A general approach to synthesis of dihydroxanthone derivatives is described here. In vitro evaluation of these dihydroxanthones demonstrated that some derivatives possess moderate anti-cholinesterase activities and better selectivities than tacrine for acetylcholinesterase over butyrylcholinesterase. Structural effects on anti-cholinesterase activities were also examined, and docking experiments were carried out to provide preliminary understandings of these experimental observations.
Title: Arisugacins A and B, novel and selective acetylcholinesterase inhibitors from Penicillium sp. FO-4259. I. Screening, taxonomy, fermentation, isolation and biological activity Kuno F, Otoguro K, Shiomi K, Iwai Y, Omura S Ref: Journal of Antibiotics, 49:742, 1996 : PubMed
An in vitro screening method for selective acetylcholinesterase (AChE) inhibitors was established. Inhibitory activity of AChE and butyrylcholinesterase (BCHE) was measured and the culture broths of microorganisms that showed selective inhibition against AChE were characterized. By using this method, a strain producing the novel and selective inhibitors of AChE, arisugacins A and B, was picked out among over seven thousand microorganisms tested. Arisugacins were obtained as white powders from the culture broth together with three known compounds, territrems B and C and cyclopenin that also showed selective inhibition against AChE. Arisugacins and territrems are members of the meroterpenoid compounds. They showed potent inhibitory activities against AChE with IC50 values in range of 1.0 approximately 25.8 nM. Furthermore, they showed greater than 2,000-fold more potent inhibition against AChE than BCHE.
Title: Arisugacins A and B, novel and selective acetylcholinesterase inhibitors from Penicillium sp. FO-4259. II. Structure elucidation Kuno F, Shiomi K, Otoguro K, Sunazuka T, Omura S Ref: Journal of Antibiotics, 49:748, 1996 : PubMed
The structures of new acetylcholinesterase inhibitors, arisugacins A and B, were elucidated by NMR study. Arisugacins have a (4aR,6aR,12aS,12bS)-4a,6,6a,12,12a, 12b-hexahydro-4a,12a-dihydroxy-4,4,6a,12b-tetramethyl-4H,11H -naphtho[2,1-b] pyrano[3,4-e]pyran-1,11(5H)-dione moiety in common and 3,4-dimethoxyphenyl or 4-methoxyphenyl residues are attached to C-9 of the moiety.
A general approach to synthesis of dihydroxanthone derivatives is described here. In vitro evaluation of these dihydroxanthones demonstrated that some derivatives possess moderate anti-cholinesterase activities and better selectivities than tacrine for acetylcholinesterase over butyrylcholinesterase. Structural effects on anti-cholinesterase activities were also examined, and docking experiments were carried out to provide preliminary understandings of these experimental observations.
Synthetic inhibitors of acetylcholinesterase (AChE) recently have attracted particular attention for treatment of Alzheimer's 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 Alzheimer's disease. Also reviewed is the current status of development of antidementia drugs.
Title: Arisugacins A and B, novel and selective acetylcholinesterase inhibitors from Penicillium sp. FO-4259. I. Screening, taxonomy, fermentation, isolation and biological activity Kuno F, Otoguro K, Shiomi K, Iwai Y, Omura S Ref: Journal of Antibiotics, 49:742, 1996 : PubMed
An in vitro screening method for selective acetylcholinesterase (AChE) inhibitors was established. Inhibitory activity of AChE and butyrylcholinesterase (BCHE) was measured and the culture broths of microorganisms that showed selective inhibition against AChE were characterized. By using this method, a strain producing the novel and selective inhibitors of AChE, arisugacins A and B, was picked out among over seven thousand microorganisms tested. Arisugacins were obtained as white powders from the culture broth together with three known compounds, territrems B and C and cyclopenin that also showed selective inhibition against AChE. Arisugacins and territrems are members of the meroterpenoid compounds. They showed potent inhibitory activities against AChE with IC50 values in range of 1.0 approximately 25.8 nM. Furthermore, they showed greater than 2,000-fold more potent inhibition against AChE than BCHE.
Title: Arisugacins A and B, novel and selective acetylcholinesterase inhibitors from Penicillium sp. FO-4259. II. Structure elucidation Kuno F, Shiomi K, Otoguro K, Sunazuka T, Omura S Ref: Journal of Antibiotics, 49:748, 1996 : PubMed
The structures of new acetylcholinesterase inhibitors, arisugacins A and B, were elucidated by NMR study. Arisugacins have a (4aR,6aR,12aS,12bS)-4a,6,6a,12,12a, 12b-hexahydro-4a,12a-dihydroxy-4,4,6a,12b-tetramethyl-4H,11H -naphtho[2,1-b] pyrano[3,4-e]pyran-1,11(5H)-dione moiety in common and 3,4-dimethoxyphenyl or 4-methoxyphenyl residues are attached to C-9 of the moiety.
