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. 2020 Feb 28;21(5):1665.
doi: 10.3390/ijms21051665.

Design, Synthesis, and Biological Evaluation of Two Series of Novel A-Ring Fused Steroidal Pyrazines as Potential Anticancer Agents

Shijun Wang  1 , Xiaorong Yuan  1 , Hao Qian  1 , Na Li  2 , Junru Wang  1
Affiliations

Design, Synthesis, and Biological Evaluation of Two Series of Novel A-Ring Fused Steroidal Pyrazines as Potential Anticancer Agents

Shijun Wang et al. Int J Mol Sci. .

Abstract

Background: Increasingly, different heterocyclic systems have been introduced into the steroid nucleus to significantly enhance the antitumor activities of steroid molecules. However, in this study, few literature precedents describing the pyrazine heterocyclic-condensed modification to an A-ring of steroid monomers were found, although the pyrazine group is thought to be essential for the potent anticancer activity of clinically relevant drugs and natural steroid dimers.

Methods and results: Two series of novel A-ring fused steroidal pyrazines were designed and efficiently synthesized from commercially available progesterone via key α-ketoenol intermediates. Through a cell counting kit-8 cytotoxic assay of 36 derivatives for three tumor cells, 14 compounds displayed significant antiproliferative activity compared to 5-fluorouracil, especially for human prostatic tumor cells (PC-3) in vitro. Further mechanistic studies indicated that the most active compound, 12n (IC50, 0.93 μM; SI, 28.71), could induce the cell apoptosis of PC-3 cells in a dose-dependent manner and cause cell cycle arrest in the G2/M phase. The molecular docking study suggested that compound 12n fitted the active sites of cytochrome P450 17A1 (6CIZ) well.

Conclusions: 12n might serve as a promising lead compound for the development of novel anticancer drugs. This facile ring-closing strategy may provide a novel and promising avenue for the cycloaddition reaction of the steroidal skeleton through α-ketoenol intermediates.

Keywords: anticancer activity; docking; fused steroids; mechanism; pyrazines; synthesis.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Current potential anticancer steroid stuctures with the IC50/GI50 values below 1.0 μM.
Figure 2
Figure 2
The structures of anticancer agents containing a pyrazine moiety.
Scheme 1
Scheme 1
Synthesis of A-ring fused steroidal benzopyrazines.
Scheme 2
Scheme 2
Synthesis of steroidal A-ring fused pyrazinamides. Reagents and conditions: i. (a) amine, EtOH, ρ-TSA, reflux, 85–90%; (b) 1M HCl, 95–99%; ii. NaBH4, dry MeOH/THF (v/v, 2:1), 0 °C, 85–90%.
Figure 3
Figure 3
Morphological changes of PC-3 cells through Giemsa staining. (a) DMSO used as the negative control; (b,c) dealt with compound 12n for 48 h at the concentration of 1.0 and 4.0 μM, respectively.
Figure 4
Figure 4
Compound 12n induced apoptosis in PC-3 cells after 48 h through treatment with 12n at different concentrations (0.2, 1.0, and 5.0 μM).
Figure 5
Figure 5
Effects of compound 12n on the cell cycle distribution of PC-3 cells after treatment for 48 h.
Figure 6
Figure 6
Interaction of the compound 12n with the CYP17A1 (6CIZ) receptor: (a) docking of compound 12n (green) with 6CIZ and Abiraterone (purple) was used as the reference; (b) interaction of compound 12n with 6CIZ.
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