Tryptophan-replacement and indole-modified apicidins: synthesis of potent and selective antiprotozoal agents

Colletti, Steven L.; Li, Chunshi; Fisher, Michael H.; Wyvratt, Matthew J.; Meinke, Peter T.

doi:10.1016/s0040-4039(00)01363-0

Cited by 35 publications

(30 citation statements)

References 22 publications

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“…The indole nucleus or suitable replacements in that position have previously been shown to be an important part of potent HDAC inhibitors in the apicidin series. 22 To see whether the combination of the two most successful structural modifications among the amide and the methyl ester series with regard to rat liver HDAC inhibition does lead to a further increase in inhibitory potency, we have synthesized the phenethylamide of 1-naphthylalanine and have converted it to the requisite suberoylamide hydroxamate 11r. However, it does not reach the activity of either the parent phenethylamide 11d or the naphthylalanine 11n in the inhibition of the rat enzyme preparation whereas it is indeed the best inhibitor of maize HD-2 (35 nM).…”

Section: Resultsmentioning

confidence: 99%

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Structure−Activity Relationships on Phenylalanine-Containing Inhibitors of Histone Deacetylase: In Vitro Enzyme Inhibition, Induction of Differentiation, and Inhibition of Proliferation in Friend Leukemic Cells

et al. 2002

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Inhibitors of histone deacetylases (HDACs) are a new class of anticancer agents that affect gene regulation. We had previously reported the first simple synthetic HDAC inhibitors with in vitro activity at submicromolar concentrations. Here, we present structure-activity data on modifications of a phenylalanine-containing lead compound including amino acid amides as well as variations of the amino acid part. The compounds were tested for inhibition of maize HD-2, rat liver HDAC, and for the induction of terminal cell differentiation and inhibition of proliferation in Friend leukemic cells. In the amide series, in vitro inhibition was potentiated up to 15-fold, but the potential to induce cell differentiation decreased. Interestingly, an HDAC class selectivity was indicated among some of these amides. In the amino acid methyl ester series, a biphenylalanine derivative was identified as a good enzyme inhibitor, which blocks proliferation in the submicromolar range and is also a potent inducer of terminal cell differentiation.

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Section: Resultsmentioning

confidence: 99%

“…Extensive structure-activity data have been reported on analogues of the tetrapeptide apicidin that also displays antiprotozoal activity. [22][23][24][25][26][27] New reports that aim toward subtype selective HDAC inhibitors have been presented as well. 28,29 So far, there is only limited structural information on HDACs available.…”

Section: Introductionmentioning

confidence: 99%

Structure−Activity Relationships on Phenylalanine-Containing Inhibitors of Histone Deacetylase: In Vitro Enzyme Inhibition, Induction of Differentiation, and Inhibition of Proliferation in Friend Leukemic Cells

et al. 2002

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“…Reducing chlamydocin's C8-ketone to the corresponding alcohol or replacing its 9(S),10-oxiranyl moiety with -CH 2 CH 2 OH, -CH=CH 2 or -CH 2 CH 3 yielded biologically uninteresting molecules [67]. Similar losses in potency resulted from analogous manipulations of HC-toxin [75,81,109,110] and trapoxin [68]. Inverting the stereochemistry of chlamydocin's epoxide also attenuated potency.…”

Section: Structure-activity Relationship In the Cyclopeptide Seriesmentioning

confidence: 97%

“…This lack of parasite selectivity therefore precluded apicidin's develop-ment as an antiprotozoal agent and consequently its chemical modification to identify parasite-selective and hence potentially non-toxic apicidin-derived HDAC inhibitors was required. Two recent reports from Merck have described transformations of apicidin's tryptophan moiety which successfully conferred parasite-selectivity [109,127].…”

Section: Structure-activity Relationship In the Cyclopeptide Seriesmentioning

confidence: 99%

Histone Deacetylase: A Target for Antiproliferative and Antiprotozoal Agents

Meinke¹,

Liberator²

2001

CMC

108

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Histone deacetylase (HDAC) and histone acetyltransferase (HAT) are enzymes that influence transcription by selectively deacetylating or acetylating the eta-amino groups of lysines located near the amino termini of core histone proteins. It is well-established that in transcriptionally active chromatin, histones generally are hyperacetylated and, conversely, hypoacetylated histones are coincident with silenced chromatin. Revived interest in these enzymatic pathways and how they modulate eukaryotic transcription has led to the identification of multiple cofactors whose complex interplay with HDAC affects gene expression. Concurrent with these discoveries, screening of natural product sources yielded new small molecules that were subsequently identified as potent inhibitors of HDAC. While predominantly identified using antiproliferative assays, the biological activity of these new HDAC inhibitors also encompasses significant antiprotozoal, antifungal, phytotoxic and antiviral applications. These newly discovered HDAC inhibitors served as lead structures for the development of improved derivatives including related reagents with considerable potential as tools to further elucidate the mechanism of transcriptional regulation.

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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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Tryptophan-replacement and indole-modified apicidins: synthesis of potent and selective antiprotozoal agents

Cited by 35 publications

References 22 publications

Structure−Activity Relationships on Phenylalanine-Containing Inhibitors of Histone Deacetylase: In Vitro Enzyme Inhibition, Induction of Differentiation, and Inhibition of Proliferation in Friend Leukemic Cells

Structure−Activity Relationships on Phenylalanine-Containing Inhibitors of Histone Deacetylase: In Vitro Enzyme Inhibition, Induction of Differentiation, and Inhibition of Proliferation in Friend Leukemic Cells

Histone Deacetylase: A Target for Antiproliferative and Antiprotozoal Agents

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

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