Membrane plasticity induced by myo-inositol derived archaeal lipids: chemical synthesis and biophysical characterization.

Archaeal membrane lipids have specific structures that allow Archaea to withstand extreme conditions of temperature and pressure. In order to understand the molecular parameters that govern such resistance, the synthesis of 1,2-di-O-phytanyl-sn-glycero-3-phosphoinositol (DoPhPI), an archaeal lipid derived from myo-inositol, is reported. Benzyl protected myo-inositol was first prepared and then transformed to phosphodiester derivatives using a phosphoramidite based-coupling reaction with archaeol. Aqueous dispersions of DoPhPI alone or mixed with DoPhPC can be extruded and form small unilamellar vesicles, as detected by DLS. Neutron, SAXS, and solid-state NMR demonstrated that the water dispersions could form a lamellar phase at room temperature that then evolves into cubic and hexagonal phases with increasing temperature. Phytanyl chains were also found to impart remarkable and nearly constant dynamics to the bilayer over wide temperature ranges. All these new properties of archaeal lipids are proposed as providers of plasticity and thus means for the archaeal membrane to resist extreme conditions.

Synthesis of Phospholipids Under Plausible Prebiotic Conditions and Analogies with Phospholipid Biochemistry for Origin of Life Studies.

Phospholipids are essential components of biological membranes and are involved in cell signalization, in several enzymatic reactions, and in energy metabolism. In addition, phospholipids represent an evolutionary and non-negligible step in life emergence. Progress in the past decades has led to a deeper understanding of these unique hydrophobic molecules and their most pertinent functions in cell biology. Today, a growing interest in "prebiotic lipidomics" calls for a new assessment of these relevant biomolecules.

Modular Total Synthesis of iso-Archazolids and Archazologs.

Full details on the design, development, and successful implementation of suitable synthetic strategies directed toward the total synthesis of iso-archazolids and archazologs are reported. Both a biomimetic and a multistep total synthesis of iso-archazolid B, the most potent and least abundant archazolid, are described. The bioinspired conversion from archazolid B was realized by a high-yielding 1,8-Diazabicyclo[5.4.0]undec-7-ene catalyzed one-step double-bond shift. A highly stereoselective total synthesis was accomplished in 25 steps, involving a sequence of highly stereoselective aldol reactions, an efficient aldol condensation to forge two elaborate fragments, and a challenging ring-closing metathesis macrocyclization with an unusual Stewart-Grubbs catalyst. These strategies proved to be generally useful and could be successfully implemented for the preparation of three novel iso-archazolids as well as five novel archazologs, lacking the thiazole side chain. A wide variety of further archazolids and archazologs may now be targeted for exploration of the promising anticancer potential of these polyketide macrolides.

Straightforward Synthesis of Chiral Terpenoid Building Blocks by Ru-Catalyzed Enantioselective Hydrogenation.

Starting from commercially available (R)- and (S)-ß-citronellol, two strategies were designed to synthesize all four stereoisomers of 2,6-dimethyloctane monoterpene chirons in four or five steps in 32-47% overall yield. The desired fragments were obtained by a key Ru-catalyzed asymmetric olefin hydrogenation step under moderate temperature (50 °C), pressure (4 bar), and low catalyst loadings (0.5 mol %) under optimized conditions. Screening of commercially available catalysts highlighted the key role of DM-SEGPHOS as an economically advantageous alternative to commonly used H8-BINAP for equal performances. These results open new possibilities for versatile and scalable syntheses of these useful building blocks.

Synthesis of Novel Potent Archazolids: Pharmacology of an Emerging Class of Anticancer Drugs.

Vacuolar type ATPase (V-ATPase) has recently emerged as a promising novel anticancer target based on extensive in vitro and in vivo studies with archazolids, complex polyketide macrolides, which present the most potent V-ATPase inhibitors known to date. Herein, we report a biomimetic, one-step preparation of archazolid F, the most potent and least abundant archazolid, the design and synthesis of five novel, carefully selected archazolid analogues, and the biological evaluation of these antiproliferative agents, leading to the discovery of a very potent but profoundly simplified archazolid analogue. Furthermore, the first general biological profiling of the archazolids against a broad range of more than 100 therapeutically relevant targets is reported, leading to the discovery of novel and important targets. Finally, first pharmacokinetic data of these natural products are disclosed. All of these data are relevant in the further preclinical development of the archazolids as well as the evaluation of V-ATPases as a novel and powerful class of anticancer targets.

α-Hydroxyallylsilanes as propionaldehyde enolate equivalents and their use toward iterative aldol reactions.

Smooth and efficient reaction conditions have been found for the transformation of protected ß-hydroxyacylsilanes into the corresponding aldehydes. This opens a new route to iterative aldol reactions, and it has been used for the synthesis of fragments of several bioactive natural products.