Curcumin derivatives have been shown to provide antitumor activity. For example, the antitumor activity of curcumin derivatives is described in U.S. patent application Ser. No. 11/057,636, entitled “Method and Compounds for Cancer Treatment Utilizing NFkB as a Direct or Ultimate Target for Small Molecule Inhibitors,” filed Feb. 14, 2005, by Vander Jagt et al. and incorporated herein by reference, and U.S. patent application Ser. No. 11/373,444, entitled “ Cancer Treatment Using Curcumin Derivatives,” filed Mar. 10, 2006, also by Vander Jagt et al. and incorporated herein by reference.

Curcumin is a natural chemoprotective agent that elevates the activities of Phase 2 detoxification enzymes, while inhibiting procarcinogen activating Phase 1 enzymes. It decreases expression of several proto-oncogenes including c-jun, c-fos, and c-myc, and of particular interest, it suppresses the activation of NF?B. Related to this, curcumin has also been shown to induce apoptosis in several tumor cell lines. In addition to the down-regulation of uPA by dominant negative inhibitors of NF?B, numerous other factors, including VEGF, IL-8, and MMP-9 that contribute to angiogenesis, invasion, and metastasis are down-regulated by dominant negative inhibitors of NF?B. Likewise, curcumin inhibits angiogenesis in vivo. Curcumin can be viewed as a lead compound that inhibits metastasis and promotes apoptosis. Other antiangiogenic properties of curcumin are also known. Shim et al. have shown that curcumin causes the irreversible inhibition of CD13/aminopeptidase N, a membrane-bound, zinc-dependent metalloproteinase that plays a key role in tumor invasion and angiogenesis. Shim et al., “Irreversible inhibition of CD13/aminopeptidase N by the antigenic agent curcumin”, Chem. Biol. 10(8): 695-704 (August 2003).

Curcumin is known to inhibit the formation of Jun-Fos heterodimers in TPA induced cells and curcumin analogs are known to be up to 90 times more potent than curcumin (Hahm et al., Cancer Lett. 184, 89-96 (2002). It is also known that besides curcumin (turmeric), several natural products including resveratrol (peanuts and grape skins) (Manna et al., J. Immunol. 164, 6509-6519 (2000)), silymarin (artichoke) (Manna et al., J. Immunol. 163(12), 6800-6809 (1999)), oleandrin (Manna et al., Cancer Res. 60, 3838-3847 (2000)) and several compounds isolated from both green and black tea leaves (Chung et al., Cancer Res. 59, 4610-4617 (1999)) inhibit the AP-1 activation cascade. It is possible that curcumin analogs exhibit their activities on JNK since it is known that both silymarin (Manna et al., J. Immunol., 163(12), 6800-6809 (1999)) and oleandrin (Manna et al., Cancer Res. 60, 3838-3847 (2000)) inhibit JNK activity.

In addition, curcumin exhibits anti-inflammatory activity and is a potent anti-oxidant and free radical scavenger. Leu et al., (2002) Curr Med Chem Anti-Canc Agents 2, 357-370. In APP-overexpressing transgenic mice, curcumin reduced levels of oxidized proteins and inflammatory cytokine IL1 (Lim et al., (2001) J Neurosci 2, 8370-8377), thus offering a potential therapy against microglial activation in patients with Alzheimer's disease. Curcumin has additional activities of interest: it limits the progression of renal lesions in the STZ-diabetic rat model (Suresh Babu et al., (1998) Mol Cell Biochem 181, 87-96), and ameliorates oxidative stress-induced renal injury in mice (Okada et al., (2001) J Nutr 131, 2090-2095). Consequently, there has been extensive interest in the anti-oxidant properties of curcumin and the possibility that many of its biological activities are derived from its anti-oxidant properties. Balasubramanyam et al., (2003) J Biosci 28, 715-721.

Curcumin also inhibits the activation of NF?B (Bharti et al., (2003) Blood 101, 1053-1062), which may explain its anti-inflammatory properties. Curcumin was shown to attenuate the plasma inflammatory cytokine surge and cardiomyocyte apoptosis following cardiac ischemia/reperfusion in experimental animals by inhibiting activation of NF?B. Yeh et al., (2005) J Surg Res 125, 109-110. Curcumin suppressed NOS induction in LPS-stimulated macrophages by inhibiting the activation of NF?B. Pan et al., (2000) Biochem Pharmacol 60, 1655-1676. Likewise, curcumin inhibited mitogen stimulation of lymphocyte proliferation by inhibiting activation of NF?B. Ranjan et al., (2004) J Surg Res 121, 171-177. Of particular interest is the report that curcumin inhibits the activation of NF?B in BV2 microglia cells (Kang et al, (2004) J Pharmacol Sci 94, 325-328). The limited bioavailability of curcumin (Garcea et al., (2004) Br J Cancer 90, 1011-1015) suggests that clinical use of this natural product will be limited and points to the need to develop curcumin analogs with improved properties including improved bioavailability.

