The Essential Medicinal Chemistry of Curcumin

Abstract

Curcumin is a constituent (up to ∼5%) of the traditional medicine known as turmeric. Interest in the therapeutic use of turmeric and the relative ease of isolation of curcuminoids has led to their extensive investigation. Curcumin has recently been classified as both a PAINS (pan-assay interference compounds) and an IMPS (invalid metabolic panaceas) candidate. The likely false activity of curcumin in vitro and in vivo has resulted in >120 clinical trials of curcuminoids against several diseases. No double-blinded, placebo controlled clinical trial of curcumin has been successful. This manuscript reviews the essential medicinal chemistry of curcumin and provides evidence that curcumin is an unstable, reactive, nonbioavailable compound and, therefore, a highly improbable lead. On the basis of this in-depth evaluation, potential new directions for research on curcuminoids are discussed.

Figure 1

Structural comparison of curcumin and artemisinin. Curcumin has been the focus of heavy research for new drug development. Artemisinin is an FDA approved antimalarial.

Figure 2

Comparison of publication frequency for biological studies of curcumin and artemisinin. The numbers of manuscripts per year were retrieved from SciFinder by searching for the substances curcumin (CAS no. 458-37-7) or artemisinin (CAS no. 63968-64-9) and then filtering by “biological study” and “document type” = journal. (Data accessed May 3, 2016.)

Figure 3

Major phytoconstituents of extracts of Curcuma longa. Compounds 1, 3, and 4, often grouped together as “curcuminoids”, generally make up approximately 1–6% of turmeric by weight. Of a curcuminoid extract, 1 makes up 60–70% by weight, while 3 (20–27%) and 4 (10–15%) are more minor components. The major constituent of a curcuminoid extract, 1, and the properties important for its consideration as a lead compound for therapeutic development are the focus of this review.

Figure 4

Tautomerization of compound 1. NMR studies show that compound 1 is not present in solution as the diketone (1a) but only as a mixture of the equally present (due to symmetry) enol structures (1b).

Figure 5

Major chemical degradation pathways of compound 1. (A) Solvolysis under alkaline pH in buffered aqueous solution rapidly leads to multiple fragmentation byproducts. (B) Autoxidation in buffered medium creates a bicyclopentadione (8) that is the major degradation product in aqueous conditions. (C) Photodegradation of 1 can occur when in crystalline form and dissolved in organic solvent. (D) When dissolved in certain organic solvents (like isopropanol), photodegradation can include reaction with the solvent as a substrate.