Mono-carbonyl Analogues Of Curcumin Research Articles

Mono-carbonyl curcumin analogues as 11β-hydroxysteroid dehydrogenase 1 inhibitors

A series of structurally novel mono-carbonyl curcumin analogues have been synthesized and biologically evaluated to test their inhibitory potencies and the structure–activity relationship (SAR) on human and rat 11β-hydroxysteroid dehydrogenase isoform (11β-HSD1) activities. 11β-HSD1 selective inhibitors have been discovered and compound A10 is discovered as a very potent with an IC50 value of 97nM without inhibiting 11β-HSD2.

Promising Curcumin-based Drug Design: Mono-carbonyl Analogues of Curcumin (MACs)

Promising Curcumin-based Drug Design: Mono-carbonyl Analogues of Curcumin (MACs)

Discovery and evaluation of piperid-4-one-containing mono-carbonyl analogs of curcumin as anti-inflammatory agents

We previously reported the design and discovery of three series of 5-carbon linker-containing mono-carbonyl analogs of curcumin (MCACs) as excellent anti-inflammatory agents. In continuation of our ongoing research, we designed and synthesized the fourth series of MCACs, whose central linker is a piperid-4-one. Their inhibitory effects against IL-6 production were evaluated in lipopolysaccharide (LPS)-stimulated macrophages. Among them, compounds F8, F29, F33, F35, and F36 exhibited the IC50 values under 5μM. The structure–activity relationship was discussed. Mechanistically, F35 and F36 dose-dependently prevented LPS-induced NF-κB and ERK activation. Finally, pretreatment with F35 and F36 significantly protected the C57B/L6 mice from LPS-induced septic death. Together, these data present a series of new analogs of curcumin as promising anti-inflammatory agents.

Promising Curcumin-based Drug Design: Mono-carbonyl Analogues of Curcumin (MACs)

Curcumin exhibits a surprisingly wide range of chemo-preventive and chemo-therapeutic activities. Curcumin has undergone more than 40 clinical trials for the treatment of inflammatory diseases and various human cancers. However, phase I/II clinical trials have shown that curcumin exhibit poor bioavailability in humans. Major reasons resulting in the low plasma and tissue levels of curcumin appear to be its poor absorption, fast metabolism, and rapid systemic elimination. It is suggested that the β-diketone moiety is responsible for the instability and weak pharmacokinetic profiles of curcumin. To attenuate the fast metabolism of curcumin, numerous approaches have been considered, including the adjuvant, the liposomal curcumin, curcumin nanoparticles and phospholipid complex, and structural modification to prepare the analogues without the β-diketone moiety. Particularly, the latter called mono-carbonyl analogs of curcumin (MACs) has been reported to has an enhanced stability in vitro and an improved pharmacokinetic profile in vivo. Thus, MACs have attracted a high attention for development of new curcumin-based agents with both enhanced bioactivities and pharmacokinetic profiles. A number of MACs have shown potential anticancer and anti-inflammatory activity in various models. Several of them have been studied intensively in order to develop novel agents. This review covers 607 MACs as well as their biological activities reported in the past two decades.

Synthesis and Anticancer Activity of Mono-Carbonyl Analogues of Curcumin

Curcumin has been reported to possess multifunctional bioactivities with low toxicity. However, the clinical application of curcumin has been significantly limited by its instability and poor metabolic property. Up to now, multiple approaches are being sought to overcome these limitations to obtaining “super curcumin”, and many analogues of curcumin have been designed and synthesized. In all of those analogues, a series of mono-carbonyl curcumin analogues deleting the β-diketone draw our attention. Since the seven-carbon β-diketone linker in curcumin may be responsible for its instability, the series of mono-carbonyl curcumin analogues deleting the β-diketone may be potential prodrug with improved pharmacokinetic and pharmacodynamic properties. This review just focuses on these more stable mono-carbonyl analogues of curcumin, and shows the new class of active structure by introducing the synthesis and anticancer activity of them.

