Chalcone is a unique template that is associated with several biological activities. In this review, an update of the cytotoxic and chemoprotective activities of chalcones is provided. Cytotoxicity against tumour cell lines may be the result of disruption of the cell cycle, inhibition of angiogenesis, interference with p53-MDM2 interaction, mitochondrial uncoupling or induction of apoptosis. Structural requirements for cytotoxic activity vary according to the mechanisms of action. For anti-mitotic activity, the presence of methoxy substituents, alpha-methylation of the enone moiety and the presence of 2' oxygenated substituents are favourable features. Conformational restraint of the chalcone template generally leads to a decrease in cytotoxic activity. Chemoprotection by chalcones may be a consequence of their antioxidant properties, mediated via inhibition or induction of metabolic enzymes, by an anti-invasive effect or a reduction in nitric oxide production. Hydroxyl and prenyl substituents are associated with antioxidant properties and induction of quinone reductase activities. The thiol reactivity of chalcones is likely to contribute to both cytotoxic and chemoprotective properties of these compounds.

Chalcones with 2',3',4'-trimethoxy, 2',4'-dimethoxy, 4'-methoxy, 4'-ethoxy, 2',4'-dihydroxy, and 4'-hydroxy groups on ring B were synthesized and evaluated in vitro against Plasmodium falciparum (K1) in a [3H] hypoxanthine uptake assay. The other ring A was quinoline, pyridine, naphthalene, or phenyl rings with electron-donating or electron-withdrawing substituents of varying lipophilicities. Trimethoxy 6 and 27, dimethoxy 7, 8, 29, and methoxy 31 analogues had good in vitro activities (IC(50) < 5 microM). 3-Quinolinyl ring A derivatives were well represented among the active compounds. Hydroxylated chalcones were less active than the corresponding alkoxylated analogues. When evaluated in vivo, 8 and 208 were comparable to chloroquine in extending the lifespan of infected mice. Multivariate data analysis showed that in vitro activity was mainly determined by the properties of ring B. Quantitative structure-activity relationship models with satisfactory predictive ability were obtained for various B ring chalcones using projections to latent structures. A model with good predictability was proposed for 19 active chalcones. Size and hydrophobicity were identified as critical parameters.

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Posttranslational processing of so-called CaaX proteins has received much attention in the past two decades due to the important roles these proteins play in biological regulations and diseases (1, 2). This processing is initiated by isoprenoid modification of the cysteine residue of the C-terminal CAAX motif of the protein, subsequent proteolytic removal of the three C-terminal amino acids, i.e. the ϪAAX residues, and the methylation of the newly exposed carboxyl group of the prenylated cysteine residue. The overall process, termed protein prenylation, has been shown to be important for the localization, stability, and ultimate functions of a broad array of CaaX proteins (3).Most members of the Ras superfamily of GTPases are CaaX proteins, and Ras proteins themselves, which are farnesylated, have been extensively studied due to the high prevalence of dysregulated Ras signaling in human cancers (4). Inhibitors of protein farnesyltransferase (FTase) 2 have been under development as anticancer agents for over a decade, but their efficacy, especially in solid tumors, has been disappointing (5, 6). The realization that some CaaX proteins, including forms of Ras in which mutations are prevalent in human tumors, are subject to alternative prenylation by protein geranylgeranyltransferase I when FTase is inhibited (7) spurred efforts to target the postprenylation processing steps of proteolysis and methylation since each of these steps is catalyzed by a single enzyme that acts on both farnesylated and geranylgeranylated proteins (8, 9). In particular, targeting of CaaX protein methylation via inhibition of the enzyme responsible, isoprenylcysteine carboxylmethyltransferase (Icmt), through both genetic and pharmacological approaches, has been shown to dramatically impair oncogenesis in several tumor cell models (10, 11).The mechanism(s) through which inhibition of Icmt impacts on cell proliferation and oncogenesis are still far from clear. Interference with cell cycle progression, however, is a cornerstone of many chemotherapeutic agents, and both 2 The abbreviations used are: FTase, farnesyltransferase; Icmt, isoprenylcysteine carboxylmethyltransferase; LC3, microtubule-associated protein 1 light chain 3; LC3-II, activated form of LC3; J3, cysmethynil analog 1-octylm-tolyl-1H-indole; atg5, autophagy related 5 homolog; 4EBP1, eukaryotic initiation factor 4E-binding protein 1; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; DMEM, Dulbecco's modified Eagle's medium; 3-MA, 3-methyladenine; siRNA, small interfering RNA; DMSO, dimethyl sulfoxide.