It was reported that curcumin inhibits TNF-?-induced NF-?B activation in human myelomonoblastic leukemia cells and phorbol ester-induced c-Jun/AP-1 activation in mouse fibroblast cells (Singh et al., J. Biol. Chem. 270:24995 (1995); Huang et al., Proc. Natl. Acad. Sci. USA 88:5292 (1991). The molecular mechanism for NF-?B inhibition by curcumin was unclear, but involved inhibition of I-?B degradation (Kumar et al., Biochem. Pharmacol. 55:775 (1998). More recent work has demonstrated that curcumin blocks intestinal endothelial cell gene expression by inhibiting the signal leading to IKK activation without directly interfering with NIK or IKK, and that blockade of IKK activation causes inhibition of I-?B phosphorylation/degradation and NF-?B activation (Jobin et al., J. Immunol. 163, 3474-83 (1999)).

The anti-inflammatory properties of curcumin and its ability to inhibit the immune response upon exposure to a variety of external stimuli may, at least in part, result from inhibition of the activation of NF-?B by these external signals, since many of the genes that are implicated in the immune/inflammatory response are up-regulated by NF?B. For example, curcumin inhibits the LPS-induced production of IL-1? and TNF? (Chan, M. M. Biochem. Pharmacol. 49, 1551 (1995)) and the IL-1?-induced expression of IL-2 (Chaudhary, L. R.; Avioli, L. V. J. Biol. Chem. 271, 16591 (1996)), as well as the TNF?-induced expression of ICAM-1, VCAM-1 and E-selectin (Gupta, B.; Ghosh, B. Int. J. Immunopharmacol. 21, 745 (1999)). NF-?B is implicated in these signaling pathways (Wang et al., Cytokine 29, 245 (2005); Krunkosky et al., Free Radical Biol. Med. 35, 1158 (2003)). However, curcumin has also been shown to be a direct inhibitor of enzymes that are important in the inflammatory response, including lipoxygenase and cyclo-oxygenase (Skrzypczak-Jankun et al., J. Int. J. Mol. Med. 6, 521 (2000)).

Further, curcumin has been shown to have possible application in the treatment of cystic fibrosis defects caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR), particularly for A508 mutations. Egan, et al., “ Curcumin, A Major Constituent of Turmeric, Corrects Cystic Fibrosis Defects”, Science, 304: 600-602 (23 Apr. 2004).

The large consumption of curcumin by the Indian population may help explain their relatively low (4 times less) incidence of Alzheimer's disease compared to the U.S. population. Chandra et al., (2001) Neurology 57, 985-989. Although no systematic trials have been preformed using curcumin in India, recent studies have provided valuable insights on curcumin's role in Alzheimer's disease. Yang et al., (2005) J Biol Chem 280, 5892-5901; Ono et al., (2004) J Neurosci Res 75, 742-750. Curcumin was shown to inhibit the formation of A? oligomers and fibrils in vitro and reduce A? amyloid burden in vivo. Specifically, Ono et al. have indicated that curcumin inhibits the accumulation of amyloid ?-peptide (A?) and the formation of ?-amyloid fibrils (fA?) from A? and destabilizes preformed fA?. Ono et al., “ Curcumin Has Potent Anti-Amyloidogenic Effects for Alzheimer's ?-Amyloid Fibrils In Vitro”, J. Neuroscience Res., 75: 742-750 (2004). Importantly, curcumin administered by intravenous (i.v.) injection lowered A? deposition in aged APP(Swedish)-transgenic mice (Tg2576), clearly demonstrating its ability to cross the blood-brain barrier in sufficient quantities to reduce amyloid burden. Curcumin is structurally similar to other inhibitors of A? aggregation such as Congo Red and Chrysamine G.

Thus, NF?B and its upstream regulators, as well as AP-1 and GSTP1-1, present inviting targets for development of anti-inflammatory drugs, and curcumin represents a promising lead compound. Analogues of curcumin that function as small molecules inhibitors of NF?B, AP-1 and GSTP1-1 activation are highly desirable for the treatment of diseases with inflammatory symptoms or components such as Alzheimer's disease, diabetes, cystic fibrosis and cancer, and also as assistive or adjuvant agents in the chemotherapeutic treatment of cancer.