Broad spectrum antiprotozoal agents that inhibit histone deacetylase: structure–activity relationships of apicidin. Part 2

Colletti, Steven L.; Myers, Robert W.; Darkin-Rattray, Sandra J.; Gurnett, Anne; Dulski, Paula M.; Galuska, Stefan; Allocco, John; Ayer, Michelle B.; Li, Chunshi; Lim, Julie; Crumley, Tami; Cannova, Christine; Schmatz, Dennis M.; Wyvratt, Matthew J.; Fisher, Michael H.; Meinke, Peter T.

doi:10.1016/s0960-894x(00)00605-3

Cited by 65 publications

(40 citation statements)

References 5 publications

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“…HDAC enzymes in malarial parasites may be a promising new target for antimalarial drug development (6). HDAC inhibitors that can arrest growth and induce differentiation and/or apoptotic cell death in various human cancer cell lines also show antimalarial activity in vitro (1,(4)(5)(6)24). These include compounds that are antiproliferative in vitro against P. falciparum at low micromolar-to-nanomolar concentrations but that are rapidly metabolized in vivo (e.g., TSA, apicidin, and trapoxin) (6) and others that are more bioavailable but 10-to 1,000-fold less potent (e.g., azelaic bishydroxamic acid, SAHA, and SBHA) (1).…”

Section: Discussionmentioning

confidence: 99%

“…One of these compounds, SAHA, which has modest potency against P. falciparum (IC 50 of 0.9 to 1.8 M) (24) was recently approved by the FDA for the treatment of T-cell lymphomas (14). However, all these inhibitors have relatively poor selectivity for P. falciparum versus normal mammalian cells (1,(4)(5)(6)24) (Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…Other less potent, but more bioavailable, inhibitors of hHDACs also have antimalarial activity against P. falciparum at low micromolar concentrations (e.g., azelaic bishydroxamic acid [50% inhibitory concentration {IC 50 }, 3.2 to 4.9 M]) and suberohydroxamic acid [SBHA] [IC 50 , 0.8 to 1.3 M]) (1), with SBHA being apparently cytostatic against the acute rodent malaria organism Plasmodium berghei in mice (1). Although all of these compounds nonselectively inhibit the growth of malarial parasites, cancer cells, and mammalian cells in vitro (12,21), their antiparasitic activities support the idea that PfHDACs may be valuable new antimalarial targets (4,5).…”

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confidence: 96%

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Potent Antimalarial Activity of Histone Deacetylase Inhibitor Analogues

Andrews

Tran

Lucke

et al. 2008

Antimicrob Agents Chemother

111

121

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The malaria parasite Plasmodium falciparum has at least five putative histone deacetylase (HDAC) enzymes, which have been proposed as new antimalarial drug targets and may play roles in regulating gene transcription, like the better-known and more intensively studied human HDACs (hHDACs). Fourteen new compounds derived from L-cysteine or 2-aminosuberic acid were designed to inhibit P. falciparum HDAC-1 (PfHDAC-1) based on homology modeling with human class I and class II HDAC enzymes. The compounds displayed highly potent antiproliferative activity against drug-resistant (Dd2) or drug sensitive (3D7) strains of P. falciparum in vitro (50% inhibitory concentration of 13 to 334 nM). Unlike known hHDAC inhibitors, some of these new compounds were significantly more toxic to P. falciparum parasites than to mammalian cells. The compounds inhibited P. falciparum growth in erythrocytes at both the early and late stages of the parasite's life cycle and caused altered histone acetylation patterns (hyperacetylation), which is a marker of HDAC inhibition in mammalian cells. These results support PfHDAC enzymes as being promising targets for new antimalarial drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 96%

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Potent Antimalarial Activity of Histone Deacetylase Inhibitor Analogues

Andrews

Tran

Lucke

et al. 2008

Antimicrob Agents Chemother

111

121

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“…From these findings, a number of HDACi from different laboratories were screened for evualuating their antiproliferative effects against P. falciparum, in some cases in comparison of their activity on mammalian cells ( Table 1) (Fig. (4)) [72][73][74][75][76][77][78][79].…”

