65026-49-5Relevant articles and documents
Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine's Biological Activity
Norwood, Verrill M.,Brice-Tutt, Ariana C.,Eans, Shainnel O.,Stacy, Heather M.,Shi, Guqin,Ratnayake, Ranjala,Rocca, James R.,Abboud, Khalil A.,Li, Chenglong,Luesch, Hendrik,McLaughlin, Jay P.,Huigens, Robert W.
, p. 5119 - 5138 (2020/06/10)
Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction.
Cycloaddition Reaction of Mesoionic Betaines as an Approach toward Trialkylindoline Alkaloids
Padwa, Albert,Harring, Scott R.,Semones, Mark A.
, p. 44 - 54 (2007/10/03)
Intramolecular 1,4-dipolar cycloaddition of an anhydro-4-hydroxy-2-oxo-1,3-thiazium hydroxide across a tethered indole π-bond has been used for the construction of the pentacyclic skeleton of epi-16,17-dihydroeburnamenine. The reaction of 3-ethyl-3-(alkenyl)piperidinones with diketene and trimethylsilyl triflate in benzene at ambient temperature produced annulated pyridones in good yield. The initial reaction involved formation of a N-acetoacetylated amide which was further converted to the pyridone with TMSOTf. The overall process was found to proceed with complete stereospecificity. Treating a sample of 3-ethyl-3-[(E)-4-phenyl-3-butenyl]-2-piperidone with diketene and TMSOTf produced a cycloadduct in 63% yield whose stereochemistry was elucidated by a X-ray crystallographic study. The epimeric Z-isomer produced a different stereoisomer of the annulated dihydropyridone. The mechanism of the annulation involves a TMSOTf induced cyclization followed by proton removal and generation of a cross-conjugated heteroaromatic betaine. This 1,4-dipole undergoes a subsequent intramolecular dipolar cycloaddition across the neighboring π-bond, and the resulting cycloadduct is subsequently converted to the annulated lactam. A related annulation sequence leading to a key intermediate previously utilized in the synthesis of the (±)-vallesamidine has been developed which is based on the intramolecular dipolar cycloaddition of a mesoionic betaine intermediate.
Flow Thermolysis Rearrangements in the Indole Alkaloid Series: 1,2-Dehydroaspidospermidine
Hugel, Georgette,Royer, Daniel,Sigaut, Francoise,Levy, Jean
, p. 4631 - 4636 (2007/10/02)
Flow thermolysis of 1,2-dehydroaspidospermidine (1) at various temperatures allowed isolation of all four predictable rearrangement products, namely indolenines 2 and 3 and indoles 4 and 5.The structures of the rearranged products were confirmed by chemical and spectroscopic means, particularly HMBC and HMQC NMR techniques.
