Two Highly Populated Conformations at Room Temperature of Monterine and Granjine, Antitumor Bisbenzylisoquinoline Alkaloids:  Origin and Tridimensional Structures

• Published in: Journal of organic chemistry 1996-05, Vol.61 (9), p.3023-3030
• Main Authors: Jossang, Akino, Cavé, Adrien, Saez, Jairo, Bartoli, Marie Hélène, Cavé, André, Jossang, Per
• Format: Article
• Language: English
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo950767n

Monterine 1 as well as granjine 3, 1R,1‘S configured biphenylic bisbenzylisoquinoline alkaloids, generate two highly populated conformers. The interconversion of two forms was detected by saturation tranfer in 1H NMR NOEs experiments. Tridimensional structure of the conformers was determined on the basis of 1H NMR analysis of anisotropic shielding protons, by NOEs measurements and vicinal proton coupling constants of CH1−CH2α and CH1‘−CH2α‘. The structures established from NMR data were further refined to observe the mobility of 3D conformations by molecular dynamics simulation in vacuo. The highly populated conformers, monterine 1a and 1b, as well as granjine 3a and 3b, are interconvertible by rotation about the C1‘−Cα‘, Cα‘−C9‘, and C11‘−C11 bonds and inversion of the benzyl D ring by reference to CH2α‘. The slow exchange system was investigated by dynamic NMR spectroscopy:  ΔG ⧧ c 77.9 KJ/mol and k c 200 s-1 for monterine 1; ΔG ⧧ c 77.7 KJ/mol and k c 211 s-1 for granjine 3. Natural and synthetic biphenylic bisbenzylisoquinolines displayed, in vitro, cytotoxic activities against human prostate and breast cancer cell lines.