Total Synthesis of (±)-Cylindrospermopsin

Xie, Chaoyu; Runnegar, and Maria T. C.; Snider, Barry B.

doi:10.1021/ja000647j

Cited by 55 publications

(68 citation statements)

References 62 publications

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“…15 The yield was improved to 90% in the presence of chlorotrimethylsilane (TMSCl) (entry 4). 16 Since BF 3 · OEt 2 appears to cause an increase in trans-isomer production, we next attempted the reaction without Cu(I). The reaction proceeded smoothly and the ratio of trans product ( 17 ) was increased (ca.…”

Section: Resultsmentioning

confidence: 99%

Stereocontrolled Synthesis and Pharmacological Evaluation ofcis-2,6-Diphenethyl-1-azabicyclo[2.2.2]octanes as Lobelane Analogues

Zheng

Dwoskin²,

Deaciuc³

et al. 2009

J. Org. Chem.

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An efficient and highly stereocontrolled approach for the synthesis of the quinuclidine incorporated lobelane analogues, endo,endo- and exo,exo-2,6-cis-diphenethyl-1-azabicyclo-[2.2.2]octane (2 and 3), has been developed. Analogues 2 and 3 were designed to mimic the axial and equatorial geometry, respectively, of the vesicular monoamine transporter-2 (VMAT2) inhibitor, lobelane. The exo,exo analogue 2 had comparable affinity to lobelane and had greater affinity than the endo,endo analogue 3 at the tetrabenazine binding site onVMAT2, indicating that the preferred binding mode of lobelane is likely the extended conformation.

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Section: Resultsmentioning

confidence: 99%

Stereocontrolled Synthesis and Pharmacological Evaluation ofcis-2,6-Diphenethyl-1-azabicyclo[2.2.2]octanes as Lobelane Analogues

Zheng

Dwoskin²,

Deaciuc³

et al. 2009

J. Org. Chem.

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“…3). To prepare trans-9a and b, ketone 21 was stereoselectively reduced with L-selectride to yield alcohol 23, 21) which was submitted to a Mitsunobu reaction using diphenylphosphoryl azide (DPPA), diisopropyl azodicarboxylate (DIAD), and triphenylphosphine (TPP).…”

Section: Synthesismentioning

confidence: 99%

Design and Synthesis of a Piperidinone Scaffold as an Analgesic through Kappa-Opioid Receptor: Structure–Activity Relationship Study of Matrine Alkaloids

et al. 2016

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The matrine-type alkaloid 4-dimethylamino-1-pentanoylpiperidine (3a) has an antinociceptive effect through its impact on the κ-opioid receptor (KOR). Derivatives of 3a were synthesized by altering its amide and tertiary amine groups, and were evaluated for their antinociceptive effects. The results indicated that the distance between these groups on 3a was optimal for the antinociceptive effect. The effects obtained with compounds 8 and 9 indicated that the relative configuration of the 3-and 4-substituents influenced the effect mediated through the KOR.Key words antinociception; kappa opioid receptor (KOR); matrine; piperidone; acetic acid-induced abdominal contraction test; mouse Narcotic analgesics such as morphine are administered for pain relief to cancer patients. Most narcotic analgesics are µ-opioid receptor (MOR) agonists and have adverse effects such as addiction, 1) respiratory depression, 2) and constipation.3,4) Although stimulation of the κ-opioid receptor (KOR) results in significant analgesia, KOR agonists do not suffer from the same adverse effects as MOR agonists. Many KOR agonists, including ethylketocyclazocine, U-50,488H, and nalfurafine (TRK-820), have been developed and investigated for their analgesic, anti-inflammatory and antipruritic activity 5,6) ( Fig. 1). However, these agonists suffer from dose-limiting dysphoria, sedation, and psychotomimetic effects. 7,8) Consequently, the development of a KOR agonist that does not cause adverse effects is important.We previously reported that (+)-matrine (1) and (+)-allomatrine (2), typical matrine-type lupine alkaloids produced by Sophora Leguminosae, have antinociceptive properties identical to those of pentazocine.9) The effects of 1 were mediated mainly through activation of the KOR and partially through the MOR, and those of 2 were mediated only through the KOR.10) Furthermore, we found that neither 1 nor 2 provided the activation in the guanosine-5′-O-(3-[ 11) Although intracerebroventricular pretreatment with an antiserum against dynorphin A (1-17) did not affect the antinociceptive effect induced by subcutaneous (s.c.) treatment of 1 and 2, the antinociceptive effect was greatly attenuated by intrathecal (i.t.) pretreatment with an antiserum against dynorphin A (1-17) in mice. This suggested that the antinociceptive effect induced by s.c. treatment of 1 and 2 occurred without binding to the KOR in the ventricles of the brain, in where might stimulate the descending dynorphinergic neuron and production of dynorphin in the spinal cord.Because the pharmacological mechanism of action and chemical structures of 1 and 2 differ from conventional KOR agonists, we performed structure-activity relationship (SAR) studies for 1 and 2 and their antinociceptive activity using modifications of the A-D ring systems. The SAR studies showed that the amide group, tertiary amine group, and Cring of 1 and 2 were important in determining their activity. 4-Dimethylamino-1-pentanoylpiperidine (3) was identified as a lead compound through the antinociceptive eff...

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“…While 3 and 4 were shown to be equipotent hepatotoxic glutathione biosynthesis inhibitors, the deoxy analogue 5 showed no activity. During the course of our efforts, Snider (5) and Weinreb (6) had reported racemic syntheses of 3 , while White (7) had synthesized 4 in optically active form.…”

Section: Cylindrospermopsinmentioning

confidence: 99%

ChemInform Abstract: New Tricks in Amino Acid Synthesis: Applications to Complex Natural Products

Williams

Burnett

2009

ChemInform

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Total Synthesis of (±)-Cylindrospermopsin

Cited by 55 publications

References 62 publications

Stereocontrolled Synthesis and Pharmacological Evaluation ofcis-2,6-Diphenethyl-1-azabicyclo[2.2.2]octanes as Lobelane Analogues

Stereocontrolled Synthesis and Pharmacological Evaluation ofcis-2,6-Diphenethyl-1-azabicyclo[2.2.2]octanes as Lobelane Analogues

Design and Synthesis of a Piperidinone Scaffold as an Analgesic through Kappa-Opioid Receptor: Structure–Activity Relationship Study of Matrine Alkaloids

ChemInform Abstract: New Tricks in Amino Acid Synthesis: Applications to Complex Natural Products

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