Comparison of the cytotoxic effects of enantiopure PPAPs, including nemorosone and clusianone

School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Electronic address: .
Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 08/2012; 22(19):6144-7. DOI: 10.1016/j.bmcl.2012.08.023
Source: PubMed


The synthesis of an unnatural polyprenylated acylphloroglucinol (PPAP), regioisomeric with nemorosone and clusianone, has been accomplished. The separated enantiomers of this new PPAP, along with those of nemorosone and clusianone, have been screened for activity against HeLa (cervix carcinoma), MIA-PaCa-2 (pancreatic carcinoma), and MCF7 (mamma carcinoma) cancer cell lines. All of the isomers examined gave surprisingly similar results in the screens.

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    • "Clusianone (Fig. 1A) is a regioisomer analogue of nemorosone (Fig. 1B), a well-known cytotoxic/anti-cancer agent [12] [13]. The separated enantiomers of nemorosone and clusianone reduce the viability of HeLa, MIA-PaCa-2, and MCF7 cancer cells [14]. Their structural differences occur at the position of the benzoyl group in the bicyclo ring; the benzyl group is at the C3 and C1 position for clusianone and nemorosone, respectively. "
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    ABSTRACT: Clusianone is a member of the polycyclic polyprenylated acylphloroglucinol family of natural products; its cytotoxic mechanism is unknown. Clusianone is a structural isomer of nemorosone, which is a mitochondrial uncoupler and a well-known cytotoxic anti-cancer agent; thus, we addressed clusianone action at the mitochondria and its potential cytotoxic effects on cancer cells. In the HepG2 hepatocarcinoma cell line, clusianone induced mitochondrial membrane potential dissipation, ATP depletion and phosphatidyl serine externalization; this later event is indicative of apoptosis induction. In isolated mitochondria from rat liver, clusianone promoted protonophoric mitochondrial uncoupling. This was evidenced by the dissipation of mitochondrial membrane potential, an increase in resting respiration, an inhibition of Ca(2+) influx, stimulation of Ca(2+) efflux in Ca(2+)-loaded mitochondria, a decrease in ATP and NAD(P)H levels, generation of ROS, and swelling of valinomycin-treated organelles in hyposmotic potassium acetate media. The cytotoxic and uncoupling actions of clusianone were appreciably less than those of nemorosone, likely due to the presence of an intra-molecular hydrogen bond with the juxtaposed carbonyl group at the C15 position. Therefore, clusianone is capable of pharmacologically increasing the leakage of protons from the mitochondria and with favorable cytotoxicity in relation to nemorosone.
    Full-text · Article · Jan 2014 · Chemico-biological interactions
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    • "Hyperforin and nemorosone are among the best studied members of the diverse class of polycyclic polyprenylated acylphloroglucinols and both are considered lead compounds for the development of anticancer therapeutics [4,6,12,19]. However, up to now anticancer activity in vivo has only been demonstrated for hyperforin but not for nemorosone [6]. "
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    ABSTRACT: Pancreatic cancer is one of the leading cancer-related causes of death in the western world with an urgent need for new treatment strategies. Recently, hyperforin and nemorosone have been described as promising anti-cancer lead compounds. While hyperforin has been thoroughly investigated in vitro and in vivo, in vivo data for nemorosone are still missing. Thus, we investigated the growth-inhibitory potential of nemorosone on pancreatic cancer xenografts in NMRI nu/nu mice and determined basic pharmacokinetic parameters. Xenograft tumors were treated with nemorosone and gemcitabine, the current standard of care. Tumor sections were subjected to H&E as well as caspase 3 and Ki-67 staining. Nemorosone plasma kinetics were determined by HPLC and mass spectrometry. Induction of CYP3A4 and other metabolizing enzymes by nemorosone and hyperforin was tested on primary hepatocytes using qRT-PCR. At a dose of 50 mg/kg nemorosone per day, a significant growth-inhibitory effect was observed in pancreatic cancer xenografts. The compound was well tolerated and rapidly absorbed into the bloodstream with a half-life of approximately 30 min. Different metabolites were detected, possibly resembling CYP3A4-independent oxidation products. It is concluded that nemorosone is a potential anti-cancer lead compound with good bioavailability, little side-effects and promising growth-inhibitory effects, thus representing a valuable compound for a combination therapy approach.
    Preview · Article · Sep 2013 · PLoS ONE
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    ABSTRACT: The polycyclic polyprenylated acylphloroglucinol (PPAP) family of natural products includes important compounds with notable biological activities, such as garsubellin A, hyperforin and clusianone. The synthesis of these complex, bridged, highly oxidized and substituted systems presents a formidable challenge to synthetic chemists. This feature article describes how the use of unconventional bridgehead substitution chemistry has enabled the synthesis of these natural products and their analogues.
    No preview · Article · Dec 2012 · Chemical Communications
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