Development of a Water Soluble Self-assembling Analogue of Vizantin.

Vizantin, 6,6'-bis-O-(3-nonyldodecanoyl)-α,α'-trehalose, has been developed as a safe immunostimulator on the basis of a structure-activity relationship study with trehalose 6,6'-dicorynomycolate. Our recent study indicated that vizantin acts as an effective Toll-like receptor-4 (TLR4) partial agonist to reduce the lethality of an immune shock caused by lipopolysaccharide (LPS). However, because vizantin has low solubility in water, the aqueous solution used in in vivo assay systems settles out in tens of minutes. Here, vizantin was chemically modified in an attempt to facilitate the preparation of an aqueous solution of the drug. This paper describes the concise synthesis of a water-soluble vizantin analogue in which all the hydroxyl groups of the sugar unit were replaced by sulfates. The vizantin derivative displayed micelle-forming ability in water and potent TLR-4 partial agonist activity.

Tetrachlorovancomycin: Total Synthesis of a Designed Glycopeptide Antibiotic of Reduced Synthetic Complexity.

A technically straightforward total synthesis of a new class of vancomycin analogues of reduced synthetic complexity was developed that provided tetrachlorovancomycin (1, LLS = 15 steps, 15% overall yield) and its precursor aglycon 29 (nearly 20% overall yield). The class retains all the intricate vancomycin structural features that contribute to its target binding affinity and selectivity, maintains the antimicrobial activity of vancomycin, and achieves the simplification by an unusual addition, not removal, of benign substituents to the core structure. The modification, accomplished by addition of two aryl chloride substituents to provide 1, permitted a streamlined total synthesis of the new glycopeptide antibiotic class by removing the challenges associated with CD and DE ring system atropisomer stereochemical control. This also enabled their simultaneous and further-activated SNAr macrocyclizations that establish the tricyclic skeleton of 1. Key elements of the approach include catalyst-controlled diastereoselective formation of the AB biaryl axis of chirality (>30:1 dr), an essentially instantaneous macrolactamization of the AB ring system free of competitive epimerization (>30:1 dr), racemization free coupling of the E ring tetrapeptide, room temperature simultaneous CD and DE ring system cyclizations, a highly refined 4-step conversion of the cyclization product to the aglycon, and a protecting-group-free one-pot enzymatic glycosylation for disaccharide introduction. In addition to the antimicrobial evaluation of tetrachlorovancomycin (1), the preparation of key peripherally modified derivatives, which introduce independent and synergistic mechanisms of action, revealed their exceptional antimicrobial potency and provide the foundation for future use of this new class of synthetic glycopeptide analogues.

A Concise Total Synthesis of Dehydroantofine and Its Antimalarial Activity against Chloroquine-Resistant Plasmodium falciparum.

The total synthesis of dehydroantofine was achieved by employing a novel, regioselective, azahetero Diels-Alder reaction of easily accessible 3,5-dichloro-2H-1,4-oxazin-2-one with 14 a as a key step. Furthermore, it is demonstrated that dehydroantofine is a promising candidate as a new antimalarial agent in a biological assay with chloroquine-resistant Plasmodium falciparum.

Sulfated vizantin inhibits biofilm maturation by Streptococcus mutans.

Streptococcus mutans is the main pathogen of dental caries and adheres to the tooth surface via soluble and insoluble glucans produced by the bacterial glucosyltransferase enzyme. Thus, the S. mutans glucosyltransferase is an important virulence factor for this cariogenic bacterium. Sulfated vizantin effectively inhibits biofilm formation by S. mutans without affecting its growth. In this study, less S. mutans biofilm formation occurred on hydroxyapatite discs coated with sulfated vizantin than on noncoated discs. Sulfated vizantin showed no cytotoxicity against the human gingival cell line Ca9-22. Sulfated vizantin dose-dependently inhibited the extracellular release of cell-free glucosyltransferase from S. mutans and enhanced the accumulation of cell-associated glucosyltransferase, compared with that observed with untreated bacteria. Sulfated vizantin disrupted the localization balance between cell-associated glucosyltransferase and cell-free glucosyltransferase, resulting in inhibited biofilm maturation. These results indicate that sulfated vizantin can potentially serve as a novel agent for preventing dental caries.

