Total Synthesis and Biological Evaluation of Rakicidin†A and Discovery of a Simplified Bioactive Analogue.

We report a concise asymmetric synthesis of rakicidin A, a macrocyclic depsipeptide that selectively inhibits the growth of hypoxic cancer cells and stem-like leukemia cells. Key transformations include a diastereoselective organocatalytic cross-aldol reaction to build the polyketide portion of the molecule, a highly hindered ester fragment coupling reaction, an efficient Helquist-type Horner-Wadsworth-Emmons (HWE) macrocyclization, and a new DSC-mediated elimination reaction to construct the sensitive APD portion of rakicidin A. We further report the preparation of a simplified structural analogue (WY1) with dramatically enhanced hypoxia-selective activity.

Ester coupling reactions--an enduring challenge in the chemical synthesis of bioactive natural products.

In this review we investigate the use of complex ester fragment couplings within natural product total synthesis campaigns. We first outline the different biosynthetic and chemical strategies for performing complex ester couplings and on this mechanistic background we then present and discuss a collection of successful examples from the literature.

Aminomethyltetrazoles as potential inhibitors of the γ-aminobutyric acid transporters mGAT1-mGAT4: synthesis and biological evaluation.

1,5-Disubstituted and 5-monosubstituted aminomethyltetrazole derivatives derived from glycine were synthesized employing a TMSN(3)-modified variant of the Ugi reaction as a key step. All compounds were evaluated regarding their inhibitory potency and subtype selectivity at the four murine GABA transporter subtypes mGAT1-mGAT4. Though none of the 5-monosubstituted tetrazoles turned out to inhibit [(3)H]GABA uptake to a significant extent, the 1,5-disubstituted tetrazole derivatives displayed a distinct activity, especially at the GABA transport proteins mGAT2-mGAT4. Thus, a reasonable potent and selective inhibitor of mGAT3 was found. Additionally, two more compounds were identified as potent inhibitors of mGAT2. This is especially relevant, as up to date only few potent inhibitors of mGAT2 that do not affect mGAT1 are known.

The amido-pentadienoate-functionality of the rakicidins is a thiol reactive electrophile--development of a general synthetic strategy.

We demonstrate that a unique class-defining functionality (mc-APD) found in macrocyclic natural products with potent anti-cancer activity, imparts these compounds with electrophilic reactivity. The mc-APD group represents an interesting structural hybrid between canonical biologically relevant Michael-acceptors. Further, a novel thiol-elimination method for preparation of the mc-APD group is outlined.

The natural product brartemicin is a high affinity ligand for the carbohydrate-recognition domain of the macrophage receptor mincle.

We demonstrate that the natural product brartemicin, a newly discovered inhibitor of cancer cell invasion, is a high-affinity ligand of the carbohydrate-recognition domain (CRD) of the C-type lectin mincle. Recent studies have revealed that mincle is a key macrophage receptor for the mycobacterial virulence factor trehalose dimycolate (TDM), which is a glycolipid component of the mycobacterial cell wall. Major uncertainties, however, remain concerning the mechanism of TDM-binding and subsequent signal transduction as well as interplay of potential co-receptors. Due to the lipid nature of TDM, functional studies are difficult and soluble mincle-ligands are therefore of significant interest. Brartemicin, together with designed analogs also presented in this paper, may thus serve as useful molecular probes for future studies of mincle. Through computational studies, we further provide an insight into the probable mode of binding of brartemicin.