Kazuhiko Otoguro

Arisugacins, selective acetylcholinesterase inhibitors of microbial origin

Synthetic inhibitors of acetylcholinesterase (AChE) recently have attracted particular attention for treatment of Alzheimers disease. By systematic screening of microbial metabolites, we were able to discover the new AChE inhibitors, named arisugacins A and B, from the culture broth of Penicillium sp. FO-4259. The structures of arisugacins are members of the meroterpenoid compounds. Arisugacin A is a potent and highly selective inhibitor of AChE but does not inhibit butyrylcholinesterase in vitro. Arisugacin A is a good candidate as an excellent potential drug for treatment of Alzheimers disease. Also reviewed is the current status of development of antidementia drugs.

Total synthesis of (-)-borrelidin.

The total synthesis of borrelidin has been achieved. The best feature of our synthetic route is SmI2-mediated intramolecular Reformatsky-type reaction for macrocyclization after esterification between two segments. The two key segments were synthesized through chelation-controlled carbotitanation, chelation-controlled hydrogenation, stereoselective Reformatsky reaction, and MgBr2·Et2O-mediated chelation-controlled allylation.

Selective and Potent in Vitro Antitrypanosomal Activities of Ten Microbial Metabolites

More than 400 compounds isolated from soil microorganisms, and catalogued in the antibiotic library of the Kitasato Institute for Life Sciences, were screened against African trypanosomes. Ten compounds were found to have selective and potent antitrypanosomal activity in vitro: aureothin, cellocidin, destomycin A, echinomycin, hedamycin, irumamycin, LL-Z 1272β, O-methylnanaomycin A, venturicidin A and virustomycin A. Results of the in vitro assays using the GUTat 3.1 strain of Trypanosomal brucei brucei and the STIB900 strain of T. b. rhodesiense are presented. Cytotoxicity was determined using a human MRC-5 cell line. This is the first report of antitrypanosomal activities of the 10 microbial metabolites listed above.

Spoxazomicins A–C, novel antitrypanosomal alkaloids produced by an endophytic actinomycete, Streptosporangium oxazolinicum K07-0460 T

Three novel antitrypanosomal alkaloids, named spoxazomicins A–C, were isolated by silica gel column chromatography and HPLC from the culture broth of a new endophytic actinomycete species, Streptosporangium oxazolinicum K07-0460T. The structures of the spoxazomicins were elucidated by NMR and X-ray crystal analyses and shown to be new types of pyochelin family antibiotic. Spoxazomicin A showed potent and selective antitrypanosomal activity with an IC50 value of 0.11 μg ml−1 in vitro without cytotoxicity against MRC-5 cells (IC50=27.8 μg ml−1).

Acylated pregnane glycosides from Caralluma tuberculata and their antiparasitic activity.

Five pregnane glycosides were isolated from Caralluma tuberculata (1-5), in addition to a known one (russelioside E, 6). The structures of the isolated compounds were elucidated by the analysis of NMR data and FAB-MS experiments. All the isolated compounds were tested for their antimalarial and antitrypanosomal activities as well as their cytotoxicity against human diploid embryonic cell line (MRC5).

Generation of Anti-trypanosomal Agents through Concise Synthesis and Structural Diversification of Sesquiterpene Analogues

To access high-quality small-molecule libraries to screen lead candidates for neglected diseases exemplified by human African trypanosomiasis, we sought to develop a synthetic process that would produce collections of cyclic scaffolds relevant to an assortment of natural products exhibiting desirable biological activities. By extracting the common structural features among several sesquiterpenes, including artemisinin, anthecularin, and transtaganolides, we designed six types of scaffolds with systematic structural variations consisting of three types of stereochemical relationships on the sp(3) ring-junctions and two distinct arrays of tricyclic frameworks. A modular and stereodivergent assembly of dienynes exploiting a versatile manifold produced a series of cyclization precursors. Divergent cyclizations of the dienynes employing tandem ring-closing metathesis reactions overrode variant reactivities of the cyclization precursors, leading to the six canonical sets of the tricyclic scaffolds incorporating a diene group. Screenings of trypanosomal activities of the canonical sets, as well as regio- and stereoisomers of the tricyclic dienes, allowed generation of several anti-trypanosomal agents defining the three-dimensional shape of the pharmacophore. The candidate tricyclic dienes were selected by primary screenings and further subjected to installation of a peroxide bridge, which generated artemisinin analogues that exhibited potent in vitro anti-trypanosomal activities comparable or even superior to those of artemisinin and the approved drugs, suramin and eflornithine.

In vitro antitrypanosomal activity of plant terpenes against Trypanosoma brucei.

During the course of screening to discover antitrypanosomal compounds, 24 known plant terpenes (6 sesquiterpenes, 14 sesquiterpene lactones and 4 diterpenes) were evaluated for in vitro antitrypanosomal activity against Trypanosoma brucei brucei. Among them, 22 terpenes exhibited antitrypanosomal activity. In particular, α-eudesmol, hinesol, nardosinone and 4-peroxy-1,2,4,5-tetrahydro-α-santonin all exhibited selective and potent antitrypanosomal activities in vitro. Detailed here in an in vitro antitrypanosomal properties and cytotoxicities of the 24 terpenes compared with two therapeutic antitrypanosomal drugs (eflornithine and suramin). This finding represents the first report of promising trypanocidal activity of these terpenes. Present results also provide some valuable insight with regard to structure-activity relationships and the possible mode of action of the compounds.

Merobatzelladines A and B, Anti-Infective Tricyclic Guanidines from a Marine Sponge Monanchora sp.

Merobatzelladines A (1) and B (2) have been isolated from a marine sponge Monanchora sp. as antibacterial constituents. Their structures including relative stereochemistry were determined by interpretation of spectral data. The absolute stereochemistry of merobatzelladine B (2) was elucidated after introduction of the fourth ring system preinstalled with a secondary hydroxyl group to which the modified Mosher method was applied. Merobatzelladines exhibit moderate anti-infective activity against a bacterium and protozoa.

In vitro and in vivo antimalarial activity of puberulic acid and its new analogs, viticolins A–C, produced by Penicillium sp. FKI-4410

In the course of screening for antimalarial agents, five tropolone compounds were isolated from the culture broth of Penicillium sp. FKI-4410. Two were known compounds, puberulic acid and stipitatic acid. Three were new analogs of puberulic acid, designated viticolins A–C. Among them, puberulic acid exhibited potent antimalarial inhibition, with IC50 values of 0.01 μg ml−1 against chloroquine-sensitive and -resistant Plasmodium falciparum strains in vitro. Furthermore, puberulic acid showed weak cytotoxicity against human MRC-5 cells, with an IC50 value of 57.2 μg ml−1. The compound also demonstrated a therapeutic effect in vivo, which compared well against the currently used antimalarial drugs, and thus shows promise as a leading candidate for development into a new antimalarial compound.

Total synthesis of borrelidin.

The total synthesis of borrelidin has been achieved. The best feature of our synthetic route is macrocyclization at C11-C12 for the construction of an 18-membered ring after esterification between two segments. A detailed examination of the macrocyclization led us to the samarium(II) iodide-mediated intramolecular Reformatsky-type reaction as the most efficient synthetic approach. The two key segments were synthesized through regioselective methylation, directed hydrogenation, stereoselective Reformatsky-type reaction, and MgBr2.Et2O-mediated chelation-controlled allylation.