Synthesis of new steroidal quinolines with antitumor properties
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. 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.
References (27)
- et al.
CYP17 inhibitors – abiraterone, C17,20-lyase inhibitors and multi-targeting agents
Nature Rev. Urol.
(2014) - et al.
Sae Melo ML: anticancer steroids: linking natural and semi-synthetic compounds
Natural Product Reports
(2013) - et al.
Structurally novel steroidal spirooxindole by241 potently inhibits tumor growth mainly through ROS-mediated mechanisms
Sci. Rep.
(2016) - et al.
Invasion mechanism in human melanoma cells
Med. Oncol.
(2018) - et al.
Overcoming resistance to TRAIL-induced apoptosis in solid tumor cells by simultaneously targeting death receptors, c-FLIP and IAPs
Int. J. Oncol.
(2016) Approaches to total synthesis of heterocyclic steroidal systems
Angewandte Chemie Int. Ed.
(1971)- et al.
Recent advances on the synthesis and antitumor evaluation of exonuclear heterosteroids
Chinese J. Org. Chem.
(2017) - et al.
Efficient synthesis of new antiproliferative steroidal hybrids using the molecular hybridization approach
Eur. J. Med. Chem.
(2016) - et al.
A novel [1,2,4] triazolo [1,5-a] pyrimidine-based phenyl-linked steroid dimer: synthesis and its cytotoxic activity
Eur. J. Med. Chem.
(2013) - et al.
Stereoselective synthesis of novel antiproliferative steroidal (E, E) dienamides through a cascade aldol/cyclization process
Steroids
(2013)
Facile synthesis of novel D-ring modified steroidal dienamides via rearrangement of 2H-pyrans
Steroids
Efficient three-component one-pot synthesis of steroidal polysubstituted anilines
Steroids
Multicomponent assembly of novel antiproliferative steroidal dihydropyridinyl spirooxindoles
Steroids
Cited by (16)
Dihydrotestosterone-based A-ring-fused pyridines: Microwave-assisted synthesis and biological evaluation in prostate cancer cells compared to structurally related quinolines
2023, Journal of Steroid Biochemistry and Molecular BiologyOxazolinyl derivatives of androst-16-ene as inhibitors of CYP17A1 activity and prostate carcinoma cells proliferation: Effects of substituents in oxazolinyl moiety
2023, Journal of Steroid Biochemistry and Molecular BiologySecosteroid–quinoline hybrids as new anticancer agents
2023, Journal of Steroid Biochemistry and Molecular BiologyRecent advances on synthesis and biological activities of C-17 aza-heterocycle derived steroids
2022, Bioorganic and Medicinal ChemistryCitation 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.