An improved synthesis of psammaplin A

Godert, Amy M.; Angelino, N.; Woloszynska‐Read, Anna; Morey, Shannon R.; James, Smitha R.; Karpf, Adam R.; Sufrin, Janice R.

doi:10.1016/j.bmcl.2006.03.008

Cited by 41 publications

(30 citation statements)

References 21 publications

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“…Although psammaplin A administration at low doses was found to exert a strong cytotoxic effect in human tumor cell lines and to limit tumor cell growth in a A549 lung xenograft mouse model, DNMT inhibition was not followed by DNA demethylation and reexpression of tumor suppressor genes, suggesting that an intracellular target different from DNMT1 is responsible for the cytotoxic effect of the molecule. 83,84 Another natural molecule found to exhibit DNMT inhibitory activities is EGCG (Epigallocatechin-3-Gallate), a polyphenolic component of green tea. EGCG is methylated by the enzyme catechol-O-methyltransferase (COMT), which catalyzes O-methylation of various catecholic compounds.…”

Section: Nonnucleoside Dnmt Inhibitorsmentioning

confidence: 99%

DNA Demethylating Antineoplastic Strategies: A Comparative Point of View

et al. 2010

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IntroductionEpigenetics is the study of somatically heritable and reversible modifications of genome functions (gene expression and genomic stability) not involving changes in DNA sequence. DNA methylation, together with histone posttranslational modifications (PTMs), represents the most characterized epigenetic modification and is known to participate in the regulation of gene expression by modifying the chromatin structure and, consequently, the accessibility of transcription factors to regulatory regions of genes. Aberrant epigenetic patterns are involved at early stages of cancer initiation and, altering both global gene expression and genomic stability, strongly contribute to cancer progression. 1 DNA methylation involves the covalent addition of a methyl group (-CH3) to the C-5 position of cytosine, mostly in the context of the CpG dinucleotide. This chemical reaction is catalyzed by enzymes belonging to the DNA methyltransferase family (DNMTs). DNMT1 is predominantly responsible for maintaining the preexistent methylation pattern during DNA replication, whereas DNMT3a and DNMT3b are required for de novo DNA methylation. 2,3 CpG dinucleotides are clustered in regions, named CpGislands, present in almost 60% of all gene promoters. 4 DNMT activity regulates global gene expression by hypermethylation of promoter CpG-islands and, as recently shown, of regulatory sequences near the promoter (CpG island shores), thus causing gene silencing. Not surprisingly, the DNA methylation pattern is altered in cancer. Paradoxically, tumor cells exhibit global genome hypomethylation and increased levels of DNMT1 expression at the same time. Moreover, both DNA hypo-and hypermethylation occur at specific gene loci, leading to the overexpression of proto-oncogenes and the silencing of tumor suppressor genes, respectively. These phenomena are thought to be promoting factors of cellular transformation. 5,6 Evidence regarding the involvement of DNA methylation in tumorigenesis gave rise to the development of new therapeutic strategies that target this modification. In the past few years, many drugs have been proposed. Some have already been approved for clinical use, and many others are still under evaluation. In this review, we focus on antineoplastic strategies affecting DNA methylation, with particular attention to their mechanism of action and the molecular pathways involved. In addition, we compare novel approaches, such as the use of nonnucleoside inhibitors and DNMT silencing with azanucleoside administration, the only demethylating strategy approved for clinical therapy. Despite the involvement of genetic alterations in neoplastic cell transformation, it is increasingly evident that abnormal epigenetic patterns, such as those affecting DNA methylation and histone posttranslational modifications (PTMs), play an essential role in the early stages of tumor development. This finding, together with the evidence that epigenetic changes are reversible, enabled the development of new antineoplastic therapeutic approaches known as...

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Section: Nonnucleoside Dnmt Inhibitorsmentioning

confidence: 99%

DNA Demethylating Antineoplastic Strategies: A Comparative Point of View

et al. 2010

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“…Compound 4a was synthesized in two steps from the commercially available 4hydroxyphenylpyruvic acid [28]. Following a procedure reported in the literature [29], compound 4a was brominated with KBr and KBrO3 to give hydroxyiminopropionic acid 4b.…”

Section: Chemistrymentioning

confidence: 99%

Camptothecin-psammaplin A hybrids as topoisomerase I and HDAC dual-action inhibitors

Cincinelli

Musso

Artali³

et al. 2018

European Journal of Medicinal Chemistry

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Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of camptothecin derivatives and HDAC inhibitors. To exploit this synergy in a single active compound, we designed new dual-acting multivalent molecules simultaneously targeting topoisomerase I and HDAC. In particular, a selected compound containing a camptothecin and the psammaplin A scaffold showed a broad spectrum of antiproliferative activity, with IC values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted in CD-1 nude mice and very high tolerability.

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“…Because of these interesting activities, a number of synthetic studies on these alkaloids have been reported. [6][7][8][9][10][11][12][13][14][15][16] Moloka'iakitamide (1) 17) has been isolated from the Red Sea sponge Pseudoceratina arabica (Pseudoceratinidae) and shows significant parasympatholytic effects on isolated rabbit heart and jejunum, and weakly antifungal activity, contains one bromotyrosine unit and oxalamide moiety (Fig. 1).…”

Section: Notesmentioning

confidence: 99%