Abstract
DNA methyltransferases (DNMTs) play a relevant role in epigenetic control of cancer cell survival and proliferation. Since only two DNMT inhibitors (azacitidine and decitabine) have been approved to date for the treatment of hematological malignancies, the development of novel potent and specific inhibitors is urgent. Here we describe the design, synthesis, and biological evaluation of a new series of compounds acting at the same time as DNMTs (mainly DNMT3A) inhibitors and degraders. Tested against leukemic and solid cancer cell lines, 2a–c and 4a–c (the last only for leukemias) displayed up to submicromolar antiproliferative activities. In HCT116 cells, such compounds induced EGFP gene expression in a promoter demethylation assay, confirming their demethylating activity in cells. In the same cell line, 2b and 4c chosen as representative samples induced DNMT1 and -3A protein degradation, suggesting for these compounds a double mechanism of DNMT3A inhibition and DNMT protein degradation.
Highlights
DNA methylation is one of the most extensively studied epigenetic marks, playing an important role in genomic imprinting; DNA repair; X-chromosome inactivation; and silencing of retrotransposons, repetitive elements, and tissue-specific genes
By microwave irradiation yielded the nitrophenyl derivatives 11 and 12, respectively, which were in turn reduced with stannous chloride dihydrate and 37% hydrochloric acid (HCl) in ethanol to the corresponding anilines
The results indicated that 2b inhibited at values ranging from 70% to 98% the biochemical activity of IKK-α (70%), IRK (86%), PKC-β (79%), RAF-1 (79%), Src (94%), TRKA (98%) kinases, all of them found involved in leukemia initiation and development [37,38,39,40,41,42]
Summary
DNA methylation is one of the most extensively studied epigenetic marks, playing an important role in genomic imprinting; DNA repair; X-chromosome inactivation; and silencing of retrotransposons, repetitive elements, and tissue-specific genes. Both the hypo- and hypermethylation of different genome regions play a crucial role in tumorigenesis [1]. For this reason, focal hypermethylation has been intensively studied in cancer, as a causative factor of transcriptional inactivation of tumor suppressor genes (TSG) [2]. DNA methylation occurs mainly in the context of CpG dinucleotides clustered in CpG islands [4,5,6] and is governed by catalytically active DNA methyltransferase (DNMT) enzymes, which methylate the 5-position of cytosine by using S-adenosyl-l-methionine (SAM) as the cosubstrate.
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