Fatty acid synthase inhibitors from plants: isolation, structure elucidation, and SAR studies.
Fatty acid synthase (FAS) has been identified as a potential antifungal target. FAS prepared from Saccharomyces cerevisiae was employed for bioactivity-guided fractionation of Chlorophora tinctoria,Paspalum conjugatum, Symphonia globulifera, Buchenavia parviflora, and Miconia pilgeriana. Thirteen compounds (1-13), including three new natural products (1, 4, 12), were isolated and their structures identified by spectroscopic interpretation. They represented five chemotypes, namely, isoflavones, flavones, biflavonoids, hydrolyzable tannin-related derivatives, and triterpenoids. 3'-Formylgenistein (1) and ellagic acid 4-O-alpha-l-rhamnopyranoside (9) were the most potent compounds against FAS, with IC(50) values of 2.3 and 7.5 microg/mL, respectively. Furthermore, 43 (14-56) analogues of the five chemotypes from our natural product repository and commercial sources were tested for their FAS inhibitory activity. Structure-activity relationships for some chemotypes were investigated. All these compounds were further evaluated for antifungal activity against Candida albicans and Cryptococcus neoformans. Although there were several antifungal compounds in the set, correlation between the FAS inhibitory activity and antifungal activity could not be defined.
Li
Xing-Cong
XC
National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, Department of Pharmacognosy, School of Pharmacy, The University of Mississippi, University, MS 38677, USA. xli@olemiss.edu
Joshi
Alpana S
AS
ElSohly
Hala N
HN
Khan
Shabana I
SI
Jacob
Melissa R
MR
Zhang
Zhizheng
Z
Khan
Ikhlas A
IA
Ferreira
Daneel
D
Walker
Larry A
LA
Broedel
Sheldon E
SE
Raulli
Robert E
RE
Cihlar
Ronald L
RL
D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects; D029764:Combretaceae / Q000737:chemistry; D003455:Cryptococcus neoformans / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D007529:Isoflavones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D035322:Melastomataceae / Q000737:chemistry; D015394:Molecular Structure; D029586:Moraceae / Q000737:chemistry; D031781:Paspalum / Q000737:chemistry; D010946:Plants, Medicinal / Q000737:chemistry*; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013634:Tannins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology
D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D007529:Isoflavones; D013634:Tannins; D014315:Triterpenes; D064429:Fatty Acid Synthases