Original article
Synthesis of novel curcumin analogues for inhibition of 11β-hydroxysteroid dehydrogenase type 1 with anti-diabetic properties

https://doi.org/10.1016/j.ejmech.2014.03.012Get rights and content

Highlights

  • We synthesized analogues of curcumin which were much more stable than the curcumin.

  • We found 4 curcumin analogues are selective inhibitors of human and rat 11β-HSD1.

  • Analogues of curcumin display anti-diabetic properties.

Abstract

In the present study, a series of mono-carbonyl analogues of curcumin were designed and synthesized by deleting the reactive beta-diketone moiety, which is responsible for the pharmacokinetic limitation of curcumin. We demonstrated that 4 of 9 curcumin analogues were selective inhibitors of human and rodent 11β-HSD1. The level of this inhibitor was 4–20 times more than that of curcumin. Curcumin analogues weakly inhibited 11β-HSD2, and further analyses revealed that these compounds were highly selective, favoring 11β-HSD1. These 4 curcumin analogues are potential therapeutic agents for type-2 diabetes by targeting 11β-HSD1. The compound 8 displays anti-diabetic properties in diabetic mice induced by streptozocin and high-fat-diet (STZHFD).

Introduction

Glucocorticoids (mainly cortisol in humans and corticosterone in rodents) play a fundamental role in controlling physiologic homeostasis. However, when present in excess, they can have a detrimental impact on glucose control, blood pressure and lipid levels. Glucocorticoids increase glucose output in the liver, induce fat accumulation, dampen glucose-dependent insulin sensitivity in the adipose tissue, thus increasing the risks of metabolic syndrome [1]. Obesity and type-2 diabetes are associated with abnormal regulation of glucocorticoids metabolism. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes functionally inert glucocorticoid precursors (cortisone) to active glucocorticoids (cortisol) within the insulin target tissues, such as adipose tissue, thereby regulating local glucocorticoid action [2], [3]. 11β-HSD has two known isoforms: an NADP+/NADPH dependent 11β-HSD1 oxidoreductase that behaves a primary reductase in the liver and fat tissues and an NAD+-dependent 11β-HSD2 [4]. 11β-HSD2 acts a unidirectional oxidase to prevent cortisol from stimulating the mineralo-corticoid receptor in the kidneys, and the mutation of human 11β-HSD2 causes severe hypertension and hypokalemia [5], [6].

Recent data, mainly from rodents, provide considerable evidence for the causal role of 11β-HSD1 in the development of visceral obesity and type-2 diabetes. Thus, 11β-HSD1 inhibitors have the potential of becoming an interesting novel class of drugs in the future for the treatment of obesity and type-2 diabetes [7]. It is also important that 11β-HSD1 inhibitors not significantly inhibit 11β-HSD2 in order to avoid undesirable actions such as sodium retention, hypokalemia, and hypertension. This led to the industry-wide search for selective 11β-HSD1 inhibitors.

Curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] (Fig. 1) is one of the hundreds of components isolated from the ancient spice turmeric (Curcuma longa). Tumeric has been widely used for centuries as a dietary spice and pigment. In addition to its unique flavor and color, tumeric has been extensively used in traditional medicine in several countries including the United States, India, Japan, Korea, Thailand, China, Turkey, South Africa, Nepal, and Pakistan [8]. It is being studied intensively today for its potential therapeutic activity in the treatment of diabetes and obesity-related metabolic disorders [9], [10]. Curcumin has exhibited inhibitory action against human and rat 11β-HSD1 in intact cells, with IC50 values of 2.29 and 5.79 μM, respectively, and selectivity against 11β-HSD2 (IC50, 14.56 and 11.92 μM) [11]. At the same time, in the preclinical and clinic studies, curcumin has been shown to possess several disadvantages in pharmacokinetics due to its poor bioavailability, rapid metabolism and requirement of repetitive oral doses, which limit its candidacy as a drug. For instance, it has been reported that plasma and tissue curcumin levels in human volunteers and patients are 11.1 nM and 1.3 μM, respectively. However, it required oral dose administration of up to 3.6 g/day [12], [13]. In the present study, a series of curcumin analogues with more stable structures and good pharmacokinetic properties were synthesized.

The analogues that deleting the methylene group and one carbonyl group of curcumin, we previously synthesized three series of mono-carbonyl curcumin analogues without the central methylene functional groups and β-diketone moiety. These compounds demonstrated better anti-bacterial and anti-inflammatory properties [14].

In this study, we designed and synthesized a series of mono-carbonyl analogues of curcumin by deleting the beta-diketone moiety (Scheme 1). The 9 curcumin analogues were evaluated for selective 11β-HSD1 inhibitors activity. We performed a degradation degree assay in vitro and a pharmacokinetic study in vivo to examine the eight mono-carbonyl analogues that exhibit enhanced stability. We found our bis-halo derivatives had more activities against human HSD1 than the previous report of the analogs with Single halo derivatives [15]. The compound 8 improved pharmacokinetic profiles compared to that of curcumin.

Inhibition of 11β-HSD1 is being pursued as an approach to the treatment of type-2 diabetes and visceral obesity [16]. Since 11β-HSD1 primarily modulates levels of cortisol within tissues, these findings led us to hypothesize that the generated curcumin analogues will display anti-diabetic activity in the mice.

Section snippets

Chemistry

Four series of mono-carbonyl analogues of curcumin, penta-1,4-dien-3-one (compound 1,5), together with cyclopentanone (compound 2, 4, 8), cyclohexanone (compound 3, 6, 9) and piperidin-4-one (compound 7) analogues, were designed by displacing beta-diketone moiety with a single carbonyl group based on previous reports [14], [15]. Different substituents with opposing electronic properties in the benzene rings were designed to investigate the structure–activity relationship. Compounds 1–9 (shown

Conclusion

Although curcumin is the natural 11β-HSD1 inhibitor, its poor bioavailability and rapid metabolism make it less promising for clinical applications. In this paper, we designed and synthesized a series of mono-carbonyl analogues of curcumin. Curcumin analogues significantly inhibited human and rat 11β-HSD1 activities. In addition, their IC50s for 11β-HSD2 at the dose of >100 μM indicated good primary and secondary selectivities. The curcumin analogues compound 8 showed anti-diabetic effects,

Chemical synthesis

Melting points were determined on a OptiMelt MPA-100 apparatus (SRS, USA) and were uncorrected. 1H NMR spectra were recorded on a INOVA-400 spectrometer (Varian, USA). The chemical shifts were presented in terms of parts per million, with TMS as the internal reference. Electron-spray ionization mass spectra in positive mode (ESI-MS) data were recorded on a Esquire 3000 + spectrometer (Bruker, USA). Column chromatography purifications were carried out on Silica Gel 60 (E. Merck, 70–230 mesh).

The

Acknowledgments

This work was supported in part by the National Natural Science Funding of China (81070329 to Y.H.C and 81070477 to Y.D.H). The project was supported in part by the Guangdong Province Higher Vocational Colleges & Schools Pearl River Scholar Funded Scheme (2012), by the National Natural Science Funding of Heilongjiang Province (H201378 to X.H.Y), by the Foundation of Heilongjiang Educational Committee (13530865 to X.H.Y) and supported by the Open Project Program of the Key Laboratory of Tissue

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