Human Cytochrome P450 Liability Studies of trans-Dihydronarciclasine: A Readily Available, Potent, and Selective Cancer Cell Growth Inhibitor

Abstract

The cytochrome P45O activities of the naturally occurring Amaryllidaceae alkaloid narciclasine (3), isolated from Narcissus pseudonarcissus, and synthetic derivative trans-dihydronarciclasine (5) are reported. While narciclasine was found to possess potent inhibitory activity to human CYP3A4, its dihydro analogue was inactive. This study revealed that the C1-C10b double bond is required for inhibition of this crucial metabolizing enzyme. Compound 5 also demonstrated no inhibition of the related human cytochromes CYP19 and CYP1A1. This study elevates the status of trans-dihydronarciclasine (5) as a highly privileged, readily available molecule, with potent and selective anticancer activity.

Enantioselective Organocatalytic Michael/Aldol Sequence: Anticancer Natural Product (+)‐trans‐Dihydrolycoricidine

“…Anticancer investigations of these analogues demonstrated that 6 constitutes the minimum anticancer pharmacophore in the series 2l–p. Additionally, the 1‐10b‐styryl double bond in narciclasine ( 3 ) is associated with unwanted cytochrome P 450 activity,2q thus highlighting the importance of 5 and 6 toward developing a potent and selective anticancer agent.…”

Total Synthesis of the Natural Product (+)‐trans‐Dihydronarciclasine via an Asymmetric Organocatalytic [3+3]‐Cycloaddition and discovery of its potent anti‐Zika Virus (ZIKV) Activity

“…Natural (+)‐ trans ‐dihydronarciclasine 1 has been the subject of three prior asymmetric syntheses,– three racemic syntheses,– and the compound has also been the subject of semi‐synthesis via selective hydrogenation of narciclasine 3 . We were inspired by recent enantioselective organocatalytic approaches toward six member carbacycles to develop a stepwise [3+3]‐type Michael‐aldol sequence,– involving an α‐nitrogen‐substituted acetone moiety reacting with an unsaturated aldehyde, as a rapid entry to the amaryllidaceae core.…”

The Asymmetric Hetero‐Diels–Alder Reaction in the Syntheses of Biologically Relevant Compounds

“…The infamous azaspiracid poisoning incident happened in 1995 when at least eight people in the Netherlands fell ill after consuming blue mussels (Mytilus edulis). [23] In 1998, the Yasumoto group isolated the causative toxin for this poisoning as azaspiracid-1 (33). [24] Since then, 11 azaspiracid analogues have been described.…”

“…An interesting application of an enantioselective nitroso-Diels-Alder reaction was reported in the total synthesis of trans-dihydronarciclasine (45; Scheme 7). [33] The desired stereochemistry in the target molecule was induced by the key HDA reaction between a decorated cyclohexadiene (39) and 2-nitrosopyridine (40), thus yielding the regioisomeric bicyclic compounds 42 and 43 with ee values of up to 99 %. [34] The HDA reaction was catalyzed with the chiral Walphos catalyst 41 in the presence of copper(I).…”