Synthesis and anti-inflammatory activities of mono-carbonyl analogues of curcumin

Abstract

Curcumin has been extensively studied for its anti-inflammatory activities. However, its potential beneficial effects on various disease preventions and treatments are limited by its unstable structure. The β-diketone moiety renders curcumin to be rapidly metabolized by aldoketo reductase in liver. In the present study, a series of curcumin analogues with more stable chemical structures were synthesized and several compounds showed an enhanced ability to inhibit lipopolysaccharide (LPS)-induced TNF-α and IL-6 synthesis in macrophages.Curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, Fig. 1] is the major active constituent of turmeric, a yellow compound originally isolated from the plant Curcuma longa L. Tumeric has been widely used for centuries as a dietary spice and pigment. 1 In addition to its unique flavor and color, tumeric has been extensively used in traditional medicine in China and India, particularly as an anti-inflammatory agent. 2 During the last two decades, numerous studies have shown that curcumin has a variety of biological and pharmacological activities such as anti -carcinogen, immuno-modulation, anti-oxidant, antiangiogenesis, and chemo-prevention. 3-9 Recent studies have demonstrated that inflammation is implicated in the pathogenesis of various diseases including cancer, atherosclerosis, diabetes, fatty liver, rheumatoid arthritis, and inflammatory bowel disease. 10-13 Anti-inflammation is the major focus of current drug development. 14 Cytokines are local mediators produced by lymphocytes and macrophages as well as by epithelial and mesenchymal cells. 15 It has been demonstrated that cytokines are involved in a variety of biological processes and play a central role in the development of inflammation and immunity. TNF-α is a multifunctional cytokine produced primarily by activated monocytes/macrophages and plays a critical role in the initiation and continuation of inflammation and immunity. 16 It is well-known that TNF-α is a key proinflammatory cytokine in the pathogenesis of various inflammatory diseases and cancer. 13, 17 In addition to directly *Corresponding authors: Huiping Zhou: 1217 East Marshall Street, MSB#533, Richmond, VA 23298, USA. E-mail: hzhou@vcu.edu; Tel:804-828-6817; Fax:804-828-0676., Xiaokun Li: College of Pharmacy, Wenzhou Medical College., E-mail: xiaokunli@163.com. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In order to identify the crucial structural motifs leading to anti-inflammatory activity and gain insight into future directions for designing new analogues with better activity, thre...

Crystal structure of (Z)-1-(1,5-dimethyl-1H-pyrazol-3-yl)-3-hydroxybut-2-en-1-one C9H12N2O2

“…Their versatile utility in medicinal chemistry is rmly established including anti-HIV [1,2], antitumor [3][4][5], anti-in uenza [6], antioxidant [7], and anti-in ammatory [8] activities. In this study we coupled ethyl pyrazole carboxylate with acetone to produce the title compound in acceptable yield.…”

Crystal structure of (Z)-1-(1,5-dimethyl-1H-pyrazol-3-yl)-3-hydroxy-3-phenylprop-2-en-1-one, C14H14N2O2

“…Many heterocycles branched β-keto-enol are useful synthetic intermediates in a wide variety of applications including anti-tumor [1][2][3], anti-in ammatory [4] and anti-HIV [5,6] activities. Recently, we have reported some new heterocyclic keto-enol compounds that have shown remarkable biological activities [7] and e cient coordination properties [8,9].…”

Crystal structure of (2E,6E)-2,6-bis(2,4-dimethoxybenzylidene)- cyclohexanone, C24H26O5

“…However, although curcumin is non-toxic and has promising anti-cancer activities, preclinical and clinical studies indicate that its poor bioavailability and weak pharmacokinetic profiles derived from its structural instability under physiological conditions have seriously limited its application in anti-cancer therapies [6,7]. In the past two decades, alot of efforts has been put into the chemical modification of curcumin to identify potential analogues with better bioavailability and antitumor activities [5,[8][9][10]. The title compound, one of monocarbonyl curcumin analogues has demonstrated excellent cytotoxic properties against several human cancer cell lines in vitro (data not shown).…”