Abstract

Brefeldin A (1), a potent cytotoxic natural macrolactone, was produced by the marine fungus Penicillium sp. (HS-N-29) from the medicinal mangrove Acanthus ilicifolius. Series of its ester derivatives 2–16 were designed and semi-synthesized, and their structures were characterized by spectroscopic methods. Their cytotoxic activities were evaluated against human chronic myelogenous leukemia K562 cell line in vitro, and the preliminary structure–activity relationships revealed that the hydroxy group played an important role. Moreover, the monoester derivatives exhibited stronger cytotoxic activity than the diester derivatives. Among them, brefeldin A 7-O-2-chloro-4,5-difluorobenzoate (7) exhibited the strongest inhibitory effect on the proliferation of K562 cells with an IC50 value of 0.84 µM. Further evaluations indicated that 7 induced cell cycle arrest, stimulated cell apoptosis, inhibited phosphorylation of BCR-ABL, and thereby inactivated its downstream AKT signaling pathway. The expression of downstream signaling molecules in the AKT pathway, including mTOR and p70S6K, was also attenuated after 7-treatment in a dose-dependent manner. Furthermore, molecular modeling of 7 docked into 1 binding site of an ARF1–GDP-GEF complex represented well-tolerance. Taken together, 7 had the potential to be served as an effective antileukemia agent or lead compound for further exploration.

Highlights

  • Chronic myelogenous leukemia (CML) is characterized by the translocation of chromosomes 9 and 22, which generates the BCR-ABL fusion oncogene with constitutively active tyrosine kinase [1]

  • The structure–activity relationships (SARs) studies revealed that the monoester derivatives exhibited stronger cytotoxic activity than those of diester derivatives

  • The results exhibited that compound 7 showed great potential cytotoxic activity on K562 cells compared to other tested compounds, while the effect was slightly weaker than 1

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Summary

Introduction

Chronic myelogenous leukemia (CML) is characterized by the translocation of chromosomes 9 and 22, which generates the BCR-ABL fusion oncogene with constitutively active tyrosine kinase [1]. This aberrant tyrosine kinase exerts its oncogenic function for malignant transformation mainly by activating multiple cellular signaling pathways, including the PI3K/AKT, MAPK/ERK, and JAK-STAT, which contributes to the insensitivity of chemotherapy drugs [2,3]. The second-generation TKIs, such as nilotinib, dasatinib, and bosutinib, were employed to overcome acquired resistance to imatinib [5,6,7]. Novel agents to improve therapeutic outcomes of CML are needed urgently

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