Development of an Advanced Synthetic Route to Macrosphelides and Its Application to the Discovery of a More Potent Macrosphelide Derivative

Heo, Yu Mi; Lee, Hunseok; Shin, Young Kee; Paek, Seung‐Mann

doi:10.3390/molecules191015572

Cited by 2 publications

(3 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Macrosphelide A has been shown to be capable of inhibiting the mycelial growth of Sclerotinia sclerotiorum and Sclerotium sepivorum at low concentrations (46.6 and 2.9 µg/mL, respectively) [53,55]. 3-Phenyl-macrosphelide A with higher cytotoxic properties has been obtained [56]. The apoptosis-inducing ability of hybrid compounds composed of macrosphelides and a thiazole-containing side chain of epothilones has been investigated.…”

Section: Discussionmentioning

confidence: 99%

The Potential of Arctic Pseudogymnoascus Fungi in the Biosynthesis of Natural Products

et al. 2023

View full text Add to dashboard Cite

Scarce research into the secondary metabolites of the fungi Pseudogymnoascus spp. has shown a hidden biosynthetic potential for biologically active compounds. This work investigated the biosynthesis of secondary metabolites by two Pseudogymnoascus fungal strains, VKM F-4518 and VKM F-4519, isolated from the surface soil layer of the Kolyma Lowland, Russia, in the Arctic. In these strains, 16-membered trilactone macrolides, (+)-macrosphelides A and B, were identified using 1D and 2D NMR, UHRMS, and optical rotation data. In the fungi of this genus, these metabolites were found for the first time. The studied strains are highly active producers of macrosphelide A, which is being considered as a promising agent for the cure of cancer. Using the antiSMASH secondary metabolite analysis tool, we found that the genome of strain VKM F-4518 contained 32 of the biosynthetic clusters of the secondary metabolite genes (BGC) and that of VKM F-4519 had 17 BGCs. Based on the comparison of the cluster of macrotriolide genes from the fungus Paraphaeosphaeria sporulosa, we found the complete supposed cluster BGCs of macrosphelides in the genomes of two Pseudogymnoascus strains using the BLAST+ program.

show abstract

Section: Discussionmentioning

confidence: 99%

The Potential of Arctic Pseudogymnoascus Fungi in the Biosynthesis of Natural Products

et al. 2023

View full text Add to dashboard Cite

show abstract

“…This late manifestation of cell death could be due to the high molecular size and low lipophilicity of MSPA. Further studies on the modification of the molecules could help improve the cell permeability and molecular effects of MSPA [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

“…Macrosphelide A (MSPA), a derivative of a natural product [ 9 ], belongs to a group of macrolactone polyketides that have been the source of several drug leads due to their unique biological activities and structural features. Previously, we reported a method for use in the concise syntheses of MSPA and the discovery of a more cytotoxic MSPA derivative [ 10 , 11 , 12 ]. MSPA shows anti-cancer properties in a variety of cell lines, and the compound inhibits the major features of carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Macrosphelide A Exhibits a Specific Anti-Cancer Effect by Simultaneously Inactivating ENO1, ALDOA, and FH

et al. 2021

Self Cite

View full text Add to dashboard Cite

Aerobic glycolysis in cancer cells, also known as the Warburg effect, is an indispensable hallmark of cancer. This metabolic adaptation of cancer cells makes them remarkably different from normal cells; thus, inhibiting aerobic glycolysis is an attractive strategy to specifically target tumor cells while sparing normal cells. Macrosphelide A (MSPA), an organic small molecule, is a potential lead compound for the design of anti-cancer drugs. However, its role in modulating cancer metabolism remains poorly understood. MSPA target proteins were screened using mass spectrometry proteomics combined with affinity chromatography. Direct and specific interactions of MSPA with its candidate target proteins were confirmed by in vitro binding assays, competition assays, and simulation modeling. The siRNA-based knockdown of MSPA target proteins indirectly confirmed the cytotoxic effect of MSPA in HepG2 and MCF-7 cancer cells. In addition, we showed that MSPA treatment in the HEPG2 cell line significantly reduced glucose consumption and lactate release. MSPA also inhibited cancer cell proliferation and induced apoptosis by inhibiting critical enzymes involved in the Warburg effect: aldolase A (ALDOA), enolase 1 (ENO1), and fumarate hydratase (FH). Among these enzymes, the purified ENO1 inhibitory potency of MSPA was further confirmed to demonstrate the direct inhibition of enzyme activity to exclude indirect/secondary factors. In summary, MSPA exhibits anti-cancer effects by simultaneously targeting ENO1, ALDOA, and FH.

show abstract

Development of an Advanced Synthetic Route to Macrosphelides and Its Application to the Discovery of a More Potent Macrosphelide Derivative

Cited by 2 publications

References 38 publications

The Potential of Arctic Pseudogymnoascus Fungi in the Biosynthesis of Natural Products

The Potential of Arctic Pseudogymnoascus Fungi in the Biosynthesis of Natural Products

Macrosphelide A Exhibits a Specific Anti-Cancer Effect by Simultaneously Inactivating ENO1, ALDOA, and FH

Contact Info

Product

Resources

About