Obovatols, new chitin synthase 2 inhibitors of Saccharomyces cerevisiae from Magnolia obovata.
In the course of the search for inhibitors of ScCHS2 from natural sources, we have isolated a new type of chitin synthase 2 inhibitor, obovatol, which has a biphenol skeleton, from Magnolia obovata. Obovatol inhibited chitin synthase 2 activity of Saccharomyces cerevisiae with an IC(50) of 38 microM. Its derivative, tetrahydroobovatol, inhibited chitin synthase 2 activity under the same conditions with an IC(50) of 59 microM. These compounds exhibited no inhibitory activity for ScCHS3, and showed less inhibitory activity for chitin synthase 1 than for chitin synthase 2 (IC(50) > 1 mM). These results indicated that obovatol and tetrahydroobovatol are specific inhibitors of ScCHS2. They also inhibited CaCHS1, which is structurally and functionally analogous to ScCHS2, with similar IC(50)s to ScCHS2 (IC(50) 28 and 51 microM, respectively). The compounds exhibited mixed competitive inhibition with respect to UDP-N-acetyl-D-glucosamine as substrate [inhibition constant (K(i)) 21.8 microM for obovatol and 23.1 microM for tetrahydroobovatol]. Furthermore, they showed antifungal activities against various pathogenic fungi, with a particularly strong inhibitory activity against Cryptococcus neoformans (MIC 7.8 mg/L). The results indicate that obovatol and tetrahydroobovatol can potentially serve as antifungal agents.
Hwang
Eui-Il
EI
Antibiotics Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, PO Box 115, Yusung, Taejon 305-333, Korea.
Kwon
Byoung-Mog
BM
Lee
Seoung-Ho
SH
Kim
Na-Rae
NR
Kang
Tae-Hoon
TH
Kim
Young-Tae
YT
Park
Byoung-Keun
BK
Kim
Sung-Uk
SU
D000890:Anti-Infective Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology; D002687:Chitin Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D029562:Magnoliaceae / Q000737:chemistry*; D010647:Phenyl Ethers / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D008517:Phytotherapy / Q000379:methods; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D018515:Plant Leaves / Q000737:chemistry; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000201:enzymology
D000890:Anti-Infective Agents; D000935:Antifungal Agents; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010647:Phenyl Ethers; D010936:Plant Extracts; C036795:obovatol; D002687:Chitin Synthase; C400821:chitin synthase 2