Cytotoxic Minor Piericidin Derivatives from the Actinomycete Strain Streptomyces psammoticus SCSIO NS126

Abstract

The mangrove-sediment-derived actinomycete strain Streptomyces psammoticus SCSIO NS126 was found to have productive piericidin metabolites featuring anti-renal cell carcinoma activities. In this study, in order to explore more diverse piericidin derivatives, and therefore to discover superior anti-tumor lead compounds, the NS126 strain was further fermented at a 300-L scale under optimized fermentation conditions. As a result, eight new minor piericidin derivatives (piericidins L-R (1-7) and 11-demethyl-glucopiericidin A (8)) were obtained, along with glucopiericidin B (9). The new structures including absolute configurations were determined by spectroscopic methods coupled with experimental and calculated electronic circular dichroism. We also proposed plausible biosynthetic pathways for these unusual post-modified piericidins. Compounds 1 and 6 showed selective cytotoxic activities against OS-RC-2 cells, and 2-5 exhibited potent cytotoxicity against HL-60 cells, with IC₅₀ values lower than 0.1 μM. The new piericidin glycoside 8 was cytotoxic against ACHN, HL-60 and K562, with IC₅₀ values of 2.3, 1.3 and 5.5 μM, respectively. The ability to arrest the cell cycle and cell apoptosis effects induced by 1 and 6 in OS-RC-2 cells, 2 in HL-60 cells, and 8 in ACHN cells were then further investigated. This study enriched the structural diversity of piericidin derivatives and confirmed that piericidins deserve further investigations as promising anti-tumor agents.

Keywords: absolute configuration; actinomycete; cytotoxicity; piericidins.

Figure 1

Structures of compounds 1–9, PA and GPA.

Figure 2

Key COSY, HMBC and NOESY correlations in 1–4.

Figure 3

(A) Experimental ECD spectra of 1–2, 5–6, 8, and iakyricidin A. (B) Experimental ECD spectra of 7, and the calculated ECD spectra of truncated models 7a/7b. (C) Experimental ECD spectra of 3, and the calculated ECD spectrum of truncated model 3a. (D) Experimental ECD spectra of 4, and the calculated ECD spectra of truncated models 4a/4b.

Figure 4

Δ δ_H values (δ_S−δ_R, in ppm) for 3A and 3B.

Scheme 1

Plausible biogenetic pathways.

Figure 5

(A) 1- and 6-arrested cell cycle progression during the G2/M phase in OS-RC-2 cells; (B) 2-arrested cell cycle progression during the S phase in HL-60 cells; (C) 8-arrested cell cycle progression during the S phase in ACHN cells.

Figure 6

(A) 1- and 6-induced apoptosis in OS-RC-2 cells; the OS-RC-2 cells were treated with 1 or 6 (5 μM) for 24 h. (B) 2-induced apoptosis in HL-60 cells; the HL-60 cells were treated with 2 (0.1 and 0.4 μM) for 72 h.