Design and synthesis of polyhydroxy steroids as selective inhibitors against AKR1B10 and molecular docking

doi:10.1016/j.steroids.2016.03.004

Steroids

Volume 110, June 2016, Pages 1-8

https://doi.org/10.1016/j.steroids.2016.03.004 Get rights and content

Highlights

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Five pairs analogues of polyhydroxy steroids were designed, synthesized and structure identified.
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Novel inhibitors for AKR1B10 were developed.
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The brand new compound 6 shows the high selective inhibitory activity for AKR1B10 against AKR1B1.

Abstract

AKR1B10 is a member of the human aldo–keto reductase superfamily which is highly expressed in several types of cancers, and has been regarded as a promising cancer therapeutic target. In this paper, a series of polyhydroxy steroids were designed and synthesized to selectively inhibit AKR1B10 activity. The most selective compound, novel compound 6, has an IC₅₀ of 0.83 ± 0.07 μM and a selectivity of more than 120-fold for AKR1B10/AKR1B1. Structure–activity relation analyses indicate that hydroxyl at C-19 can significantly improve the selective inhibition of AKR1B10. The binding mode of AKR1B10 and its inhibitors were studied.

Graphical abstract

Introduction

Aldo–keto reductase 1B10 (AKR1B10) belongs to the human NADPH-dependent aldo–keto reductase superfamily [1]. Recently, a number of reports have indicated that AKR1B10 is highly expressed in several types of cancers, such as hepatocellular carcinoma, breast cancer, lung cancer, colorectal cancer, uterine cancer and cervical cancer [2], [3], [4], [5], [6]. The silencing of the AKR1B10 gene in colorectal cancer cells inhibits growth, reduces the rate of foci formation and reduces the colony size [7]. In addition, studies of the role of AKR1B10 in cancer cells suggest that the monomeric enzyme highly correlates with carcinogenesis and tumor cell proliferation by regulating retinoic acid homeostasis [8], fatty acid synthesis [9], lipid metabolism [10] and isoprenoid metabolism [11]. AKR1B1 is closely related to hyperglycemic injury and obesity [12], [13] and is very similar to AKR1B10. Numerous reports indicate that AKR1B10 is a new cancer therapeutic target, and its selective inhibitors may serve as promising antitumor agents.

C-24 carboxyl bile acids, which are polyhydroxy bile acids, were reported to possess anti-tumor activity [14], [15], [16], [17], [18], [19], [20] which may due to their ability to inhibit AKR1B10 [11], [15]. Most polyhydroxy steroids exert various biological activities, including anti-tumor activities [21], [22]. Our previous studies demonstrated that polyhydroxy steroids have anti-tumor activities [23], [24]. A series of polyhydroxy steroids bearing different side chain sterols and sterones were synthesized to selectively inhibit AKR1B10 [25]. However, the ability of polyhydroxy steroids, which have been identified as antitumor agents, to inhibit AKR1B10 is unknown.

To discover the new AKR1B10 selective inhibitors as anti-tumor candidates, a series of polyhydroxy steroids were designed and synthesized, and their ability to inhibit AKR1B10 was assessed by measuring their IC₅₀ values. The selective inhibitory activities and structure- activity relationship (SAR) of the compounds on AKR1B10/AKR1B1 were studied in silico.

Section snippets

Chemistry

The starting materials were purchased from commercial sources or synthesized in our laboratory. All solvents used in the tests were of analytic grade and reagents were synthesized or purchased from commercial sources unless otherwise indicated. All reactions were monitored with thin-layer chromatography (TLC) on silica gel G (G-254). The melting points were measured on an X6 melting point apparatus without correction. The IR spectra were recorded using KBr pellets on an EQUINOX 55 FT

Chemistry

To study the effects of different side chain at C-17 on the activity and selectivity for AKR1B10, a series of steroidal triols and tetrols were designed and synthesized with androst-5 -en-3-ol, cholesterol, 3-hydroxy-cholest-5-en-24-oic aid and 3-hydroxy-cholest-5-en-24-one as starting materials.

The steroidal triols (Compound 1–4) were synthesized with oxidation and alkaline hydrolysis, and the characteristic of the steroidal structure contains 3β, 5α, 6β-triol which have three significant

Conclusion

The polyhydroxyl steroids can selectively inhibit AKR1B10; the IC₅₀ for AKR1B10 inhibition ranges from 0.76 to 2.83 μM. The compound 9 has the most effective inhibition with the IC50 0.76 μM. However, the most selective compound for AKR1B10, novel compound 6, has an IC₅₀ of 0.83 μM and shows ∼120-fold selectivity for AKR1B10 over AKR1B1. A hydroxy group at C-19 and the carbonyl group at C-17 may play an important role in enhancing the inhibitory activity for both AKR1B10 and AKR1B1. But no side

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Design and synthesis of polyhydroxy steroids as selective inhibitors against AKR1B10 and molecular docking

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Chemistry

Conclusion

Chem. Biol. Interact.

Chem. Biol. Interact.

Biochem. Biophys. Res. Commun.

Arch. Biochem. Biophys.

Theriogenology

Bioorg. Med. Chem.

Eur. J. Med. Chem.

Cancer Lett.

Steroids

Steroids

Structure

Statil suppresses cancer cell growth and proliferation by the inhibition of tumor marker AKR1B10

Anticancer Drugs

Impaired self-renewal and increased colitis and dysplastic lesions in colonic mucosa of AKR1B8-deficient mice

Clin. Cancer Res.

Induced fit binding of aldose reductase inhibitors to AKR1B10

Med. Chem. Res.

Enzymes of the AKR1B and AKR1C subfamilies and uterine diseases

Front. Pharmacol.