Cytotoxic Cyclodepsipeptides and Cyclopentane Derivatives from a Plant-Associated Fungus Fusarium sp.

Abstract

In this work, four new cyclodepsipeptides, fusarihexins C–E (1–3) and enniatin Q (4), four new cyclopentane derivatives, fusarilins A–D (5–8), together with eight known compounds (9–16), were isolated from cultures of the endophytic fungus Fusarium sp. The structures of the isolated compounds were elucidated by analysis of HRMS and NMR spectroscopic data. The absolute configurations were determined using Marfey’s method, a modified Mosher’s method, single-crystal X-ray diffraction analysis, and ECD analysis. The antitumor activities of the isolated compounds in vitro were evaluated. Cyclodepsipeptides displayed cytotoxicities against the Huh-7, MRMT-1, and HepG-2 cell lines. Compounds 4, 9, 10, and 12 with IC50 values of 1.0–9.1 μM exhibited the most potent cytotoxicities against the three cell lines as compared to the positive control-5-fluorouracil. Compounds 1–3 and 11 exhibited moderate cytotoxic activities (IC50 values of 10.7–20.1 μM).

Discovery and Characterization of Pyridoxal 5′-Phosphate-Dependent Cycloleucine Synthases

“…The differences in mass of 16 mu between 4 and 6, and between 5 and 7, suggest that 6 and 7 are the 3hydroxylated products of 4 and 5, respectively (Figure 3C). The stereochemistry of 3 was assigned using microcrystalline electron diffraction (MicroED), which is consistent with the reported absolute stereochemistry 34 of 1 (Figures 3C and S63, Table S10). Based on the stereochemistry at C 3 as seen in the MicroED structure of 3, the FusD-catalyzed hydroxylation of 3−5 proceeds with retention of stereochemistry.…”

“…Fusarilin A ( 1 ) was isolated from the endophytic fungus Fusarium sp. and contains a cycloleucine core with 2-acyloxy, 3-phenyl, and 3-hydroxy substituents .…”

“…To mine for a putative cycloleucine synthase from microbial biosynthetic pathways, we searched for natural products containing a cycloleucine substructure in databases (Reaxys and Dictionary of Natural Products) and in the literature. In addition to altemicidin, four such natural products were found, including fusarilin A (1) 34 (Figure 1B), 1-amino-2-nitrocyclopentanecarboxylic acid, 35 stephadiamine, 36 and tagetitoxin 37 (Figure S1). Fusarilin A (1) was isolated from the endophytic fungus Fusarium sp.…”

“…and contains a cycloleucine core with 2-acyloxy, 3-phenyl, and 3-hydroxy substituents. 34 1 can be classified as an unknown (core enzyme)-known (compound)-natural product as it does not appear to be derived from well-studied families of biosynthetic core enzymes. 38 Based on our proposal in Figure 2B, the 3phenyl-2-hydroxy-cycloleucine core (2) could be derived from the proposed PLP-dependent enzyme-catalyzed net [3+2] annulation between 2-phenylacetaldehyde and an L-homoserine-derived electrophile (Figure 2B).…”

Two New Eudesmane‐Type Sesquiterpene from Clonostachys sp. Y6‐1and Their Cytotoxic Activity

“…[1] The majority of medicines used today are either natural or their derivatives. [2] However, it is difficult to obtain enough natural products from plants to support the subsequent activity research, which has become a bottleneck in drug development. Endophytic exchange DNA fragments with host plants, forming a biological metabolic pathway similar to the host in the longterm evolution process.…”