Abstract
Pim kinases (proviral integration site for Moloney murine leukemia virus kinases) are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Thus, Pim kinases are validated as targets for antitumor therapy. In this context, our combined efforts in natural product-inspired library generation and screening furnished very promising dibenzo[b,d]furan derivatives derived from cercosporamide. Among them, lead compound 44 was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC50 value against CLK1 (cdc2-like kinases 1) and displayed a low micromolar anticancer potency towards the MV4-11 (AML) cell line, expressing high endogenous levels of Pim-1/2 kinases. The design, synthesis, structure–activity relationship, and docking studies are reported herein and supported by enzyme, cellular assays, and Galleria mellonella larvae testing for acute toxicity.
Highlights
Licensee MDPI, Basel, Switzerland.Cercosporamide is a natural product isolated from pathogen fungus Cercosporidium henningsii, commonly found in extensively cultivated plants (Manihot esculenta) for domestic consumption of tapioca in tropical and subtropical regions worldwide [1]
The synthetic strategies to prepare dibenzofurans can be classified into two main catresistance is evident
The second approach refers nanomolar range inhibition of MAPK-interacting kinases (Mnk1/2) by cercosporamide has to the intramolecular O-arylation of 2-arylphenols according to a mechanism of etherifibeen shown to be an efficient alternative to block the activation of the translation initiation cation [40,41]
Summary
Cercosporamide is a natural product isolated from pathogen fungus Cercosporidium henningsii, commonly found in extensively cultivated plants (Manihot esculenta) for domestic consumption of tapioca in tropical and subtropical regions worldwide [1]. This substance can be found in cultures of Phoma fungi isolated from Guinea plant Saurauia scaberrinae [2] and Chinese medicinal plant Arisaema erubescensor [3], or can be produced by fungi of the genus Lachnum and Pseudaegerita [4]. Taking into account the biological activity of the structural models used in the study, the main goal of the project was to obtain novel Pim-1/Pim-2 kinase inhibitors as anticancer agents. Until now, dibenzofurans have not been described in the literature as Pim kinase inhibitors [21,29–
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