Broad spectrum antiprotozoal agents that inhibit histone deacetylase: structure–activity relationships of apicidin. Part 1

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)00604-1

Cited by 69 publications

(46 citation statements)

References 22 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%

See 1 more Smart Citation

Potent Antimalarial Activity of Histone Deacetylase Inhibitor Analogues

Andrews

Tran

Lucke

et al. 2008

Antimicrob Agents Chemother

111

121

View full text Add to dashboard Cite

show abstract

“…and Cryptospridium parvum, causative agents for malaria and cryptosporidiosis, respectively [1][2]. The antiparasitic activity of apicidin appears to be mediated by the low nanomolar inhibition of Apicomplexan histone deacetylase (HDAC), a key eukaryotic transcription factor essential for chromatin remodeling and the functional regulation of gene transcription [1][2][3]. Histone deacetylases (HDACs) and histone acetyl transferases (HATs) are two types of enzymes with opposing activity involved in determining the state of deacetylation and acetylation of histones.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of a novel histone deacetylase inhibitor, apicidin, in rats

Shin

Chang

Park

et al. 2006

Biopharm. Drug Dispos.

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This study is the first report of the pharmacokinetics of a novel histone deacetylase inhibitor, apicidin, in rats after i.v. and oral administration. Apicidin was injected intravenously at doses of 0.5, 1.0, 2.0 and 4.0 mg/kg. The terminal elimination half-life (t1/2), systemic clearance (Cl) and steady-state volume of distribution (Vss) remained unaltered as a function of dose, with values in the range 0.8-1.1 h, 59.6-68.0 ml/min/kg and 2.4-2.7 l/kg, respectively. Whereas, the initial serum concentration (C0) and AUC increased linearly as the dose was increased. Taken together, the pharmacokinetics of apicidin were linear over the i.v. dose range studied. The extent of urinary and biliary excretion of apicidin was minimal (0.017%-0.020% and 0.049% +/- 0.016%, respectively). Oral pharmacokinetic studies were conducted in fasting and non-fasting groups of rats at a dose of 10 mg/kg. The Tmax, Cl/F and Vz/F were in the range 0.9-1.1 h, 520.3-621.2 ml/min/kg and 67.6-84.4 l/kg, respectively. No significant difference was observed in the oral absorption profiles between the two groups of rats. Apicidin was poorly absorbed, with the absolute oral bioavailability of 19.3% and 14.2% in fasting and non-fasting rats.

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“…Apicidin has been known to possess potent HDAC inhibitory activity [19,20,21]. Therefore, it is of interest to assess the rate and extent of the formation of apicidin after SD-2007 administration.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of a Novel Histone Deacetylase Inhibitor, Cyclo{(2S)-2-Amino-8-[(Aminocarbonyl)Hydrazono] Decanoyl-1-L-Tryptophyl-L-Isoleucyl-(2R)-2-Piperidinecarbonyl} (SD-2007), and Its Metabolic Conversion to Apicidin after Intravenous Injection and Oral Administration in Rats

et al. 2011

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Background: This study assessed the population pharmacokinetics and metabolic conversion of a novel histone deacetylase (HDAC) inhibitor, SD-2007, into its active metabolite, apicidin, in rats. Methods: SD-2007 was given to rats by intravenous injection (4 mg/kg) and oral administration (40 mg/kg). Serum concentrations of SD-2007 and apicidin were determined by LC-MS/MS. All concentrations were analyzed using a population pharmacokinetic model with 9 compartments in S-ADAPT. Results: The area under the curve for apicidin was 96 ± 16 mg·h/ml after 4 mg/kg administered intravenously and 2,455 ± 1,211 mg·h/ml after 40 mg/kg given orally. The population pharmacokinetic model described all profiles well. After oral administration of SD-2007, the median absolute bioavailability of SD-2007 was 6.67% (range 3.83–9.89) and the median apparent bioavailability was 22.3% (range 15.7–35.8) for apicidin, whereas only a median of 8.85% (range 7.57–9.34) of an intravenous SD-2007 dose was converted to apicidin. Conclusions: Oral SD-2007 displayed a substantial presystemic metabolism to active apicidin. The high serum concentrations of apicidin after oral administration of SD-2007 may cause significant HDAC inhibition.

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Broad spectrum antiprotozoal agents that inhibit histone deacetylase: structure–activity relationships of apicidin. Part 1

Cited by 69 publications

References 22 publications

Potent Antimalarial Activity of Histone Deacetylase Inhibitor Analogues

Potent Antimalarial Activity of Histone Deacetylase Inhibitor Analogues

Pharmacokinetics of a novel histone deacetylase inhibitor, apicidin, in rats

Population Pharmacokinetics of a Novel Histone Deacetylase Inhibitor, Cyclo{(2S)-2-Amino-8-[(Aminocarbonyl)Hydrazono] Decanoyl-1-L-Tryptophyl-L-Isoleucyl-(2R)-2-Piperidinecarbonyl} (SD-2007), and Its Metabolic Conversion to Apicidin after Intravenous Injection and Oral Administration in Rats

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