(3E,5E)-3,5-Bis(2-chlorobenzylidene)-1-propylpiperidin-4-one

The title compound, C22H21Cl2NO, is a derivative of mono-carbonyl analogues of curcumin (MACs). The mol­ecule has an E conformation for each of the olefinic bonds. The 1-propyl­piperidin-4-one ring has a distorted chair conformation with the ring N and the C and O atoms of the carbonyl group deviating from the mean plane of the remaining four ring C atoms by 0.682 (2), −0.134 (3) and −0.340 (4) Å, respectively. The dihedral angle between the benzene rings is 26.5 (1)°. In the crystal, mol­ecules are connected by weak C—H⋯O and C—H⋯π inter­actions.

Inhibitory effect of curcumin analogs on tissue factor procoagulant activity and their preliminary structure–activity relationships

With the aim to explore the multifunctional behaviors of curcumin analogs and to discover new small molecular tissue factor inhibitors, twelve mono carbonyl curcumin analogs of three classes were synthesized and their effect on tissue factor procoagulant activity was evaluated in the human monoblastic leukemia THP-1 cells stimulated by LPS. The most potent compounds 2a exhibited the dramatically enhanced activity with the IC50 values of 0.053 nM. Their preliminary structure–activity relationship was also discussed.

Synthesis, antimalarial activity and cytotoxic potential of new monocarbonyl analogues of curcumin

A series of novel monocarbonyl analogues of curcumin have been designed, synthesized and tested for their activity against Molt4, HeLa, PC3, DU145 and KB cancer cell lines. Six of the analogues showed potent cytotoxicity towards these cell lines with IC50 values below 1μM, which is better than doxorubicin, a US FDA approved drug. Several analogues were also found to be active against both CQ-resistant (W2 clone) and CQ-sensitive (D6) strains of Plasmodium falciparum in an in-vitro antimalarial screening. This level of activity warrants further investigation of the compounds for development as anticancer and antimalarial agents.

A synthetic compound, 1,5‐bis(2‐methoxyphenyl)penta‐ 1,4‐dien‐3‐one (B63), induces apoptosis and activates endoplasmic reticulum stress in non‐small cell lung cancer cells

Endoplasmic reticulum (ER) stress-induced cancer cell apoptosis has become a novel signaling target for the development of therapeutic drugs for cancer treatment. Curcumin, a dietary phytochemical, exhibits growth-suppressive activity against cancer cells via multitarget mechanisms. However, the low stability and poor pharmacokinetics significantly limit its clinical applications. Thus, we designed and synthesized a novel monocarbonyl analog of curcumin, 1,5-bis(2-methoxyphenyl) penta-1,4-dien-3-one (B63). This compound exhibited a higher chemical stability in cultural medium and a better intracellular profile than curcumin. Treatment with B63 potently induced apoptosis of human non-small cell lung cancer (NSCLC) cells in a dose-responsive manner, while exhibiting no cytotoxicity in normal lung fibroblast cells. Its antitumor effect was associated with the ER stress-mediated apoptotic pathway and, ultimately, the activation of the caspase cascades. However, curcumin at the same concentrations did not cause ER stress in H460 cells. Further, C/EBP homologous protein knockdown by siRNA attenuated B63-induced cell apoptosis, indicating that the apoptotic pathway is ER stress-dependent. In vivo, the volume and weight of the tumor were reduced significantly by pretreating the H460 tumor cells with B63 before implantation. Taken together, these insights on the novel compound B63, from both chemical and biological perspectives, may provide a novel anticancer candidate for the treatment of NSCLC.

Synthesis and anti-inflammatory evaluation of novel mono-carbonyl analogues of curcumin in LPS-stimulated RAW 264.7 macrophages

Curcumin is a multifunctional natural product with regulatory effects on inflammation. However, a major limitation for the application of curcumin is its poor bioavailability. We previously demonstrated that the mono-carbonyl analogues of curcumin possessed improved pharmacokinetic profiles. In this study, 33 novel mono-carbonyl analogues of curcumin were synthesized and their inhibition against TNF-α and IL-6 release was evaluated in LPS-stimulated RAW 264.7 macrophages. Based on the screening data, quantitative structure–activity relationship was conducted, indicating that electron-withdrawing groups in benzene ring are favourable to anti-inflammatory activities of B-class compounds. Furthermore, compounds AN1 and B82 demonstrated anti-inflammatory abilities in a dose-dependent manner. These raise the possibility that these compounds might serve as potential agents for the treatment of inflammatory diseases.

