New and known mandelalides for biological mechanism and structure-activity relationship studies

Abstract

Mandelalides A-D are polyketide macrolides reported from a new Lissoclinum species of South African ascidian in 2012. The conformational flexibility of the macrolactone skeleton and the presence of two discrete and independent stereochemical regions confounded the absolute assignments of mandelalides A-D by spectroscopic methods. The absolute structure of mandelalide A was subsequently corrected, through total synthesis, to a configuration where all five stereocenters in the northern hemisphere were inverted. The revision of mandelalide A makes it likely that mandelalides B-D were also misassigned. Further evaluation of the potent biological activity is also needed given that the glycosylated mandelalides A and B showed potent cytotoxicity to human NCI-H460 lung cancer cells (IC50, 12 and 44 nM, respectively) and mouse Neuro-2A neuroblastoma cells (IC50, 29 and 84 nM, respectively), while insufficient amounts of non-glycosylated mandelalides C and D prevented their biological testing as pure compounds. Herein, computational methods have been used to predict 13C and 1H NMR chemical shifts for comparison to the experimental data for mandelalide A and investigate the absolute configurations of mandelalides B-D, which contain an additional furanone compared to mandelalide A. In addition, new members of the mandelalide family have been isolated and characterized from a re-collection of the source tunicate, and provide further insight into the structure-activity relationships of this compound series.