Section: C) Antimalarial Activity Of Hdac Inhibitorsmentioning

confidence: 99%

“…Research Laboratories, and a structure-activity-relationship (SAR) has been generated by modifying either apicidin's side chain (8-oxo-2-aminodecanoic acid, Aoda) or its tryptophan moiety [72][73][74]. In particular, the replacement of tryptophan with quinolone/quinoline nuclei led to apicidin analogues (25)(26)(27)(28)(29)(30) showing 50-to >267-fold parasite selectivity.…”

Section: Many Apicidin Analogues Have Been Prepared By Merckmentioning

confidence: 99%

Non-Cancer Uses of Histone Deacetylase Inhibitors: Effects on Infectious Diseases and β-Hemoglobinopathies+

Rotili

Simonetti

Savarino

et al. 2009

CTMC

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After the approval of suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza) for the treatment of cutaneous T cell lymphoma (CTCL), a number of HDAC inhibitors (HDACi) are currently in Phase II or III clinical trials (alone or in combination) for the treatment of a great number of tumors. In addition to these cancer uses, HDACi can be successfully used in non-cancer diseases. In this review we focused on the uses of HDACi in some infectious diseases and beta-hemoglobinopaties. In C. albicans cultures, HDACi increased the frequency of cell switching (a relevant virulence trait) in the white-to-opaque transition, reduced the azole trailing effect through reduction in azole-dependent upregulation of CDR and ERG genes, and inhibited the fluconazole-dependent resistance induction. Moreover, they inhibited germination in several strains, and caused 90% reduction in the adherence of C. albicans to human cultured pneumocytes. In HIV-1-infected cells, the treatment with HDACi reactivates the HIV-1 expression in latent cellular reservoirs. Thus, the use of HDACi as adjuvant to highly active antiretroviral therapy (HAART) can represent a new potential therapeutic strategy to eradicate the viral infection. A number of HDACi have been reported as active against P. falciparum infection. Two recent papers show some 2-aminosuberic acid-based compounds as well as a series of phenylthiazolyl suberoyl hydroxamates as very potent and selective antimalarial agents. Among the many agents capable to perform post-natal reactivation of fetal hemoglobin production, HDACi for their capacity to de-repress gamma-globin gene expression in adult red cell, are presently considered promising molecules for personalized therapy of beta-hemoglobinopathies.

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Antimalarials

Smithson¹,

Guiguemde²,

Guy³

2010

Burger's Medicinal Chemistry and Drug Discovery

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While the treatment of malaria has until recently relied upon a small number of therapeutic agents with a few mechanisms of action, the past decade has seen a huge growth in the number of targets being addressed and new agents being pushed to the clinic. This chapter briefly reviews existing agents and close homologs in development and then carefully explores new targets and new chemotypes being developed.

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Broad spectrum antiprotozoal agents that inhibit histone deacetylase: structure–activity relationships of apicidin. Part 2

Cited by 65 publications

References 5 publications

Potent Antimalarial Activity of Histone Deacetylase Inhibitor Analogues

Potent Antimalarial Activity of Histone Deacetylase Inhibitor Analogues

Non-Cancer Uses of Histone Deacetylase Inhibitors: Effects on Infectious Diseases and β-Hemoglobinopathies+

Antimalarials

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Broad spectrum antiprotozoal agents that inhibit histone deacetylase: structure–activity relationships of apicidin. Part 2

Cited by 65 publications

References 5 publications

Potent Antimalarial Activity of Histone Deacetylase Inhibitor Analogues

Potent Antimalarial Activity of Histone Deacetylase Inhibitor Analogues

Non-Cancer Uses of Histone Deacetylase Inhibitors: Effects on Infectious Diseases and &#946;-Hemoglobinopathies+

Antimalarials

Contact Info

Product

Resources

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Non-Cancer Uses of Histone Deacetylase Inhibitors: Effects on Infectious Diseases and β-Hemoglobinopathies+