Efficient total synthesis of novel bioactive microbial metabolites.
Bioactive natural products produced by microbes have almost limitless potential in pharmaceutical applications, and the organic synthesis of such products as lead compounds will result in the creation of new and widely useful pharmaceutical products. A program of discovery of naturally occurring bioactive microbial metabolites has been ongoing at the Kitasato Institute. We have also developed efficient, rational, and highly flexible production methods for generation of target compounds, synthesis of related compounds, elucidation of their structure-activity relationships, and the possible creation of improved bioactive compounds. In this Account, the isolation and total synthesis of naturally occurring bioactive microbial metabolites in order to create novel medicines for specific illnesses is described. This covers diseases and conditions such as atherosclerosis, Alzheimer's disease, cancer, inflammation, and osteoporosis, among others, and focuses on six specific compounds. Pyripyropenes were discovered from Aspergillus fumigatus FO-1289 through our screening of microbial metabolites that strongly inhibit acyl-CoA cholesterol acyltransferase (ACAT) in order to develop a new class of cholesterol-lowering agents. These novel polyoxygenated mixed polyketide-terpenoid (meroterpenoid) metabolites contain a fused pyridyl alpha-pyrone moiety. We carried out the first total synthesis of (+)-pyripyropene A via a flexible, concise, and highly efficient route and also clarified the structure-activity relationships. Arisugacins were discovered from Penicillium sp. FO-4259 by our screening of microbial metabolites that strongly inhibit acetylcholinesterase (AChE) in order to create novel medicines for Alzheimer's disease (AD). Arisugacins are also meroterpenoids. We have achieved the first convergent total synthesis of arisugacins A and B. Lactacystin was isolated from Streptomyces sp. OM-6519 via our screening of microbial metabolites that promote the differentiation of the neuroblastoma cell to further discover new AD medicines. Lactacystin has a novel gamma-lactam thioester structure and is also a selective and strong proteasome inhibitor. We have developed a concise approach to synthesize lactacystin designed to afford easy access to the original compound and a variety of analogs. Macrosphelides were isolated from Microsphaeropsis sp. FO-5050 from our screening of microbial metabolites that inhibit the adhesion of HL-60 cells to human umbilical vein endothelial cells (HUVEC). Macrosphelides are the first 16-membered macrotriolides. Macrosphelides prevent cell-cell adhesion by inhibiting the binding of sialyl Lewis X to E-selectin. We have accomplished the first efficient total synthesis of macrosphelides. Madindolines were isolated from Streptomyces nitrosporeus K93-0711 by our program to discover new interleukin 6 (IL-6) modulators. Madindolines are comprised of a 3a-hydroxyfuroindoline ring connected at nitrogen via a methylene bridge to a cyclopentene-1,3-dione ring. We have developed an efficient and practical total synthesis of madindolines. Madindoline A binds to gp130 selectively and inhibits IL-6 activity. Neoxaline was isolated from Aspergillus japonicus Fg-551. Neoxaline is a member of a novel class of biologically active indole alkaloids characterized by a unique indoline spiroaminal framework and binds to tubulin, which results in inhibition of tubulin polymerization. We have developed a concise stereoselective synthesis of the indoline spiroaminal framework of neoxaline.
Sunazuka
Toshiaki
T
Kitasato Institute for Life Sciences, Kitasato University and The Kitasato Institute, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Hirose
Tomoyasu
T
Omura
Satoshi
S
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000737:chemistry; D000470:Alkaloids / Q000737:chemistry; D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000737:chemistry; D015394:Molecular Structure; D011714:Pyrans / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry
D000470:Alkaloids; D001688:Biological Products; D007211:Indoles; D011714:Pyrans; D011725:Pyridines; C095353:arisugacin; C067713:lactacystin; C022264:neoxaline; D000111:Acetylcysteine