ABSTRACT
We report a concise asymmetric synthesis of rakicidinâ 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 rakicidinâ A. We further report the preparation of a simplified structural analogue (WY1) with dramatically enhanced hypoxia-selective activity.
Subject(s)
Lipopeptides/chemical synthesis , Lipopeptides/pharmacology , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/pharmacology , Cell Line, Tumor , Drug Discovery , HumansABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemistry , Lipopeptides/chemistry , Peptides, Cyclic/chemistry , Sulfhydryl Compounds/chemistry , Serum Albumin, Bovine/chemistryABSTRACT
An epimer of the known glycosidase inhibitor noeurostegine, galacto-noeurostegine, was synthesised in 21 steps from levoglucosan and found to be a potent, competitive and highly selective galactosidase inhibitor of Aspergillus oryzae ß-galactosidase. Galacto-noeurostegine was not found to be an inhibitor of green coffee bean α-galactosidase, yeast α-glucosidase and E. coli ß-galactosidase, whereas potent but non-competitive inhibition against sweet almond ß-glucosidase was established. The 2-deoxy-galacto-noeurostegine analogue was also prepared and found to be a less potent inhibitor of the same enzymes.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Fucose/chemical synthesis , Fucose/pharmacology , Glycoside Hydrolases/antagonists & inhibitors , Nortropanes/chemical synthesis , Nortropanes/pharmacology , Carbohydrate Conformation , Carbon-13 Magnetic Resonance Spectroscopy , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Fucose/chemistry , Glycoside Hydrolases/metabolism , Nortropanes/chemistryABSTRACT
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.
ABSTRACT
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.