Comparative nuclease and anti-cancer properties of the naturally occurring malabaricones.
The nuclease activities of the malabaricones have been studied so as to establish a structure-activity correlation and deduce the mechanistic pathway of the process. The inactivity of malabaricone A and malabaricone D revealed that the resorcinol moiety, present in the malabaricones did not contribute to the nuclease activity. Amongst the test compounds, malabaricone C (mal C) containing a B-ring catechol moiety showed significantly better Cu(II)-dependent nuclease activity than the partially methylated catechol derivative, mal B and curcumin. Mal C was found to bind efficiently with Cu(II) and DNA to facilitate the DNA nicking via a site-specifically generated Cu(I)-peroxo complex. Consistent with its Cu(II)-dependent nuclease property, mal C showed better cytotoxicity (IC(50)=5.26±1.20 μM) than curcumin (IC(50)=24.46±3.32 μM) against the MCF-7 human breast cancer cell line. The mal C-induced killing of the MCF-7 cells followed an apoptotic pathway involving oxidative damage to the cellular DNA.
Patro
Birija S
BS
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India.
Tyagi
Mrityunjay
M
Saha
Jayati
J
Chattopadhyay
Subrata
S
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects; D053837:DNA Cleavage; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D017382:Reactive Oxygen Species / Q000378:metabolism; D012118:Resorcinols / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D002614:Chelating Agents; D017382:Reactive Oxygen Species; D012118:Resorcinols; C071788:malabaricone B; C071787:malabaricone C; D003300:Copper; D004247:DNA; C427203:calf thymus DNA