Synthesis of mono-carbonyl analogues of curcumin and their effects on inhibition of cytokine release in LPS-stimulated RAW 264.7 macrophages

Curcumin has been reported to possess multifunctional bioactivities, especially the ability to inhibit proinflammatory induction. We previously demonstrated that the mono-carbonyl analogues of curcumin possessed improved pharmacokinetic profiles both in vitro and in vivo. In this study, we synthesized and examined a series of 5-carbon linker-containing mono-carbonyl analogues of curcumin with potent inhibitory activities against TNF-α and IL-6 release in LPS-stimulated RAW 264.7 macrophages. Discussion and conclusions are given regarding structure-activity relationships (SAR). The two most potent analogues among the tested compounds, B75 and C12, exhibited anti-inflammatory abilities in a dose-dependent manner in macrophages. This raises the possibility that mono-carbonyl analogues of curcumin might serve as potential agents for the treatment of various inflammatory diseases.

Inhibition of LPS-induced production of inflammatory factors in the macrophages by mono-carbonyl analogues of curcumin.

Curcumin (diferuloylmethane) is an orange–yellow compound from turmeric (Curcuma longa), a spice found in curry powder. Traditionally known for its anti-inflammatory effects, curcumin has established itself in the last two decades to be a potent immunomodulatory agent that can regulate the activation of a variety of immunocytes and the expression of inflammatory factors. Considering that the β-diketone moiety of curcumin may result in its instability and poor metabolic property, we previously designed a series of mono-carbonyl analogues of curcumin with enhanced stability by deleting this moiety. These compounds demonstrate improved pharmacokinetic profiles both in vitro and in vivo. In this study, we reported a total of 44 mono-carbonyl analogues, which have been evaluated for the inhibitory activities against LPS-induced TNF-α and IL-6 release in the macrophages. Based on the screening results of these analogues, five active compounds A01, A03, A13, B18 and C22 were investigated to inhibit TNF-α and IL-6 release in a dose-dependent manner, three of which further demonstrated inhibitory effects on LPS-induced TNF-α, IL-1β, IL-6, MCP-1, COX-2, PGES, iNOS and p65 NF-κB mRNA production. The results indicated that these mono-carbonyl analogues may possess anti-inflammatory activities similar to curcumin despite the absence of the β-diketone. These mono-carbonyl analogues may be a favourable alternative for the development of curcumin-based anti-inflammatory drugs both pharmacokinetically and pharmacologically. We further examined the biological properties of A13, the only hydrosoluble analogue when combined with hydrochloric acid. The results showed a dose-dependent inhibition of LPS-induced cytokine production. These data further indicated that compound A13 may be explored as a promising anti-inflammatory molecule.

P94 Inhibition of LPS-induced production of inflammatory factors in the macrophages by mono-carbonyl analogues of curcumin

P94 Inhibition of LPS-induced production of inflammatory factors in the macrophages by mono-carbonyl analogues of curcumin

Exploration and synthesis of curcumin analogues with improved structural stability both in vitro and in vivo as cytotoxic agents

Curcumin has a surprisingly wide range of chemo-preventive and chemo-therapeutic activities and is under investigation for the treatment of various human cancers. However, the clinical application of curcumin has been significantly limited by its instability and poor metabolic property. Although a number of synthetic modifications of curcumin have been studied intensively in order to develop a molecule with enhanced bioactivities, few synthetic studies were done for the improvement of pharmacokinetic profiles. In the present study, a series of mono-carbonyl analogues of curcumin were designed and synthesized by deleting the reactive β-diketone moiety, which was considered to be responsible for the pharmacokinetic limitation of curcumin. The results of the in vitro stability studies and in vivo pharmacokinetic studies indicated that the stability of these mono-carbonyl analogues was greatly enhanced in vitro and their pharmacokinetic profiles were also significantly improved in vivo. Furthermore, the cytotoxic activities of mono-carbonyl analogues were evaluated in seven different tumor cell lines by MTT assay and the structure–activity relation (SAR) was discussed and concluded. The results suggest that the five-carbon linker-containing analogues of curcumin may be favorable for the curcumin-based drug development both pharmacokinetically and pharmacologically.

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

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 beta-diketone moiety renders curcumin to be rapidly metabolized by aldo-keto 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-alpha and IL-6 synthesis in macrophages.