidant and a base with alkaloidal properties found in ] and '']''. It is an ] of ]. A common derivative is the diacetate form (2,6-diamino-1,6-dihydro-4,5-pyrimidinedione).<ref name=Structure>{{cite journal |author=Bendich, C. |year=1953 |journal=Biochim. Biophys. |volume=12 |page=462}}</ref> |
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'''Divicine''' (2,6-diamino-4,5-dihydroxypyrimidine) is an oxidant and a base with alkaloidal properties found in ] and '']''. It is an ] of ]. A common derivative is the diacetate form (2,6-diamino-1,6-dihydro-4,5-pyrimidinedione).<ref name=Structure>{{cite journal |author=Bendich, C. |year=1953 |journal=Biochim. Biophys. Acta |volume=12 |issue=1–2 |pages=462–77 |doi=10.1016/0006-3002(53)90166-8 |pmid=13115456 |title=A revision of the structural formulation of vicine and its pyrimidine aglucone, divicine}}</ref> |
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==Occurrence== |
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==Occurrence== |
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Divicine is found in ] and in the legume '']'', also known as khesari, which is a cheap and robust food source commonly grown in Asia and East Africa. |
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Divicine is found in ] and in the legume '']'', also known as khesari, which is a cheap and robust food source commonly grown in Asia and East Africa.{{citation needed|date=November 2021}} |
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==Synthesis== |
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==Synthesis== |
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In plants, reduced divicine is formed from the hydrolysis of the inactive β–glucoside, ].<ref name= Baker>{{cite journal |author=Baker, M.; Bosia, A. |year=1984 |title=Mechanism of Action of Divicine in a Cell-free System and in Glucose-6-phosphate Dehydrogenase-deficient Red Cells |journal=Toxicol. Pathol. |volume=12 |pages=331–336}}</ref> |
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In plants, reduced divicine is formed from the hydrolysis of the inactive β–glucoside, ].<ref name= Baker>{{cite journal |author1=Baker, M. |author2=Bosia, A. |year=1984 |title=Mechanism of Action of Divicine in a Cell-free System and in Glucose-6-phosphate Dehydrogenase-deficient Red Cells |journal=Toxicol. Pathol. |volume=12 |issue=4 |pages=331–336 |doi=10.1177/019262338401200405|pmid=6099911 |s2cid=26038580 }}</ref> |
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A simplified three-step process for artificial divicine synthesis: |
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A simplified three-step process for artificial divicine synthesis: (1) The benzyl group of 2-amino-5-benzyloxy-4-hydroxypyrimidine is removed by ], yielding 2-amino-4,5-dihydroxypyrimidine. (2) This intermediate is then treated with nitrous acid to yield the slightly soluble orange product, 2-amino-6-nitrosopyrimidine-4,5-diol (3) which is then reduced with ] to yield divicine.<ref name=Synthesis>{{cite journal |author=Chesterfield, J.; et al.|year=1964 |title=194. Pyrimidines. Part XIII. Electrophilic substitution at position 6 and a synthesis of divicine (2,4-diamino-5,6-dihydroxypyrimidine) |journal=J. Chem. Soc. |pages=1001–1005}}</ref> |
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# The benzyl group of 2-amino-5-benzyloxy-4-hydroxypyrimidine is removed by ], yielding 2-amino-4,5-dihydroxypyrimidine. |
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# This intermediate is then treated with nitrous acid to yield the slightly soluble orange product 2-amino-6-nitrosopyrimidine-4,5-diol |
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# Which is then reduced with ] to yield divicine.<ref name="Synthesis">{{cite journal |author=Chesterfield, J.|year=1964 |title=194. Pyrimidines. Part XIII. Electrophilic substitution at position 6 and a synthesis of divicine (2,4-diamino-5,6-dihydroxypyrimidine) |journal=J. Chem. Soc. |pages=1001–1005|display-authors=etal|doi=10.1039/jr9640001001 }}</ref> |
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== Reactions == |
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Some chemical characteristics of divicine have been examined. It is known that it vigorously reduces ]ne solutions of 2,6-dichlorophenolindophenol, phosphomolybdate or phosphotungstate and produces an intense blue colour when reacting with an ammoniacal ferric chloride solution, which is used for the identification and proof of the presence of an enolic ] group. |
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Divicine is very unstable if oxygen is present and the oxidation is most rapid at alkaline pH levels. The half-life of divicine, at room temperature and neutral pH, is around half an hour. Both compounds are almost immediately destroyed by boiling, and breakdown in regular conditions can be accelerated by the presence of heavy metal ions, especially Cu<sup>2+</sup>.<ref>{{Cite book|title=Toxic constituents of plant foodstuffs|last1=Mager|first1=J.|last2=Razin|first2=A.|last3=Herschko|first3=A.|publisher=Academic Press|year=1969|editor-last=Liener|editor-first=I.|location=New York|pages=293–312}}</ref> |
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==Toxicity== |
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==Toxicity== |