Chemical Hybridization of Vizantin and Lipid A to Generate a Novel LPS Antagonist.

Lipopolysaccharide (LPS) antagonists have attracted considerable interest as promising candidates for the treatment of severe sepsis triggered by Gram-negative bacteria. In this article, we describe the development of a novel LPS antagonist based on chemical hybridization of vizantin and the hydrophobic molecular unit of LPS (lipid A). Vizantin, 6,6'-bis-O-(3-nonyldodecanoyl)-α,α'-trehalose, was designed as an immunostimulator from a structure-activity relationship (SAR) study with trehalose 6,6'-dicorynomycolate (TDCM). Our recent study indicated that vizantin displays adjuvant activity by specifically binding to the Toll-like receptor 4 (TLR4)/MD2 protein complex. Because lipid A unit (or LPS) is also known to trigger an inflammatory response via the same TLR4/MD2 complex as vizantin, we designed a hybrid compound of vizantin and lipid A with the aim of developing a novel biofunctional glycolipid. Focusing on the antagonism to Escherichia coli LPS in an in vitro model with human macrophages (THP-1 cells), we identified a potent LPS antagonist among the synthesized hybrid compounds. The novel LPS antagonist effectively inhibited LPS-induced release of tumor necrosis factor-alpha (TNF-α) in a dose-dependent manner with an IC50 value of 3.8 nM, making it a candidate for the treatment drug of Gram-negative sepsis and/or septic shock.

Total synthesis of (-)-thallusin: utilization of enzymatic hydrolysis resolution.

(-)-Thallusin, isolated from a marine bacterium, is the only known natural product to act as an algal morphogenesis inducer. Because (-)-thallusin can only be obtained in exceedingly limited amounts from microbial cultivation, a synthetic supply of this compound is highly desirable. Here, we describe a novel synthetic pathway to (±)-thallusin and the first asymmetric synthesis of (-)-thallusin utilizing the enzymatic hydrolysis resolution with the combination of lipase PS-30 and lipase M Amamo-10.

Utilization of phosphonic acid compounds by marine bacteria of the genera Phaeobacter, Ruegeria, and Thalassospira (α-Proteobacteria).

Phosphonic acid (phosphonate) that possesses a carbon-phosphours bond is a chemically stable form of organic phosphorus. Various phosphonic acids are widely distributed in oceanic waters; in particular, methylphosphonic acid (namely methylphosphonate) is believed to be responsible for global methane production. To discuss the microbial degradation of phosphonic acids, we investigated the utilization of phosphonic acid compounds by cultures of marine bacteria, Phaeobacter sp., Ruegeria sp. (Rhodobacterales), and Thalassospira sp. (Rhodospirillales). These bacterial cultures were able to grow on methylphosphonic acid as well as on the tested alkyl-, carboxy-, aminoalkyl-, and hydroxyalkyl-phosphonic acid compounds. Cell yields and growth rates of Ruegeria and Thalassospira cultures grown on methyl-, ethyl-, propyl-, and butyl-phosphonic acid compounds tended to decrease with increasing alkyl chain length. In contrast, Phaeobacter sp. grew well on such alkyl-phosphonic acids. Our results suggest that these marine bacteria, which exhibit varied utilization, are involved in microbial degradation of various phosphonic acid compounds.

Aryl-Allene Cyclization via a Hg(OTf)2-Catalytic Pathway.

Hg(OTf)2-catalyzed aryl-allene cyclization accompanied by formation of a quaternary carbon center has been realized. Deuterium-labeling experiments and computational modeling were used to propose a novel catalytic pathway involving direct H-transfer from the aromatic ring to the vinyl mercury moiety followed by mercury 1,2-migration.

A carbaboranylmercuric salt catalyzed reaction; highly regioselective cycloisomerization of 1,3-dienes.

The combination of carbaboranylmercuric chloride (new type of bulky Lewis acid) and silver triflate efficiently catalyzes cycloisomerization of 1,3-dienes at room temperature. The catalytic system gives allyl-substituted azacycles and cycloalkanes in excellent yields with high to complete regioselectivity.