Structure of Cyl-2, a Novel Cyclotetrapeptide from<i>Cylindrocladium scoparium</i>

Hirota, Akira; Suzuki, Akira; Aizawa, K.; Tamura, Saburo

doi:10.1080/00021369.1973.10860775

Cited by 41 publications

(14 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The phenylalanine stereochemistry of WF-3161, although originally reported as L-Phe, was later revised to D-Phe on the basis of spectroscopic and chemical studies [70]. The fungus Cylindrocladium scoparium produced the prolyl-substituted Cyl-1 (40) as well as its pipecolyl-variant Cyl-2 (41); both were potent plant growth regulators [71][72][73]. The absolute stereochemistry of the Aoe moiety in Cyl-2 was determined using CD spectroscopy [74].…”

Section: Cyclic Histone Deacetylase In-hibitorsmentioning

confidence: 99%

Histone Deacetylase: A Target for Antiproliferative and Antiprotozoal Agents

Meinke¹,

Liberator²

2001

CMC

108

View full text Add to dashboard Cite

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.

show abstract

Section: Cyclic Histone Deacetylase In-hibitorsmentioning

confidence: 99%

Histone Deacetylase: A Target for Antiproliferative and Antiprotozoal Agents

Meinke¹,

Liberator²

2001

CMC

108

View full text Add to dashboard Cite

show abstract

“…17 All these peptides present cytotoxic or cytostatic activities and possess one D-amino acid and three L-amino acids, including L-Aoe or L-Aod. In this tentative classification, a last group of cyclopeptides can be distinguished, including fenestin A (10), 18 cyclo(L-Pro-LVal) 2 (11), 19 cyclo(L-Pro-L-Leu) 2 (12), cyclo(L-Pro-L-Phe) 2 (13), and cyclo(L-Pro-L-Tyr-L-Pro-L-Val) (14), 20 all characterized by four L-amino acids, and exhibiting cytotoxic activities as well.…”

Section: Introductionmentioning

confidence: 99%

“…Cyl-1 (3), 5 Cyl-2 (4), 6,7 and HC-toxin (5), 8 -11 which are also phytotoxic peptides, possess a D-residue instead of the dehydro-residue, and are marked by the presence of a novel amino acid residue, L-Aoe. The presence of L-Aoe and the analogous residue L-Aod also characterizes the next group of cyclotetrapeptides in Table I comprising chlamydocin (6), [12][13][14] trapoxin A (7), trapoxin B (identical to trapoxin A with a D-Pro residue in place of the D-Pip residue), 15 apicidin (8), apicidin A [identical to Apicidin with L-Trp in place of L-Trp(N-OMe)], 16 and WF-3161 (9). 17 All these peptides present cytotoxic or cytostatic activities and possess one D-amino acid and three L-amino acids, including L-Aoe or L-Aod.…”

Section: Introductionmentioning

confidence: 99%

Predicting the conformational states of cyclic tetrapeptides

et al. 2003

View full text Add to dashboard Cite

Biologically active cyclic tetrapeptides, usually found among fungi metabolites, exhibit phytotoxic or cytostatic activities that are likely to be governed by specific conformations adopted in solution. For conformational studies and drug design, there is a strong interest in using fast and reliable methods to determine correctly the conformational population of cyclotetrapeptides. We show here that standard molecular mechanics computational approach gives satisfactory results. The method was validated step by step by experimental data either obtained after synthesis and NMR analysis, or found in the literature. The cyclo(Gly)(4), cyclo(Ala)(4), cyclo(Sar)(4), and cyclo(SarGly)(2) peptides were used to evaluate the prediction of the peptide backbone conformation, and the detailed conformational analysis of tentoxin, a natural phytotoxic cyclotetrapeptide in which N-alkylated peptide bonds alternate with regular secondary ones, was used to validate the computation of conformers proportions. From the knowledge of an initial cyclic primary structure and of the D or L configuration of the amino acids, we show that it is possible to determine the exact orientation of carbonyl groups and to predict the nature of conformers present in solution. The proportion of each conformer can be inferred from a statistical thermodynamics approach by using the potential energy values of each conformer, computed by molecular mechanics methods with the TRIPOS force field, which allowed us to account for the solvent. The solvent contribution was processed by two different methods according to the nature of the interactions: whether through the dielectric constant introduced in the electrostatic potential, when interaction with solute molecules are weak or negligible, or through the computation of free energy of solvation using the algorithm SILVERWARE for solvents explicitly interacting with the solute. When applied to tentoxin, this conformational analysis yielded results in very good agreement with the experimental data reported by Pinet et al. (Biopolymers, 1995, Vol. 36, pp. 135-152), on both the nature of existing conformers and their relative proportions, whatever the nature of the considered solvent.

show abstract

“…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). Of these compounds, HC-toxin and chlamydocin have been described to inhibit HDAC (20).…”

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

Furumai¹

2000

Proceedings of the National Academy of Sciences

218

233

View full text Add to dashboard Cite

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.

show abstract

Structure of Cyl-2, a Novel Cyclotetrapeptide fromCylindrocladium scoparium

Cited by 41 publications

References 1 publication

Histone Deacetylase: A Target for Antiproliferative and Antiprotozoal Agents

Histone Deacetylase: A Target for Antiproliferative and Antiprotozoal Agents

Predicting the conformational states of cyclic tetrapeptides

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

Contact Info

Product

Resources

About