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.

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.



Molecular Targets Program

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