The synthesis of cyclic tetrapeptoid analogues of the antiprotozoal natural product apicidin

Murray, Peter; Kranz, Michael; Ladlow, Mark; Taylor, Stephen; Berst, Frédéric; Holmes, Andrew B.; Keavey, Kenneth; Jaxa‐Chamiec, Albert; Seale, P. W.; Stead, Paul; Upton, Richard J.; Croft, Simon L.; Clegg, William; Elsegood, Mark R. J.

doi:10.1016/s0960-894x(01)00049-x

Cited by 74 publications

(49 citation statements)

References 25 publications

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“…As most of these promoters would be expected to be constitutively active, histone acetylation might therefore not be a transient state. However, other HDAC drugs have been shown to inhibit kinetoplastid parasite growth (54,55), and it is noteworthy that some of these effects seem to differ between parasites and developmental stages. Whether these inhibitors influence the modification patterns shown here should be investigated.…”

Section: Discussionmentioning

confidence: 99%

Histone Acetylation and Methylation at Sites Initiating Divergent Polycistronic Transcription in Trypanosoma cruzi

Respuela

Ferella

Rada-Iglesias

et al. 2008

Journal of Biological Chemistry

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Trypanosomes are ancient eukaryotic parasites in which the protein-coding genes, organized in large polycistronic clusters on both strands, are transcribed from as yet unidentified promoters. In an effort to reveal transcriptional initiation sites, we examined the Trypanosoma cruzi genome for histone modification patterns shown to be linked to active genes in various organisms. Here, we show that acetylated and methylated histones were found to be enriched at strand switch regions of divergent gene arrays, not at convergent clusters or intra-and intergenic regions within clusters. The modified region showed a bimodular profile with two peaks centered over the 5-regions of the gene pair flanking the strand switch region. This pattern, which demarcates polycistronic transcription units originating from bidirectional initiation sites, is likely to be common in kinetoplastid parasites as well as in other organisms with polycistronic transcription. In contrast, no acetylation was found at promoters of the highly expressed rRNA and spliced leader genes or satellite DNA or at tested retrotransposonal elements. These results reveal, for the first time, the presence of specific epigenetic marks in T. cruzi with potential implications for transcriptional regulation; they indicate that both histone modifications and bidirectional transcription are evolutionarily conserved.

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Section: Discussionmentioning

confidence: 99%

Histone Acetylation and Methylation at Sites Initiating Divergent Polycistronic Transcription in Trypanosoma cruzi

Respuela

Ferella

Rada-Iglesias

et al. 2008

Journal of Biological Chemistry

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“…The apicidin (18,19), interacts with the HDAC catalytic site with their ethyl ketone component, and the trapoxin (20), which irreversible inhibits HDACs interacting to their catalytic site. Depsipeptide (7,21,22) is a natural product also able to inhibit HDACs in nanomolar concentrations.…”

Section: Hdac Inhibitorsmentioning

confidence: 99%

Histone deacetylase inhibitors: A novel target of anticancer therapy (Review)

Kouraklis¹,

Theocharis²

2006

Oncol Rep

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Abstract. Accumulating evidence suggests that the acetylation and deacetylation of histones play significant roles in transcriptional regulation of eukaryotic cells. The balance between acetylation and deacetylation is an important factor in regulating gene expression and is thus linked to the control of cell fate. The histone deacetylase inhibitors (HDIs) including the hydroxamic acids, such as suberoylanilide hydroxamic acid and pyroxamide, the benzamides MS-275 and CI-994 and the butyrate derivative 4-PBA are a new class of anti-neoplastic agents currently being evaluated in clinical trials. Moreover, new synthetic HDIs have been used recently in phase I and II clinical trials. Over the next few years experts believe that as first generation HDIs produce clinical benefits and second generation inhibitors are rationally designed with improved specificity, this class of drugs will emerge as a new way of cancer treatment. The first clinical studies have shown that histone hyperacetylation can be achieved safely in humans and that treatment of cancer with such agents seems to become possible. The use of HDIs, probably in association with classical chemotherapy drugs or in combination with DNA-demethylating agents, could be promising for cancer patients. Further evaluation is needed to establish the clinical activity of combination therapy using HDIs with cytotoxic drugs or differentiation induced agents.

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“…[6][7][8][9][10] A number of approaches to the synthesis of Aoda 1 have been adopted, including the use of chiral pool starting materials, 9,[11][12][13][14] and the use of chiral auxiliary groups. [15][16][17][18] Of most direct relevance to the topic of this paper is the report on the use of radical addition of chiral non-racemic amino acid fragments to enones.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of ω-Oxo Amino Acids and trans-5-Substituted Proline Derivatives Using Cross-Metathesis of Unsaturated Amino Acids

2016

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A range of 7-oxo, 8-oxo and 9-oxo amino acids, analogues of 8-oxo-2-aminodecanoic acid, one of the key components of the cyclic tetrapeptide apicidin, has been prepared by a three-step process involving copper-catalysed allylation of serine-, aspartic acid-and glutamic acid-derived organozinc reagents, followed by cross-metathesis of the resulting terminal alkenes with unsaturated ketones, and hydrogenation. The intermediate 7-oxo-5--catalyzed aza-Michael reaction to give trans-2,5-disubstituted pyrrolidines, 5-substituted proline derivatives. The azaMichael reaction was first observed when the starting enones were allowed to stand in solution in deuterochloroform, but can be efficiently promoted by catalytic amounts of dry HCl.3

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The synthesis of cyclic tetrapeptoid analogues of the antiprotozoal natural product apicidin

Cited by 74 publications

References 25 publications

Histone Acetylation and Methylation at Sites Initiating Divergent Polycistronic Transcription in Trypanosoma cruzi

Histone Acetylation and Methylation at Sites Initiating Divergent Polycistronic Transcription in Trypanosoma cruzi

Histone deacetylase inhibitors: A novel target of anticancer therapy (Review)

Synthesis of ω-Oxo Amino Acids and trans-5-Substituted Proline Derivatives Using Cross-Metathesis of Unsaturated Amino Acids

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