Highly Active Anticancer Curcumin Analogues

Abstract

Curcumin, a compound in the human food supply, represents a near-perfect starting point for drug discovery. Consequently, a number of research groups have taken the natural product as a starting point to prepare and biologically evaluate a wide variety of curcumin analogues. One widely used structural modification truncates the central conjugated beta-diketone in curcumin to the monocarbonyl dienone. A diverse array of the latter compounds exhibit cytotoxicities against an equally diverse set of cancer-related cell lines. Importantly, these compounds still retain toxicity profiles in rodents comparable to the parent natural product, whereas some analogues (e.g., EF-24, 41) exhibit good oral bioavailability and good pharmacokinetics in mice. Thiol conjugates of EF-24 analogues have been prepared that address stability and solubility issues while demonstrating cellular activities similar to the unmodified dienones. In parallel experiments, the factor VIIa-tissue factor complex (fVIIa-TF) has been exploited to develop a targeting strategy for the analogues. In particular, the EF24-FFRck-fVIIa protein conjugate is not only somewhat more effective relative to the drug alone against breast cancer and melanocyte cells. Both simple curcumin analogues and the protein conjugate evidence antiangiogenic activity in cell culture. The implication is that the fVIIa-TF targeting process, like the dienone drugs, permits a double-pronged attack with the potential to destroy a tumor directly by apoptosis.

Curcumin analogue GO-Y030 inhibits STAT3 activity and cell growth in breast and pancreatic carcinomas

“…Testing in animal models and human clinical trials has revealed that the bioavailability of curcumin is low, owing to its poor absorption, limited tissue distribution, rapid metabolism, and subsequent elimination from the body (3). Numerous strategies have been devised to address these shortcomings, including the design and synthesis of novel structural analogues (4).…”

Potentiation of gemcitabine by Turmeric Force™ in pancreatic cancer cell lines

“…Studies to date have indicated that poor absorption and rapid metabolism of curcumin severely curtail its bioavailability. Because of this limitation on the therapeutic use of curcumin, structural modifications of this agent has been attempted to increase its absorption and bioavailability (20)(21)(22). However, it is too early to predict their experimental and clinical success.…”

Experimental Therapeutics for the Treatment of Triple Negative Breast Cancer

“…Modification of the aromatic rings and -diketone moiety of curcumin has led to different curcumin analogues with improved activities (Table 1) (Mosley et al, 2007). The first-generation curcumin derivatives were the cyclohexanones, which exhibited enhanced activity and stability in biological medium compared to curcumin.…”