Takefumi Kuranaga

Total synthesis and structural confirmation of brevisamide, a new marine cyclic ether alkaloid from the dinoflagellate Karenia brevis.

The first total synthesis of brevisamide (1) has been accomplished in 21 linear steps starting from cis-but-2-ene-1,4-diol. A synthetic highlight is the Suzuki-Miyaura coupling between an ether ring fragment and a dienol side chain. This result confirmed the structure of 1 isolated from the dinoflagellate Karenia brevis.

Identification of a Conformational Equilibrium That Determines the Efficacy and Functional Selectivity of the μ‐Opioid Receptor

G-protein-coupled receptor (GPCR) ligands impart differing degrees of signaling in the G-protein and arrestin pathways, in phenomena called “biased signaling”. However, the mechanism underlying the biased signaling of GPCRs is still unclear, although crystal structures of GPCRs bound to the G protein or arrestin are available. In this study, we observed the NMR signals from methionine residues of the μ-opioid receptor (μOR) in the balanced- and biased-ligand-bound states. We found that the intracellular cavity of μOR exists in an equilibrium between closed and multiple open conformations with coupled conformational changes on the transmembrane helices 3, 5, 6, and 7, and that the population of each open conformation determines the G-protein- and arrestin-mediated signaling levels in each ligand-bound state. These findings provide insight into the biased signaling of GPCRs and will be helpful for development of analgesics that stimulate μOR with reduced tolerance and dependence.

Total Synthesis and Biological Evaluation of the Antibiotic Lysocin E and Its Enantiomeric, Epimeric, and N‐Demethylated Analogues

Lysocin E, a macrocyclic peptide, exhibits potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) through a novel mechanism. The first total synthesis of lysocin E was achieved by applying a full solid-phase strategy. The developed approach also provides rapid access to the enantiomeric, epimeric, and N-demethylated analogues of lysocin E. Significantly, the antibacterial activity of the unnatural enantiomer was comparable to that of the natural isomer, suggesting the absence of chiral recognition in its mode of action.

Total Synthesis of (–)-Brevisin: A Concise Synthesis of a New Marine Polycyclic Ether

The first and highly efficient total synthesis of (-)-brevisin has been achieved. The title compound was synthesized in only 29 steps (longest linear sequence) from commercially available starting materials. The synthesis provided over 70 mg of a marine polycyclic ether compound.

Rational design, synthesis, and biological evaluation of lactam-bridged gramicidin A analogues: discovery of a low-hemolytic antibacterial peptide.

A linear peptide, gramicidin A (GA), folds into a β6.3‐helix, functions as an ion channel in the cell membrane, and exerts antibacterial activity. Herein we describe the rational design, synthesis, and biological evaluation of lactam‐bridged GA analogues. The GA analogue with a 27‐membered macrolactam was found to adopt a stable β6.3‐helical conformation and exhibits higher ion‐exchange activity than GA. Furthermore, this GA analogue retains the potent antibiotic activity of GA, but its hemolytic activity and toxicity toward mammalian cells are significantly lower than those of GA. This study thus dissociates the antibacterial and hemolytic/cytotoxic activities of GA, and charts a rational path forward for the development of new ion‐channel‐based antibiotics.

Synthesis of the ABC ring fragment of brevisin, a new dinoflagellate polycyclic ether

A polycyclic ether, brevisin was isolated from the red-tide dinoflagellate Karenia brevis. Its unique skeletal structure consists of two separate tricyclic ether assemblies connected by a methylene bridge. The ABC ring fragment of brevisin was synthesized via Suzuki―Miyaura cross coupling toward a total synthesis of brevisin.

Solid-Phase Total Synthesis of Bogorol A: Stereocontrolled Construction of Thermodynamically Unfavored (E)-2-Amino-2-butenamide.

Bogorol A [(E)-1], a potent antibiotic against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp., possesses a thermodynamically unfavored (E)-2-amino-2-butenamide within its linear dodecapeptide sequence. The highly efficient total synthesis of natural (E)-isomer (E)-1 and its artificial (Z)-isomer (Z)-1 by employing a full solid-phase strategy is reported. The (E)- and (Z)-2-amino-2-butenamide moieties were stereoselectively constructed by applying traceless Staudinger ligation on the resin. Interestingly, (E)- and (Z)-1 showed comparable antimicrobial activity (MIC = 4 μg/mL).

Total Synthesis of Theonellapeptolide Id

Theonellapeptolide Id is a tridecapeptide containing a 37-membered lactone, originally isolated from the marine sponge Theonella swinhoei. In addition to moderate cytotoxicity, immunosuppressive activity had been reported for this natural cyclodepsipeptide. However, the synthetic material to verify its unique biological activity has not been available thus far. In this study, the first total synthesis of theonellapeptolide Id has been performed by solid phase peptide synthesis, and the biological activity has been confirmed in comparison with cyclosporin A.

Design and synthesis of potent substrate-based inhibitors of the Trypanosoma cruzi dihydroorotate dehydrogenase

Chagas disease, caused by the parasitic protozoan Trypanosoma cruzi, is the leading cause of heart disease in Latin America. T. cruzi dihydroorotate dehydrogenase (DHODH), which catalyzes the production of orotate, was demonstrated to be essential for T. cruzi survival, and thus has been considered as a potential drug target to combat Chagas disease. Here we report the design and synthesis of 75 compounds based on the orotate structure. A comprehensive structure-activity relationship (SAR) study revealed two 5-substituted orotate analogues (5u and 5v) that exhibit Kiapp values of several ten nanomolar level and a selectivity of more than 30,000-fold over human DHODH. The information presented here will be invaluable in the search for next-generation drug leads for Chagas disease.

Corrigendum: Biosynthetic Gene Cluster for Surugamide A Encompasses an Unrelated Decapeptide, Surugamide F

The absolute configuration of the 3-amino-2-methyl propionic acid (AMPA) residue in surugamide F was assigned incorrectly, because the supplier erroneously provided the l-3-aminoisobutyric acid as d-3-aminoisobutyric acid and vice versa. Therefore, the absolute configuration of the AMPA residue in surugamide F should be corrected to R. A. Ninomiya, Y. Katsuyama, T. Kuranaga, M. Miyazaki, Y. Nogi, S. Okada, T. Wakimoto, Y. Ohnishi, S. Matsunaga,* K. Takada*