Akihiro Ogura

Total synthesis of (-)-anisatin.

A novel synthetic route to (-)-anisatin has been developed. Our synthesis features a rhodium-catalyzed 1,4-addition of an arylboronic acid, an intramolecular Diels-Alder reaction of an ortho-quinone monoketal, a stereoselective [2,3]-Wittig rearrangement, and construction of the oxabicyclo [3.3.1] skeleton via cleavage of an epoxide by a primary amide.

In Vivo Gold Complex Catalysis within Live Mice

Metal complex catalysis within biological systems is largely limited to cell and bacterial systems. In this work, a glycoalbumin-AuIII complex was designed and developed that enables organ-specific, localized propargyl ester amidation with nearby proteins within live mice. The targeted reactivity can be imaged through the use of Cy7.5- and TAMRA-linked propargyl ester based fluorescent probes. This targeting system could enable the exploitation of other metal catalysis strategies for biomedical and clinical applications.

Visualizing Trimming Dependence of Biodistribution and Kinetics with Homo- and Heterogeneous N-Glycoclusters on Fluorescent Albumin.

A series of N-glycans, each sequentially trimmed from biantennary sialoglycans, were homo- or heterogeneously clustered efficiently on fluorescent albumin using a method that combined strain-promoted alkyne-azide cyclization and 6π-azaelectrocyclization. Noninvasive in vivo kinetics and dissection analysis revealed, for the first time, a glycan-dependent shift from urinary to gall bladder excretion mediated by sequential trimming of non-reducing end sialic acids. N-glycoalbumins that were trimmed further, in particular, GlcNAc- and hybrid biantennary-terminated congeners, were selectively taken up by sinusoidal endothelial and stellate cells in the liver, which are critical for diagnosis and treatment of liver fibrillation. Our glycocluster strategy can not only reveal the previously unexplored extracellular functions of N-glycan trimming, but will be classified as the newly emerging glycoprobes for diagnostic and therapeutic applications.

Glycan multivalency effects toward albumin enable N-glycan-dependent tumor targeting.

Multivalent interactions play an essential role in molecular recognition in living systems. These effects were employed to target tumor cells using albumin clusters bearing ∼10 molecules of asparagine-linked glycans (N-glycans). Noninvasive near-infrared fluorescence imaging clearly revealed A431 tumors implanted in BALB/cA-nu/nu mice after 1h in an N-glycan structure-dependent manner, thereby demonstrating the efficient use of glycan multivalency effects for tumor targeting in vivo.

Sequential Double “Clicks” toward Structurally Well-Defined Heterogeneous N-Glycoclusters: The Importance of Cluster Heterogeneity on Pattern Recognition In Vivo

Structurally well‐defined heterogeneous N‐glycoclusters are prepared on albumin via a double click procedure. The number of glycan molecules present, in addition to the spatial arrangement of glycans in the heterogeneous glycoclusters, plays an important role in the in vivo kinetics and organ‐selective accumulation through glycan pattern recognition mechanisms.

In vivo kinetics and biodistribution analysis of neoglycoproteins: effects of chemically introduced glycans on proteins

Biodistribution and in vivo kinetics analysis of chemically prepared neoglycoproteins are reviewed. Various mono- and oligosaccharides were conjugated onto the protein surface by use of chemical methods. Their kinetic and organ-specific accumulation have extensively been studied after intravenous injection and analyzed by conventional dissection studies, as well as noninvasive methods, such as SPECT, PET, or fluorescence imaging. These studies clearly show the glycan-structure dependency on protein kinetics, which will provide promising possibilities for pharmacological and diagnostic applications.

Chemical glycan conjugation controls the biodistribution and kinetics of proteins in live animals

The biodistributions and in vivo kinetics of chemically prepared neoglycoproteins have been examined previously and are reviewed here. A variety of mono- and oligosaccharides may be conjugated onto a protein surface using chemical methods. The kinetics and organ-specific accumulation profiles of these glycoconjugates, introduced through intravenous injection, have been analyzed using conventional dissection studies as well as noninvasive methods, such as SPECT, PET, or fluorescence imaging. These studies have revealed glycan-dependent protein distribution kinetics that may be useful for pharmacological and diagnostic applications.

Total Synthesis and Structural Revision of Clavilactone D

A structural revision of clavilactone D, a potent inhibitor of protein tyrosine kinases, was achieved by total syntheses of two newly proposed structures. The syntheses relied on ring-opening/ring-closing metathesis, which transformed a cyclobutenecarboxylate into a γ-butenolide. The syntheses confirmed that the correct structure of clavilactone D has an amino group at C-3 instead of a hydroxy group at C-2 in the originally proposed structure.

Total Synthesis of Clavilactones

Clavilactones A, B, and D are epidermal growth factor receptor tyrosine kinase inhibitors that were isolated from cultures of the fungus Clitocybe clavipes. Here, we report full details of the total synthesis of these clavilactones. A key feature of our synthetic approach is a ring-opening/ring-closing metathesis strategy that allows the concise transformation of a cyclobutenecarboxylate into a γ-butenolide. Coupled with enantioselective Ti/BINOL-catalyzed alkynylation of a multisubstituted benzaldehyde and ring-closing metathesis of a diene-bearing silylene acetal to construct the 10-membered carbocycle, this strategy enabled the total synthesis of the natural enantiomers (+)-clavilactone A and (-)-clavilactone B. In addition, the correct structure of clavilactone D was determined by the synthesis of two newly proposed structures. This research resulted in the asymmetric synthesis of the revised (+)-clavilactone D.

A viable strategy for screening the effects of glycan heterogeneity on target organ adhesion and biodistribution in live mice

This work represents the first broad study of testing diverse heterogenous glycoconjugates (7 different glycoalbumins) for their differential in vivo binding (11 different cancer cell types) in both cell- and animal-based studies. As a result, various changes in biodistribution, excretion, and even tumor adhesion were observed.