Synthesis of new steroidal quinolines with antitumor properties

doi:10.1016/j.steroids.2019.108465

Steroids

Volume 151, November 2019, 108465

https://doi.org/10.1016/j.steroids.2019.108465 Get rights and content

Highlights

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New steroidal quinolines were synthesized via the Al₂O₃/KF-promoted pfitzinger reactions.
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These new steroidal quinolines showed moderate to good antiproliferative activity against human lung cancer cells.
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Compound 2f exhibited the best potency toward the tested three lung cancer cells with IC₅₀ values <10 μM.
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Compound 2f could be used as a hit compound for developing steroid-based anti-lung cancer agents.

Abstract

The incorporation of the heterocycles into the steroid nucleus has been recognized as a useful strategy to develop new steroidal agents for disease treatment. Representative examples are abiraterone and galeterone, which are presently used in clinic for the treatment of advanced prostate cancers. Herein we have developed the first Al₂O₃/KF-promoted pfitzinger reactions for the synthesis of new steroidal quinolines. These new steroidal quinolines showed moderate to good antiproliferative activity against several human lung cancer cells. Of these compounds, compound 2f exhibited the best potency toward the tested three lung cancer cells with IC₅₀ values <10 μM. Mechanistic studies showed that compound 2f concentration-dependently inhibited colony formation, morphological changes, apoptosis, and migration of A549 cells. To conclude, compound 2f could be used as a hit compound for developing steroid-based anti-lung cancer agents.

Graphical abstract

Introduction

The polycyclic steroids are prevalent scaffolds that have been found in numerous natural products and drug molecules [1], [2]. Steroids have been proved to possess diverse biological activities and also play crucial roles in regulating normal cellular signaling pathways [3], [4], [5]. In view of the biological profiles of steroids, great efforts have been devoted to further modifications based on the steroid nucleus in last decades, generating a large number of structurally new and biological interesting steroidal compounds [6], [7], [8], [9], [10], [11], [12], [13]. Biological profiles of steroids are dependent upon structural features of the core structures and side chains. Particularly, the incorporation of different heterocyclic rings into the steroid nucleus has been recognized as a useful strategy to generate new steroidal derivatives for biological screening [14], [15]. Among these steroidal heterocycles, abiraterone [1], [16], [17] and galeterone [18], [19] (Fig. 1) bearing the pyridine and benzimidazole ring, respectively are currently used in clinic for the treatment of advanced prostate cancers. The quinoline is another privileged bicyclic N-heterocyclic scaffold that is prevalent in natural alkaloids (e.g. quinine) and various drug molecules, such as the first-generation epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib [20], [21]. In view of the anticancer potency of abiraterone and galeterone possessing the N-heterocyclic rings, we proposed that the introduction of the quinoline framework to the steroid core may yield new steroidal quinolines with anticancer potentials. Herein, we first report the Al₂O₃/KF-promoted Pfitzinger reactions of dehydroepiandrosterone (DHEA) with isatins for the synthesis of new steroidal quinolines that exhibit good antiproliferative activity against lung cancer cells (Fig. 1).

Section snippets

Chemistry

The steroidal quinolines 2a–2l were efficiently synthesized in good yields from DHEA and isatin derivatives in EtOH in the presence of Al₂O₃/KF. As shown in Scheme 1, the steroidal quinolines 2a–2l were efficiently synthesized in good yields. Generally, compounds bearing the halogen atom or electron-withdrawing groups (e.g. single bond NO₂) were obtained in higher yields compared to compound 2a, while compounds 2k and 2l possessing the methoxyl and phenyl group, respectively were obtained in 75% and 73%

Conclusions

In conclusion, we have reported the synthesis of new steroidal quinolines from DHEA and isatin derivatives via the Al₂O₃/KF-promoted pfitzinger reactions. These new steroidal quinolines showed moderate to good antiproliferative activity against several human lung cancer cells. Of these compounds, compound 2f exhibited the best potency toward the tested three lung cancer cells with IC₅₀ values <10 μM. Mechanistic studies showed that compound 2f concentration-dependently inhibited colony

General remarks

Commercially available reagents and solvents were used without particular treatment. Thin layer chromatography (TLC) was carried out on glass plates coated with silica gel and visualized by UV light (254 nm). The products were purified by column chromatography over silica gel. Melting points were determined and are uncorrected. All NMR spectra were recorded with a Bruker DPX 400 MHz spectrometer with TMS as an internal standard in solvent DMSO-d₆. Due to the complexity of the steroid nucleus,

Acknowledgement

We are grateful for the Youth Innovation Fund of the First Affiliated Hospital of Zhengzhou University.

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Citation Excerpt :
Using the Pfitzinger reaction to synthesize steroidal quinoline acids 191 was realized by Y.-T. Yang et al. in 2019 with steroidal ketones and oxoindoles. This reaction, involving the cleavage of lactam, 1,2-Michael addition and dehydration, featured good functional tolerance yielding the quinoline acids in high yields (Scheme 48) 83. The synthesis of steroidal fused imidazolopyrimidine derivatives 193 was reported by R. Jorda et al. in 2019 via the condensation of 6-dehydropregnenolone acetate with 2-aminobenzimidazoles.
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Synthesis of new steroidal quinolines with antitumor properties

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Conclusions

General remarks

Acknowledgement

CYP17 inhibitors – abiraterone, C17,20-lyase inhibitors and multi-targeting agents

Nature Rev. Urol.

Sae Melo ML: anticancer steroids: linking natural and semi-synthetic compounds

Natural Product Reports

Structurally novel steroidal spirooxindole by241 potently inhibits tumor growth mainly through ROS-mediated mechanisms

Sci. Rep.

Invasion mechanism in human melanoma cells

Med. Oncol.

Overcoming resistance to TRAIL-induced apoptosis in solid tumor cells by simultaneously targeting death receptors, c-FLIP and IAPs

Int. J. Oncol.

Approaches to total synthesis of heterocyclic steroidal systems

Angewandte Chemie Int. Ed.

Recent advances on the synthesis and antitumor evaluation of exonuclear heterosteroids

Chinese J. Org. Chem.

Efficient synthesis of new antiproliferative steroidal hybrids using the molecular hybridization approach

Eur. J. Med. Chem.

A novel [1,2,4] triazolo [1,5-a] pyrimidine-based phenyl-linked steroid dimer: synthesis and its cytotoxic activity

Eur. J. Med. Chem.

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Facile synthesis of novel D-ring modified steroidal dienamides via rearrangement of 2H-pyrans

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Efficient three-component one-pot synthesis of steroidal polysubstituted anilines

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Steroids