23291-96-5

Usage

Chemical Properties

Beige Solid

Uses

A metabolite of the potent hepatotoxin Monocrotaline.

InChI:InChI=1/C16H21NO6/c1-9-13(18)23-11-5-7-17-6-4-10(12(11)17)8-22-14(19)16(3,21)15(9,2)20/h4,6,9,11,20-21H,5,7-8H2,1-3H3/t9-,11+,15+,16-/m0/s1

Upstream product

• 315-22-0 monocrotaline 
• 480-85-3 retronecine 
• 50-89-5 thymidine 
• 315-22-0 monocrotaline 

Downstream Products

• 26543-09-9 Monocrotalic acid 
• 28333-17-7 dehydroretronecine dimethyl ether 
• 133787-47-0 C₁₉H₂₄N₆O₅ 
• 133787-51-6 1-((2R,4S,5R)-4-Hydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-4-imino-3-(7-methoxy-6,7-dihydro-5H-pyrrolizin-1-ylmethyl)-3,4-dihydro-1H-pyrimidin-2-one 
• 133787-49-2 1-((2R,4S,5R)-4-Hydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-3-(7-methoxy-6,7-dihydro-5H-pyrrolizin-1-ylmethyl)-5-methyl-1H-pyrimidine-2,4-dione 
• 133787-45-8 (2R,3S,5R)-2-Hydroxymethyl-5-[6-imino-1-(7-methoxy-6,7-dihydro-5H-pyrrolizin-1-ylmethyl)-1,6-dihydro-purin-9-yl]-tetrahydro-furan-3-ol 
• 133787-46-9 (2R,3S,5R)-2-Hydroxymethyl-5-{6-[(7-methoxy-6,7-dihydro-5H-pyrrolizin-1-ylmethyl)-amino]-purin-9-yl}-tetrahydro-furan-3-ol 
• 130816-05-6 1-ethoxy-7-ethoxymethyl-2,3-dihydro-1H-pyrrolizine 
• 26400-45-3 (+/-)-6,7-dihydro-7-hydroxy-1-(hydroxymethyl)-5H-pyrrolizine 

Relevant academic research and scientific papers

Pyrrolizidine Alkaloid Secondary Pyrrolic Metabolites Construct Multiple Activation Pathways Leading to DNA Adduct Formation and Potential Liver Tumor Initiation

Pyrrolizidine alkaloids (PAs) and their N-oxide derivatives are hepatotoxic, genotoxic, and carcinogenic phytochemicals. PAs induce liver tumors through a general genotoxic mechanism mediated by a set of four (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts. To date, the primary pyrrolic metabolites dehydro-PAs, their hydrolyzed metabolite DHP, and two secondary pyrrolic metabolites 7-glutathione-DHP (7-GS-DHP) and 7-cysteine-DHP are the known metabolites that can generate these DHP-DNA adducts in vivo and/or in PA-treated cells. Secondary pyrrolic metabolites are formed from the reaction of dehydro-PAs with glutathione, amino acids, and proteins. In this investigation, we determined whether or not more secondary pyrrolic metabolites can bind to calf thymus DNA and to cellular DNA in HepG2 cells resulting in the formation of DHP-DNA adducts using a series of secondary pyrrolic metabolites (including 7-methoxy-DHP, 9-ethoxy-DHP, 9-valine-DHP, 7-GS-DHP, 7-cysteine-DHP, and 7,9-diglutathione-DHP) and synthetic pyrroles for study. We found that (i) many secondary pyrrolic metabolites are DNA reactive and can form DHP-DNA adducts and (ii) multiple activation pathways are involved in producing DHP-DNA adducts associated with PA-induced liver tumor initiation. These results suggest that secondary pyrrolic metabolites play a vital role in the initiation of PA-induced liver tumors.

Retrorsine, but not monocrotaline, is a mechanism-based inactivator of P450 3A4

Retrorsine (RTS) and monocrotaline (MCT) cause severe toxicities via P450-mediated metabolic activation. The screening of mechanism-based inhibitors showed RTS inactivated 3A4 in the presence of NADPH. Unlike RTS, MCT failed to inhibit P450 3A4 and other enzymes tested. Further studies showed the loss of P450 3A4 activity occurred in a time- and concentration-dependent way, which was not recovered after dialysis. Dextromethorphan, a P450 3A4 substrate, protected the enzyme from the inactivation. Exogenous nucleophile glutathione (GSH) and reactive oxygen species scavengers catalase and superoxide dismutase did not protect P450 3A4 from the inactivation. GSH trapping experiments showed both P450 3A4 and 2C19 converted RTS and MCT to the corresponding electrophilic metabolites which could be trapped by GSH to form 7-GSH-DHP conjugate. We conclude that RTS and MCT are metabolically activated by P450 3A4 and 2C19, and that RTS, but not MCT, is a mechanism-based inactivator of P450 3A4.

Alkylation of nucleosides by dehydromonocrotaline, the putative toxic metabolite of the carcinogenic pyrrolizidine alkaloid monocrotaline

Reactin of dehydromonocrotaline (3), the putative toxic metabolite of the carcinogenic pyrrolizidine alkaloid monocrotaline (2), with various nucleosides proceeded mostly at the C-9'' position of 3 to give several nitrogen atom-alkylated including N-7 alkylated 2'-deoxyguanosine 14.

Kinetics of Alkylation Reactions of Pyrrolizidine Alkaloid Pyrroles

Pyrrolizidine alkaloid pyrrolws react rapidly with 4-(p-nitrobenzyl)pyridine under pseudo-first order conditions.A biexpotential first-order rate law is observed.Relative reactivities are grewatly influenced by the nature of the leaving group at C7. 2,3-Dihydro-1H-pyrrolizin-1-ol and dehydrosupinidine under pseudo-first-order reaction conditions obey a simple first-order rate expression.Evidence for oligomerization of the pyrrolizidine pyrrole nucleus has been obtained under these reaction conditions, and it is proposed that a second color-forming reaction sequence of nucleophile with the oligomer C9s accounts for the biexpotential rate law.