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Divicine has been deemed a ] component of ] and plays a role in the development of ], a disorder that involves a hemolytic response to the consumption of broad beans due to ] (G6PD or G6PDH) deficiency. This deficiency, an X-linked recessive hereditary disease, is the most common enzyme deficiency worldwide. It is particularly common in those of African, Asian, Mediterranean, and Middle-Eastern descent. Symptoms of ] include ], prolonged ], ], and even ] in extreme cases.<ref name=MostCommonEnzymeDefect>{{cite journal |author=Frank, J. |year=2005 |title=Diagnosis and management of G6PD deficiency |journal=Am. Fam. Phys. |volume=72 |pages=1277–1282}}</ref> |
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Divicine has been deemed a ] component of ] and plays a role in the development of ], a disorder that involves a hemolytic response to the consumption of broad beans due to ] (G6PD or G6PDH) deficiency. This deficiency, an X-linked recessive hereditary disease, is the most common enzyme deficiency worldwide. It is particularly common in those of African, Asian, Mediterranean, and Middle-Eastern descent. Symptoms of ] include ], prolonged ], ], and even ] in extreme cases.<ref name=MostCommonEnzymeDefect>{{cite journal |author=Frank, J. |year=2005 |title=Diagnosis and management of G6PD deficiency |journal=Am. Fam. Physician |volume=72 |issue=7 |pages=1277–1282|pmid=16225031 }}</ref> |
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Divicine reacts with oxygen in red blood cells, which creates ] such as ] and ]. These molecules are strong oxidizers of ] and ].<ref>{{Cite journal|last1=Luzzatto|first1=Lucio|last2=Arese|first2=Paolo|date=2018-01-04|editor-last=Longo|editor-first=Dan L.|title=Favism and Glucose-6-Phosphate Dehydrogenase Deficiency|journal=New England Journal of Medicine|volume=378|issue=1|pages=60–71|doi=10.1056/NEJMra1708111|pmid=29298156|issn=0028-4793}}</ref> G6PD deficient individuals cannot regenerate NADPH quickly enough to prevent depletion of glutathione. This depletion results in the cells having no protection against oxidative stress caused by the aglycones. Oxidative stress leads to damage of haemoglobin and disulphide bond aggregates (]), which result in haemolytic anaemia, called favism.<ref>{{Cite journal|last1=Pulkkinen|first1=Marjo|last2=Zhou|first2=Xiao|last3=Lampi|first3=Anna-Maija|last4=Piironen|first4=Vieno|date=December 2016|title=Determination and stability of divicine and isouramil produced by enzymatic hydrolysis of vicine and convicine of faba bean|journal=Food Chemistry|volume=212|pages=10–19|doi=10.1016/j.foodchem.2016.05.077|pmid=27374500}}</ref> |
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The specific mechanism of divicine’s toxicity is still unknown. It had been established that the β–glucosides ] and convicine were linked to the precipitation of hemolytic crises in G6PDH-deficient individuals,<ref name=VicineCovicine>{{cite book |last= Doyle |first= M. Ellin |title= ] |publisher= ] |year= 1995 |page=357 |isbn= 0-8247-9624-1}}</ref> but in a more recent study of rat erythrocyte toxicity, exposure to 1.5 mM of divicine dramatically reduced survival rates while exposure to 5 mM of ] did not. These results suggest that divicine is a direct-acting hemolytic agent and likely the direct cause of ].<ref name= McMillan>{{cite journal |author=McMillan, D.; et al. |year=2001 |title=Favism: Effect of Divicine on Rat Erythrocyte Sulfhydryl Status, Hexose Monophosphate Shunt Activity, Morphology, and Membrane Skeletal Proteins |doi=10.1093/toxsci/62.2.353|journal=Toxicol. Sci. |volume=62 |pages=353–359}}</ref> |
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Divicine is also present in and at least partially responsible for the poisonous action of '']'' - a legume commonly grown in drought- and famine-prone regions of Asia and East Africa as an ‘insurance crop’ for human consumption and livestock feed when other crops fail to grow, despite their known health hazards.<ref name=BioOnline>http://www.biology-online.org/dictionary/Divicine</ref> |
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Divicine is also present in and at least partially responsible for the poisonous action of '']'' - a legume commonly grown in drought- and famine-prone regions of Asia and East Africa as an ‘insurance crop’ for human consumption and livestock feed when other crops fail to grow, despite their known health hazards.{{cn|date=January 2024}} |
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== Effects on animals == |
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In vitro studies in rats showed that a hemotoxic dose of divicine of 1.5 mM, when added to a suspension of red blood cells, resulted in a rapid decline in cellular glutathione, formation of ]s and damage to the membrane skeleton. This resulted in a decrease in ].<ref>{{Cite journal|last=McMillan|first=D. C.|date=2001-08-01|title=Favism: Effect of Divicine on Rat Erythrocyte Sulfhydryl Status, Hexose Monophosphate Shunt Activity, Morphology, and Membrane Skeletal Proteins|journal=Toxicological Sciences|volume=62|issue=2|pages=353–359|doi=10.1093/toxsci/62.2.353|pmid=11452148|doi-access=free}}</ref> |
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== References == |
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== References == |
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