7-epiclusianone and nemorosone

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.

Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Benzophenones; Benzoquinones; Biological Products; Biological Transport; Bridged Bicyclo Compounds; Calcium; Cell Death; Cell Respiration; Hep G2 Cells; Humans; Membrane Potential, Mitochondrial; Mitochondria, Liver; NAD; Osmotic Pressure; Rats; Reactive Oxygen Species; Stereoisomerism; Structure-Activity Relationship; Uncoupling Agents

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.

Topics: Antineoplastic Agents; Benzophenones; Benzoquinones; Biological Products; Bridged Bicyclo Compounds; Catechin; Cell Line, Tumor; Humans; Phloroglucinol; Terpenes

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.

Topics: Antineoplastic Agents; Benzophenones; Benzoquinones; Bridged Bicyclo Compounds; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HeLa Cells; Humans; MCF-7 Cells; Molecular Conformation; Stereoisomerism; Structure-Activity Relationship

Topics: Benzophenones; Benzoquinones; Bridged Bicyclo Compounds; Molecular Structure