Cytotoxic Secondary Metabolites Isolated from the Marine Alga-Associated Fungus Penicillium chrysogenum LD-201810

Abstract

A new pentaketide derivative, penilactonol A (1), and two new hydroxyphenylacetic acid derivatives, (2'R)-stachyline B (2) and (2'R)-westerdijkin A (3), together with five known metabolites, bisabolane-type sesquiterpenoids 4-6 and meroterpenoids 7 and 8, were isolated from the solid culture of a marine alga-associated fungus Penicillium chrysogenum LD-201810. Their structures were elucidated based on extensive spectroscopic analyses, including 1D/2D NMR and high resolution electrospray ionization mass spectra (HRESIMS). The absolute configurations of the stereogenic carbons in 1 were determined by the (Mo₂(OAc)₄)-induced circular dichroism (CD) and comparison of the calculated and experimental electronic circular dichroism (ECD) spectra, while the absolute configuration of the stereogenic carbon in 2 was established using single-crystal X-ray diffraction analysis. Compounds 2 and 3 adapt the 2'R-configuration as compared to known hydroxyphenylacetic acid-derived and O-prenylated natural products. The cytotoxicity of 1-8 against human carcinoma cell lines (A549, BT-549, HeLa, HepG2, MCF-7, and THP-1) was evaluated. Compound 3 exhibited cytotoxicity to the HepG2 cell line with an IC₅₀ value of 22.0 μM. Furthermore, 5 showed considerable activities against A549 and THP-1 cell lines with IC₅₀ values of 21.2 and 18.2 μM, respectively.

Keywords: Penicillium chrysogenum; alga; cytotoxicity; hydroxyphenylacetic acid; marine-derived fungus; polyketide.

Figure 1

Chemical structures of 1–8.

Figure 2

(A) COSY and key HMBC correlations in 1; (B) induced circular dichroism (ICD) spectra from the Mo₂-complex and inherent CD of 1.

Figure 3

Experimental electronic circular dichroism (ECD) spectrum of 1 (blue solid); calculated ECD spectrum of (2R, 3S)-1 (UV correction = −19 nm, red dash) at the CAM-B3LYP-SCRF/def2-SVP//B3LYP/6-31G(d) level of theory in MeOH with IEFPCM solvent model (Polarized Continuum Model using the Intergral Equation Formalism).

Figure 4

(A) COSY and key HMBC correlations of 2; (B) ORTEP (Oak Ridge Thermal-Ellipsoid Plot Program) diagram for the single-crystal X-ray structure of 2.

Figure 5

Apoptosis-related morphological changes were detected by staining cells with 4’,6-diamidino-2-phenylindole (DAPI). Apoptotic cells were defined as those with blue-stained cells that exhibited a fragmented/condensed nucleus and apoptotic body (red arrow).