Synthesis and selective anticancer activity of steroidal glycoconjugates

doi:10.1016/j.ejmech.2012.06.027

European Journal of Medicinal Chemistry

Volume 54, August 2012, Pages 721-727

https://doi.org/10.1016/j.ejmech.2012.06.027 Get rights and content

Abstract

The synthesis of glucosamine derivatives of the steroidal sapogenins diosgenin and hecogenin using the N-phthaloyl protected trichloroacetimidate of d-glucosamine as donor and TMSOTf as promoter is reported. The corresponding glycoconjugates were transformed into their acetamido derivatives and the hydrochloride salt (from diosgenin) and tested against HeLa, CaSki, and ViBo cervicouterine cancer cells. These compounds showed low cytotoxicity values on tumor cells and human lymphocytes, indicating that the main cell death process is presumably not necrosis. Significantly, the antiproliferative activity of these compounds on tumor cells did not affect the proliferative potential of peripheral blood lymphocytes.

Graphical abstract

Highlights

► Steroidal 2-amino-2-deoxy-β-d-glucopyranoside derivatives were synthesized starting from steroidal sapogenins. ► Antiproliferative activity against CaSki, HeLa and ViBo cells is described. ► Proliferative potential on lymphocytes was not negatively affected. ► Cytotoxicity was tested in tumoral and healthy cells to demonstrate selectivity. ► The hydrochloride salt from diosgenin showed better activity than the N-acetylated analog.

Introduction

Saponins constitute a group of structurally related compounds widely distributed in the animal, plant, and fungal kingdoms. The medicinal chemistry of steroidal saponins has generated a large variety of structures and biological activities [1]. This group of natural products has been extensively studied in the development of new drugs for the treatment of infections, diabetes, and cancer, among others. Steroid–carbohydrate conjugates are involved in a wide variety of biological processes, and their synthesis and biological evaluation is of interest [2]. The carbohydrate moiety of steroidal saponins plays a very important role in the biological activity [3], and it is of interest, therefore, to search for new variants of steroidal glycosides with selective anticancer activity. The most common monosaccharide units present in natural and synthetic steroidal saponins are β-d-glucopyranose, α-l-rhamnopyranose and β-d-galactopyranose [1], [4]. Glucosamine is an aminosugar of great biological importance that is frequently encountered as a constituent of many naturally occurring poly- and oligosaccharides, glycoproteins, and glycolipids. Its presence in steroidal saponins opens up a broad spectrum of possibilities in biological activities since the nature of the amino group confers specific properties on different types of molecules [5]. We have described in previous work the glycosylation of several steroidal derivatives along with their corresponding anticancer activities [6]. In an extension of this work, we now report the synthesis, characterization, and biological evaluation of diosgenin and hecogenin glycosides containing β-d-glucosamine and/or β-d-N-acetylglucosamine at C-3 and their anticancer activities versus HeLa, CaSki, and ViBo cell lines.

Section snippets

Synthesis

The synthetic strategy was based on the use of anomeric trichloroacetimidates of peracetylated N-phthalimido glucosamine. The trichloroacetimidates were obtained as described in Scheme 1 [7], and were used immediately in the coupling reactions.

The glycosylation reactions of the donor 4 with diosgenin (5) and hecogenin (6) promoted by TMSOTf [6], afforded exclusively the β-glycosides 7 and 8 (Scheme 2). The structure of the coupling products was confirmed by 2D NMR and HRMS analyses. The

Conclusions

In summary, the glucosamine steroidal derivatives 9–11 were synthesized from the steroidal sapogenins diosgenin and hecogenin, and a protected glucosamine donor. The target compounds showed antiproliferative and selective activity against HeLa, CaSki, and ViBo cultures. The hydrochloride 11 showed better IC₅₀ values and more selectivity than its corresponding acetamido analog. The null cytotoxic consequence implies that the observed cell decrease in treated cultures is not a necrotic process

Materials

Optical rotations were measured at 24 °C on a Rudolph Research Autopol II polarimeter using CHCl₃ or MeOH as solvents. ¹H and ¹³C NMR spectra were recorded at 600 and 150 MHz, respectively, on a Bruker AVANCE NMR instrument. The spectra were referenced to residual protonated solvent. Coupling constants are expressed in Hertz (Hz). All assignments were confirmed with the aid of two-dimensional experiments (COSY, HSQC, and HMBC). Acquired data were processed and analyzed using MestReNova

Acknowledgments

The authors thank CONACYT for the postdoctoral fellowship to MAFH, for the doctoral fellowship to HLM and for grants 84380 and 166040 to JSR and MAFH, respectively. We thank VIEP-BUAP for academic and financial support, PAPIME-UNAM for grant PE206812 to LSS and NSERC for a grant to BMP. We also thank Dr. Dionisio Parra (Gyneco-perinatology Department) and Dr. René García (Teaching Department) from Hospital General “Ignacio Zaragoza,” ISSSTE for technical assistance.

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Original articleSynthesis and selective anticancer activity of steroidal glycoconjugates

Abstract

Graphical abstract

Highlights

Introduction

Section snippets

Synthesis

Conclusions

Materials

Acknowledgments

Chem. Rev.

New J. Chem.

Methods Cell Biol.

Saponins: Chemistry and Pharmacology of Natural Products

The biological action of saponins in animal systems: a review

Br. J. Nutr.

The glycosylation of steroids

Tetrahedron

Steroidal conjugates and their pharmacological applications

Curr. Med. Chem.

Chemistry and pharmacology of saponins: special focus on cytotoxic properties

Botanics: Targets Ther.

Isolation of pseudoprototimosaponin AIII from rhizomes of Anemarrhena asphodeloides and its hypoglycemic activity in steptozotocin-induced diabetic mice

J. Nat. Prod.

Apoptosis induced by dioscin in HeLa cells

Biol. Pharm. Bull.

In vivo anti-inflammatory effect of new steroidal saponin, mannioside A, and its derivatives isolated from Dracaena mannii

Arch. Pharm. Res.

OSW-1 analogues: modification of the carbohydrate moiety

Bioorg. Med. Chem. Lett.

Synthesis of OSW saponin analogs with modified sugar residues and their antiproliferative activities

Bioorg. Med. Chem. Lett.

Formation of the steroidal 3β-hydroxy-6-oxo-moiety. Synthesis and cytotoxicity of glucolaxogenin

Arkivoc

Original article
Synthesis and selective anticancer activity of steroidal glycoconjugates