Synthesis of diosgenin derivatives by A and B ring modifications and low-valent titanium (Ti0)-catalysed McMurry coupling reactions and designing to create novel biological agents

https://doi.org/10.1016/j.molstruc.2022.132511Get rights and content

Highlights

  • The derivatives from diosgenin were prepared via five different routes.

  • The A- and B-nor spirostanes were achieved from McMurry coupling reactions.

  • The structure of all derivatives was characterized by using spectroscopic techniques.

  • The stereochemistry of new chiral centers was determined by using COSY and NOESY-experiments.

Abstract

Diosgenin is a steroidal sapogenin ((25R)-spirost-5-en-3β-ol) occurs abundantly in therapeutic herbs such as Dioscorea alata, Smilax China, and Trigonella foenum graecum. It demonstrates a wide range of pharmacological activities and medicinal properties in a large of experimental and theoretical studies. It also constitutes an important class of compounds for new drug development. In the current study, diosgenin derivatives were synthesized and designed, aiming to discover new steroid-based biological agents. In this work, new diosgenin derivatives were synthesized through low-valent titanium (Ti0)-catalyzed McMurry coupling reaction and structural modifications to the A- and B- rings in the diosgenin. McMurry reaction gave the A-nor and B-nor derivatives in by the intramolecular reductive dimerization of carbonyl compounds in the presence of low-valent titanium agents, in moderate yields (46–47%). The modification reactions on the A and B rings of diosgenin were accomplished by using efficient reagents to give three different series, in moderate to high yields (55–97%). The structures of all novel derivatives were confirmed by FTIR, 1H NMR, 13C NMR, and HRMS methods.

Introduction

Norsteroids are a particular class of steroids that have had a five-membered ring A, B, or C, instead of a six-membered ring. Norsteroids can be utilized as biologically active compounds compared to the normal six-membered analogs shown in some studies [1], [2], [3], [4]. Some methods have been reported for the preparation of norsteroids, which involve Diels-Alder cycloadditions [5], retrosynthetic approaches [6], and McMurry coupling reactions [7]. The McMurry reaction consists of the coupling of ketones and esters mediated by low-value titanium reagents. Low-valent titanium reagents, which have an increasing interest in organic synthesis, enable a variety of molecular transformations [8,9].

A steroidal saponin, a member of widespread natural compounds, is composed of an aglycone moiety called sapogenin and a sugar moiety (monosaccharides). Sapogenins are isolated by acid/alkaline hydrolysis or by enzymatic hydrolysis of steroidal saponin. They are constituted by a spirostanol or a furostanol moiety. Spirostanol sapogenins contain a hexacyclic ABCDEF-ring system with spiroacetal at 22nd carbon while furostanol sapogenins have an open F-ring skeleton [10]. Sapogenins exhibit numerous pharmacological activities, such as antibacterial, anticancer, antiviral, anti-inflammatory, and hypocholesterolemic effects [11,12]. These compounds are used as starting materials in the production of steroid hormones and corticosteroids.

Diosgenin (DGN) is a spirostanol sapogenin abundantly available in the roots of wild yam (Dioscorea spp., Smilax spp., Costus species) as well as in some species of the Solanaceae and Fabaceae families. It is a well-known precursor compound for steroidal drugs, such as oral contraceptives, sex hormones, and other steroids in the pharmaceutical industry as it exhibits oestrogenic activity. Recent studies have demonstrated that diosgenin is a leading compound against inflammation, diabetes, thrombosis, and various type of cancers [13]. It has been also used as a natural drug with properties of nuclear factor-kappaB (NF-kappaB) binding and DNA fragmentation inhibition in the cancer cells [14]. In recent years, a great deal of research has focused on the synthesis of various diosgenin derivatives and the discovery of potent applications for them. Zhang et al. synthesized novel diosgenin derivatives containing 1,3,4-oxadiazole/thiadiazole moieties as potential antitumor agents. The results showed that the derivatives exhibited stronger cytotoxic activities than diosgenin against the HepG2 (hepatoma) and A549 (human lung cancer) cell lines [15]. Ma et al. reported that diosgenin-amino acid ester derivatives showed stronger anticancer activities than diosgenin [16]. In another study, Michalak et al. synthesized a set of diosgenin derivatives substituted with various amino acids and the results were displayed significant antiproliferative activity towards breast and prostate human cancer cells [17]. The diosgenin triazole derivatives reported by Huang et al. as neuroprotective agents demonstrated excellent neuroprotective and anti-inflammatory activity [18]. Yin et al. reported recently that the diosgenin derivatives consisting of the dicarboxylic acid linker and amines terminus showed cytotoxic activities and could act as a lead antitumor compound [19]. The above results indicated that diosgenin derivatives may be used as promising compounds for antitumor agents with improved efficacy. Most studies with diosgenin have also demonstrated that it exhibits a wide range of biological activities. Our group considered it worthwhile to design and synthesize novel diosgenin derivatives as potential biological active agents. In this present study, in consideration of the diverse biological activities of diosgenin, novel seven diosgenin derivatives (Fig. 1) and nineteen intermediates were synthesized through several structural modifications on the A and B rings of diosgenin and McMurry reactions on diosgenin. Their structural analyses were elucidated in detail by using spectroscopic techniques. We further continue to work on the structure-activity relationship of the compounds and their attitudes against a number of cancer cell lines.

Section snippets

General methods

The starting substrate diosgenin (purity ∼93%) was procured from Sigma Chemicals, USA. All the dry solvents were prepared as per standard methods. Reagents were used as such without any further purification. Reactions were monitored in Merck aluminium sheet silica gel thin layer plates (TLC, 60F254), visualized in UV-cabinet (λmax =254 and 365 nm) and further charred with 1% p-anisaldehyde in 2% aqueous sulphuric acid with subsequent heating at 105 °C. Melting points were determined in open

Reactions in the A-ring of diosgenin

The synthetic route to the preparation of 3-Keto A-Norspirostan (4) has been shown in Scheme 1. Diosgenin was oxidized by Oppenauer reaction in the presence of cyclohexanone and aluminium isopropoxide under reflux conditions in boiling toluene to yield α, β-unsaturated ketone 1. The reaction mechanism proceeds through the ring transition state. This reaction is a reversible reaction. Therefore, the excess use of reducing agents tends towards product formation. The formation of product was

Conclusion

In the present work, diosgenin derivatives that contain the A-nor, B-nor, A-ring modified, and B-ring modified systems were synthesized, designed and characterized. The reaction strategies have been successfully completed to obtain derivatives and the structures have been characterized FTIR, 1H NMR, 13C NMR, HRMS, respectively. It was considered to design novel diosgenin derivatives with potential biological activities that could be candidates for the discovery of new anticancer drugs and

CRediT authorship contribution statement

Sevinc Ilkar Erdagi: Conceptualization, Methodology, Investigation, Data curation, Visualization. Ufuk Yildiz: Conceptualization, Supervision.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

The author Sevinc I. Erdagi wishes to thank The Scientific and Technological Research Council of Turkey (TUBITAK)-2211 fellowship program and Kocaeli University for the financial support (BAP-2021) provided in the completion of this work. In addition, we extend our thanks to Prof. Dr. Cavit Uyanik (Chemistry Department, Kocaeli University), for his suggestions.

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