Anthrones, naturally occurring competitive inhibitors of adenosine‐triphosphate‐citrate lyase

Abstract

Adenosine triphosphate (ATP)-citrate iyase (ACL) is a homotetrameric liver enzyme which catalyzes the cytosolic formation of acetyl-CoA. This reaction provides the major source of acetyl-CoA for fatty acid and cholesterol biosynthesis. Inhibition of ACL offers a potentially unique way to control plasma cholesterol and triglyceride levels. In this study, we describe the activity of an active microbial metabolite derived from a soil fungus, Penicillium sp., SC2193. This culture produces a series of related anthrones and anthraquinones. We present evidence for one of these anthrones, 2-chloro-1,3,8-trihydroxy-6-methyl-9-anthrone, as a specific and competitive inhibitor of ACL against the substrate Mg citrate and mixed noncompetitive inhibition against two other required substrates for this enzyme, M g ATP and CoA. With an I C , , of 283 n M in the primary assay and, more specifically, a Ki of 4 0 0 n M against the substrate M g citrate, SC2193 represents the most potent competitive inhibitor of ACL yet described, and, as such, might prove very useful as a molecular tool for the discovery of selective, mechanistically novel hypolipidernic agents. 0 1995 Wiley-Liss, Inc.

Anti-plasmodial Activity of Some Constituents of the Root Bark of Harungana madagascariensis LAM. (Hypericaceae)

“…Forty-two fractions (200 ml) were obtained and grouped on the basis of TLC to yield three sub-fractions labelled F 21 (9).…”

“…7,8) They are also naturally occurring competive inhibitors of adenosinetriphosphate-citrate-lyase. 9) Plants of the Hypericaceae family are well known to produce bioactive anthraquinones and anthrones. They are distributed in tropical and sub-tropical regions.…”

Lipogenesis inhibitors: therapeutic opportunities and challenges

“…Additional screening of natural products identified several other ACLY inhibitors, including purpurone 151 , a series of anthrones and anthraquinones derived from Penicillium sp. 152 , radicicol, a 14-membered macrolide originally isolated from Monosporium bonorden 153 , and cucurbitacin B, a natural bioactive compound abundant in cucumber 154 . Another series of inhibitors was developed on the chemical scaffold of the natural product emodin 155 .…”

Inhibitors of lipogenic enzymes as a potential therapy against cancer

“…Another natural product, 2‐chloro‐1,3,8‐trihydroxy‐6‐methylanthrone ( 2 , Figure 2), was found to be a strong inhibitor of hACLY with an IC50 of 283 nM 31 . Compound 2 was extracted from active microbial metabolite derived from a soil fungus ( Penicillium sp ).…”

“…30 Another natural product, 2-chloro-1,3,8-trihydroxy-6-methylanthrone (2, Figure 2), was found to be a strong inhibitor of hACLY with an IC50 of 283 nM. 31 Compound 2 was extracted from active microbial metabolite derived from a soil fungus (Penicillium sp). Despite promising results, no cytotoxic study was carried out using this compound against cancer cells.…”