Curcumin is the active ingredient in the traditional herbal remedy and dietary spice turmeric (Curcuma longa). Curcumin has a surprisingly wide range of beneficial properties, including anti-inflammatory, antioxidant, chemopreventive and chemotherapeutic activity. The pleiotropic activities of curcumin derive from its complex chemistry as well as its ability to influence multiple signaling pathways, including survival pathways such as those regulated by NF-κB, Akt, and growth factors; cytoprotective pathways dependent on Nrf2; and metastatic and angiogenic pathways. Curcumin is a free radical scavenger and hydrogen donor, and exhibits both pro- and antioxidant activity. It also binds metals, particularly iron and copper, and can function as an iron chelator. Curcumin is remarkably non-toxic and exhibits limited bioavailability. Curcumin exhibits great promise as a therapeutic agent, and is currently in human clinical trials for a variety of conditions, including multiple myeloma, pancreatic cancer, myelodysplastic syndromes, colon cancer, psoriasis and Alzheimer’s disease.

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Curcumin: From ancient medicine to current clinical trials

Curcumin: The story so far

Curcuma spp. extracts, particularly the dietary polyphenol curcumin, prevent colon cancer in rodents. In view of the sparse information on the pharmacodynamics and pharmacokinetics of curcumin in humans, a dose-escalation pilot study of a novel standardized Curcuma extract in proprietary capsule form was performed at doses between 440 and 2200 mg/day, containing 36-180 mg of curcumin. Fifteen patients with advanced colorectal cancer refractory to standard chemotherapies received Curcuma extract daily for up to 4 months. Activity of glutathione S-transferase and levels of a DNA adduct (M(1)G) formed by malondialdehyde, a product of lipid peroxidation and prostaglandin biosynthesis, were measured in patients' blood cells. Oral Curcuma extract was well tolerated, and dose-limiting toxicity was not observed. Neither curcumin nor its metabolites were detected in blood or urine, but curcumin was recovered from feces. Curcumin sulfate was identified in the feces of one patient. Ingestion of 440 mg of Curcuma extract for 29 days was accompanied by a 59% decrease in lymphocytic glutathione S-transferase activity. At higher dose levels, this effect was not observed. Leukocytic M(1)G levels were constant within each patient and unaffected by treatment. Radiologically stable disease was demonstrated in five patients for 2-4 months of treatment. The results suggest that (a) Curcuma extract can be administered safely to patients at doses of up to 2.2 g daily, equivalent to 180 mg of curcumin; (b) curcumin has low oral bioavailability in humans and may undergo intestinal metabolism; and (c) larger clinical trials of Curcuma extract are merited.

https://clincancerres.aacrjournals.org/content/clincanres/7/7/1894.full.pdf

Pharmacodynamic and Pharmacokinetic Study of Oral Curcuma Extract in Patients with Colorectal Cancer

Curcumin-phospholipid complex: Preparation, therapeutic evaluation and pharmacokinetic study in rats.

Studies of curcumin and curcuminoids. XXVII. Cyclodextrin complexation: solubility, chemical and photochemical stability

Publisher Summary This chapter focuses on amidines and guanidines in medicinal chemistry. The drugs are classified under their main physiological activities and within each group are arranged roughly in order of increasing molecular complexity. Many of the compounds have given temporary excitement to their discoverers and then been dropped—the commonest experience in medicinal chemistry. There are important, clinically used, medicines in all the major categories of therapeutic action discussed in the chapter. This simple and very unstable compound is not only a neurotransmitter in the brain, but acts in the dilation of blood vessels and activates leucocytes to attack tumour cells, fungi, and bacteria. In addition, nitric oxide can inhibit blood coagulation by preventing platelet aggregation and appears to be the regulator of the male erection. No doubt other functions will be discovered in the future, but the interesting finding for the present chapter is that the NO is formed by nitric oxide synthetase from arginine—the only essential amino acid which carries a guanidine group. Since most of the active guanidine drugs have at least one unsubstituted =NH or NH 2 group, it is interesting to speculate that they will be shown to act by giving nitric oxide as well.

Amidines and guanidines in medicinal chemistry.

Studies on curcumin and curcuminoids. XXII: Curcumin as a reducing agent and as a radical scavenger

Enaminones in heterocyclic synthesis

The N-alkylation of benzotriazole and 1,2,4-triazole with alkyl halides proceeds efficiently in the presence of sodium hydroxide in N,N-dimethylformamide (DMF).

John V. Greenhill

Papers

Amidines and guanidines in medicinal chemistry.

Studies on curcumin and curcuminoids. XXII: Curcumin as a reducing agent and as a radical scavenger

Enaminones in heterocyclic synthesis

An improved method for the N‐alkylation of benzotriazole and 1,2,4‐triazole

Photochemical stability of biologically active compounds. V: Photochemical degradation of primaquine in an aqueous medium