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. 2010 Oct;26(4):447-55.
doi: 10.3892/ijmm_00000484.

Evaluation of curcumin acetates and amino acid conjugates as proteasome inhibitors

Affiliations

Evaluation of curcumin acetates and amino acid conjugates as proteasome inhibitors

Sheng Biao Wan et al. Int J Mol Med. 2010 Oct.

Abstract

Curcumin (diferuloylmethane) is the main active ingredient of turmeric, a traditional herbal medicine and food of south Asia. Curcumin has been found to have a wide range of biological activities, including antioxidant, anti-inflammatory, chemopreventive and chemotherapeutic activities. Curcumin is currently being tested in clinical trials for treatment of various types of cancers, including multiple myeloma, pancreatic cancer and colon cancer. Although no toxicity associated with curcumin (even at very high doses) has been observed, the effects of curcumin in other solid tumors have been modest, primarily due to poor water solubility and poor bioavailability in tissues remote from the gastrointestinal tract. Therefore, there is a need for the discovery of curcumin analogs with better water solubility or greater bioavailability for the treatment of solid tumors such as prostate cancer. In this study, curcumin acetates and amino acid conjugates of curcumin were studied in terms of their proteasome inhibitory and antiproliferative effects against several human cancer cell lines. It was found that the water soluble amino acid conjugates of curcumin showed a potent antiproliferative effect and are potent proteasome inhibitors. Docking studies of the curcumin amino acid conjugates for proteasome inhibition were carried out to explain their biological activities. It is suggested that they may serve as the water soluble analogs of curcumin.

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Figures

Figure 1
Figure 1
Synthesis of curcumin monoacetate (5) and curcumin diacetate (2): a, Ac2O/pyridine; b, TBDMSCl/imidazole/DMF; c, TBAF/THF.
Figure 2
Figure 2
Molecular stereo structure of compound 2.
Figure 3
Figure 3
Cell proliferation-inhibitory effects of curcumin and its analogs on colon cancer cells. Human colon cancer cells HCT116 (A) and SW480 (B) were treated with the indicated concentrations of curcumin (CUR), curcumin monoacetate (AC-CUR) or curcumin diacetate (AC2-CUR) for 36 h, followed by MTT assay.
Figure 4
Figure 4
Proteasome-inhibitory effects of curcumin and its analogs on colon cancer cells. Human colon cancer cell lines HCT116 (A) and SW480 (B) were treated with the indicated concentrations of curcumin (CUR), curcumin monoacetate (AC-CUR) or curcumin diacetate (AC2-CUR) for 36 h, followed by the proteasomal chymotrypsin (CT)-like activity assay.
Figure 5
Figure 5
Synthesis of curcumin amino acid conjugates: d, N-Boc-amino acid/EDCI/DMAP; e, i) TFA/CH2Cl2, 0°C/4 h; ii) 1 M aq. HCl.
Figure 6
Figure 6
Synthesis of curcumin poly-L-glutamic acid conjugate 13.
Figure 7
Figure 7
Inhibition on proteasome activity and cell proliferation by curcumin analogs. (A) The purified 20S proteasome was incubated with the indicated concentrations of curcumin (CUR) or its analogs for 2 h, followed by the proteasomal chymotrypsin-like activity assay. (B) LNCaP cells were treated with different concentrations of curcumin (CUR) or its analogs for 48 h, followed by the MTT assay. All of the reagents were dissolved in water.
Figure 8
Figure 8
Inhibition of purified 20S proteasome activity by curcumin analogs. The 20S proteasome was incubated with indicated concentrations of curucmin (CUR), and its analogs were dissolved in different solvents (6–9 in DMSO; 10–12 in H2O; 13 and curcumin in ethanol) for 2 h, followed by the chymotrypsin-like activity assay.
Figure 9
Figure 9
Inhibition of cell proliferation by curcumin analogs. PC-3 (A) or LNCaP (B) cells were treated with the indicated concentrations of curcumin (CUR) or its analogs which were disolved in DMSO or ehanol (EtOH) for 48 h, followed by the MTT assay.
Figure 10
Figure 10
26S proteasome inhibition by curcumin analogs. PC-3 (A) or LNCaP (B) cell extracts were incubated with the indicated concentrations of curcumin (CUR) or its analogs which were disolved in DMSO or ethanol (EtOH) for 2 h, followed by the chymotrypsin-like activity assay.
Figure 11
Figure 11
Computational docking analysis. (A–C) Electron density was analyzed in curcumin analogs 10, 11 and 12 using CaChe software. The bull's eyes with a yellow center indicated high nucleophilic susceptibility. (D–F) These compounds were docked into the β5 subunit of the proteasome. The distances from the carbonyl carbons to the OH group of Thr1 of the β5 subunit were 3.29 or 3.41 Å in compound 10, 3.29 or 3.30 Å in compound 11 and 2.85 or 4.09 Å in compound 12. Compounds 10–12 are shown as stick models. The OH group in Thr1 is shown in red and white.

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