Unequivocal determination of caulamidines A and B: application and validation of new tools in the structure elucidation tool box

Chemical Science Cover - Vol. 9, No. 2, 2018

About the Cover:
The molecular structure of the novel chlorinated alkaloid caulamidine A, with the marine bryozoan that produces it in the background.

Abstract:
Ambiguities and errors in the structural assignment of organic molecules hinder both drug discovery and total synthesis efforts. Newly described NMR experimental approaches can provide valuable structural details and a complimentary means of structure verification. The caulamidines are trihalogenated alkaloids from a marine bryozoan with an unprecedented structural scaffold. Their unique carbon and nitrogen framework was deduced by conventional NMR methods supplemented by new experiments that define 2-bond heteronuclear connectivities, reveal very long-range connectivity data, or visualize the 35/37Cl isotopic effect on chlorinated carbons. Computer-assisted structural elucidation (CASE) analysis of the spectroscopic data for caulamidine A provided only one viable structural alternative. Anisotropic NMR parameters, specifically residual dipolar coupling and residual chemical shift anisotropy data, were measured for caulamidine A and compared to DFT-calculated values for the proposed structure, the CASE-derived structure and two potential stereoisomers. Anisotropy-based NMR experiments provide an orthogonal means to verify complex structures free from investigator bias, and they unequivocally confirmed the structure and configuration of caulamidine A. Caulamidine B has the same heterocyclic scaffold as A but a different composition and pattern of halogen substitution. Caulamidines A and B inhibited both wild-type and drug-resistant strains of the malaria parasite Plasmodium falciparum at low micromolar concentrations, yet were nontoxic to human cells.

 

 

Lab/Branch/Program: 
Molecular Targets Program
Citation: 

Unequivocal determination of caulamidines A and B:  application and validation of new tools in the structure elucidation tool box. Martin GE, Gustafson KR, et al. Chem Sci. 9(2):269-534, 2018.

Published Date: 
January, 2018