Isolierung und Strukturaufklärung von Chlamydocin

Closse, Annemarie; Huguenin, R

doi:10.1002/hlca.19740570306

Cited by 192 publications

(77 citation statements)

References 19 publications

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“…Several naturally occurring cyclic tetrapeptides have been reported in the literature and are structurally related to apicidin, including HC-toxin (18), trapoxin A (19), WF-3161 (20), cly-2 (21), and chlamydocin (22) (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

Apicidin: A novel antiprotozoal agent that inhibits parasite histone deacetylase

Darkin-Rattray

Gurnett

Myers

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

534

419

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A novel fungal metabolite, apicidin [cyclo(N-O-methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)], that exhibits potent, broad spectrum antiprotozoal activity in vitro against Apicomplexan parasites has been identified. It is also orally and parenterally active in vivo against Plasmodium berghei malaria in mice. Many Apicomplexan parasites cause serious, life-threatening human and animal diseases, such as malaria, cryptosporidiosis, toxoplasmosis, and coccidiosis, and new therapeutic agents are urgently needed. Apicidin's antiparasitic activity appears to be due to low nanomolar inhibition of Apicomplexan histone deacetylase (HDA), which induces hyperacetylation of histones in treated parasites. The acetylation-deacetylation of histones is a thought to play a central role in transcriptional control in eukaryotic cells. Other known HDA inhibitors were also evaluated and found to possess antiparasitic activity, suggesting that HDA is an attractive target for the development of novel antiparasitic agents.

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Section: Resultsmentioning

confidence: 99%

Apicidin: A novel antiprotozoal agent that inhibits parasite histone deacetylase

Darkin-Rattray

Gurnett

Myers

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

534

419

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“…Chlamydocin (Fig. 1), a fungal metabolite, has been shown to exhibit potent antiproliferative activity in vitro (Closse and Huguenin, 1974). The effect of chlamydocin was examined on several human cancer cell lines with different p53 status.…”

Section: Resultsmentioning

confidence: 99%

“…1) was originally isolated from the fungus Diheterospora chlamydosporia and has been shown to exhibit potent anticancer activity in vitro (Closse and Huguenin, 1974). Chlamydocin belongs to a small family of hydrophobic cyclic tetrapeptides containing the unusual amino acid, 2-amino-8-oxo-9,10-epoxy decanoic acid (Aoe), which is essential for their biological activity.…”

mentioning

confidence: 99%

Inhibition of Histone Deacetylases by Chlamydocin Induces Apoptosis and Proteasome-Mediated Degradation of Survivin

Schepper¹,

Bruwiere²,

Verhulst³

et al. 2003

J Pharmacol Exp Ther

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The naturally occurring cyclic tetrapeptide chlamydocin is a very potent inhibitor of cell proliferation. Here we show that chlamydocin is a highly potent histone deacetylase (HDAC) inhibitor, inhibiting HDAC activity in vitro with an IC 50 of 1.3 nM. Like other HDAC inhibitors, chlamydocin induces the accumulation of hyperacetylated histones H3 and H4 in A2780 ovarian cancer cells, increases the expression of p21 cip1/waf1 , and causes an accumulation of cells in G 2 /M phase of the cell cycle. In addition, chlamydocin induces apoptosis by activating caspase-3, which in turn leads to the cleavage of p21 cip1/waf1 into a 15-kDa breakdown product and drives cells from growth arrest into apoptosis. Concomitant with the activation of caspase-3 and cleavage of p21 cip1/waf1 , chlamydocin decreases the protein level of survivin, a member of the inhibitor of apoptosis protein family that is selectively expressed in tumors. Although our data indicate a potential link between degradation of survivin and activation of the apoptotic pathway induced by HDAC inhibitors, stable overexpression of survivin does not suppress the activation of caspase-3 or cleavage of p21 cip1/waf1 induced by chlamydocin treatment. The decrease of survivin protein level is mediated by degradation via proteasomes since it can be inhibited by specific proteasome inhibitors. Taken together, our results show that induction of apoptosis by chlamydocin involves caspase-dependent cleavage of p21 cip1/waf1 , which is strikingly associated with proteasomemediated degradation of survivin.

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“…Chlamydocin, HC-toxin, Cyl-1, Cyl-2, and WF-3161 in addition to TPX A and B have been reported as cyclic tetrapeptide antibiotics containing Aoe (19). Chlamydocin and WF-3161 were described to have antifungal and antitumor activities (32,33). HC-toxin, Cyl-1, and Cyl-2 are phytotoxic substances produced by phytopathogenic fungi, causing necrotic lesions on the leaves and sometimes serious reduction of crop yield (34)(35)(36).…”

Section: Hdac Inhibition By Chaps Corresponding To Naturally Occurrinmentioning

confidence: 99%

Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin

Furumai

Komatsu

Nishino

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

354

110

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Trichostatin A (TSA) and trapoxin (TPX) are potent inhibitors of histone deacetylases (HDACs). TSA is proposed to block the catalytic reaction by chelating a zinc ion in the active-site pocket through its hydroxamic acid group. On the other hand, the epoxyketone is suggested to be the functional group of TPX capable of alkylating the enzyme. We synthesized a novel TPX analogue containing a hydroxamic acid instead of the epoxyketone. The hybrid compound cyclic hydroxamic acid-containing peptide (CHAP) 1 inhibited HDAC1 at low nanomolar concentrations. The HDAC1 inhibition by CHAP1 was reversible as it was by TSA, in contrast to the irreversible inhibition by TPX. CHAP with an aliphatic chain length of five, which corresponded to that of acetylated lysine, was stronger than those with other lengths. These results suggest that TPX is a substrate mimic and that the replacement of the epoxyketone with the hydroxamic acid converted TPX to an inhibitor chelating the zinc like TSA. Interestingly, HDAC6, but not HDAC1 or HDAC4, was resistant to TPX and CHAP1, whereas TSA inhibited these HDACs to a similar extent. HDAC6 inhibition by TPX at a high concentration was reversible, probably because HDAC6 is not alkylated by TPX. We further synthesized the counterparts of all known naturally occurring cyclic tetrapeptides containing the epoxyketone. HDAC1 was highly sensitive to all these CHAPs much more than HDAC6, indicating that the structure of the cyclic tetrapeptide framework affects the target enzyme specificity. These results suggest that CHAP is a unique lead to develop isoform-specific HDAC inhibitors.

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Isolierung und Strukturaufklärung von Chlamydocin

Cited by 192 publications

References 19 publications

Apicidin: A novel antiprotozoal agent that inhibits parasite histone deacetylase

Apicidin: A novel antiprotozoal agent that inhibits parasite histone deacetylase

Inhibition of Histone Deacetylases by Chlamydocin Induces Apoptosis and Proteasome-Mediated Degradation of Survivin

Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin

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