Mandelalides A–D, Cytotoxic Macrolides from a New Lissoclinum Species of South African Tunicate

Abstract

Mandelalides A-D are variously glycosylated, unusual polyketide macrolides isolated from a new species of Lissoclinum ascidian collected from South Africa, Algoa Bay near Port Elizabeth and the surrounding Nelson Mandela Metropole. Their planar structures were elucidated on sub-milligram samples by comprehensive analysis of 1D and 2D NMR data, supported by mass spectrometry. The assignment of relative configuration was accomplished by consideration of homonuclear and heteronuclear coupling constants in tandem with ROESY data. The absolute configuration was assigned for mandelalide A after chiral GC-MS analysis of the hydrolyzed monosaccharide (2-O-methyl-α-L-rhamnose) and consideration of ROESY correlations between the monosaccharide and aglycone in the intact natural product. The resultant absolute configuration of the mandelalide A macrolide was extrapolated to propose the absolute configurations of mandelalides B-D. Remarkably, mandelalide B contained the C-4′ epimeric 2-O-methyl-6-dehydro-α-L-talose. 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).

New Mandelalides Expand a Macrolide Series of Mitochondrial Inhibitors

“…The lyophilized tunicate was extracted and fractionated as reported previously. 4 Briefly, the organic extract (2:1 DCM-MeOH) was fractionated on Sephadex LH-20 (DCM-MeOH, 1:3), and provided two consecutively eluting fractions containing MS peaks indicative of mandelalide-type compounds, which were combined and subjected to RP 18 SPE. Exhaustive HPLC separations of the MS-targeted SPE fraction yielded the desired compounds 1 – 4, 5 , 10 and seven new congeners, named mandelalides F–L ( 6–12 ), in sufficient quantities for chemical characterization and investigation of the mechanistic basis for mandelalide action.…”

Computational Chemistry to the Rescue: Modern Toolboxes for the Assignment of Complex Molecules by GIAO NMR Calculations

“…Mandelalide A represents not only a relevant and illustrative case of the role of total synthesis in solving structural problems, but also an emblematic example of the modest performance made by DP4 in some difficult scenarios. This complex natural product was isolated in 2012 from new species of Lissoclin by McPhail and co‐workers, which after detailed and extensive NMR experiments, along with chemical derivatization analysis, proposed the structure 34 depicted in Figure . Enticed by the remarkable anticancer activity and molecular complexity, several synthetic groups focused their efforts towards the total synthesis of mandelalide A—the group of Fürstner was the first to achieve this challenging goal in 2014.…”

Strategies to Control Alkoxy Radical-Initiated Relay Cyclizations for the Synthesis of Oxygenated Tetrahydrofuran Motifs

“…12,13 The first step of these cascade reactions involves the generation of a highly reactive alkoxy radical species (3) that can undergo a 1,5-hydrogen atom transfer (1,5-HAT) of an unactivated or an activated carbon−hydrogen bond to form carbon radical 4. Once the radical has been "relayed" across the substrate, a radical cyclization cascade takes place to form the key tetrahydrofuran (5). This approach has two key advantages over previously developed methods: no prefunctionalization is required at C-5 (3), and initiating with an alkoxy radical leaves an alcohol for further synthetic manipulation.…”