Macrocyclic Peptoid–Peptide Hybrids as Inhibitors of Class I Histone Deacetylases

Olsen, Christian A.; Montero, Ana; Leman, Luke J.; Ghadiri, Mojtaba

doi:10.1021/ml300162r

Cited by 37 publications

(40 citation statements)

References 39 publications

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“…Macrolactamization, under dilute conditions (0.4 mM in DMF), using HATU as the coupling reagent afforded target peptide 9 (Scheme 4). The relatively low yield is similar to those previously achieved for similar compounds [21][22][23][24] and may, at least in part, be attributed to poor solubility in the water-acetonitrile mobile phase used in reversed-phase HPLC purication. However, further optimization of cyclization efficiency, which is known to be notoriously troublesome for small peptides, 33 may also prove worthwhile.…”

Section: 31supporting

confidence: 80%

“…For apicidin, this correlates well with values previously obtained against HeLa, Hct-116, MCF-7, KYO-1, and K-562 cells. 23 The EB-3 cell proliferation was inhibited at 1% but not at 0.5% DMSO and this resulted in a maximal reliable concentration of azumamide C of 25 mM while it was 50 mM for azumamide B and 9. For all three compounds the GI 50 values were deemed well above this limit as no reproducible growth inhibition was observed for any of the compounds.…”

Section: Effect On Cultured Cancer Cellsmentioning

confidence: 96%

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An azumamide C analogue without the zinc-binding functionality

et al. 2014

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Section: 31supporting

confidence: 80%

Section: Effect On Cultured Cancer Cellsmentioning

confidence: 96%

An azumamide C analogue without the zinc-binding functionality

et al. 2014

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“…53 In an effort to expand the conformational space of apicidin analogues, Ghadiri and co-workers introduced α-and β-peptoid residues into the apicidin backbone. 54 The two most potent compounds in this study contained an N-isobutyl-β-peptoid and a tryptamine-based peptoid residue (17 and 18; Figure 6a), and molecular dynamics simulations showed a good overlap of the projection of side chains even though the backbone conformations were different from that of apicidin ( Figure 6b). Interestingly, the two remaining backbone amide protons were perpendicular to the macrocycle in the same direction as the extended ethylketone-containing side chain, which was recently shown to be important for potent HDAC inhibition by similar macrocyclic peptides.…”

Section: Macrocyclic Histone Deacetylase Inhibitorsmentioning

confidence: 82%

β-Peptoid Foldamers at Last

2015

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For a long time, peptides were considered unsuitable for drug development due to their inherently poor pharmacokinetic properties and proteolytic susceptibility. However, this paradigm has changed significantly in the past decade with the approval of numerous antibodies and proteins as drugs. In parallel, research in the field of synthetic molecules that are able to mimic or complement folding patterns exhibited by biopolymers, but are not recognized by proteases, have received considerable attention as well. Such entities were coined "foldamers" by Professor Gellman in an Account published in this journal in the late 1990s. Oligomers of N-alkylated 3-aminopropionic acid residues have been called β-peptoids due to their structural similarity to β-peptides and peptoids (N-alkylglycines), respectively. Because bona fide foldamer behavior has been demonstrated for both parent architectures, we wondered if the β-peptoids could serve as a successful addition to the known ensemble of peptidomimetic foldamers. When we entered this field, only the seminal description of libraries of β-peptoid dimers and trimers by Hamper et al. had been published a number of years earlier [ J. Org. Chem. 1998 , 63 , 708 ]. Perhaps somewhat naïvely in retrospect, we envisioned that elongation of chain length combined with introduction of bulky α-chiral side chains would deliver folded structures as reported for the α-peptoid counterparts. Initially, we, and others, were unsucessful in obtaining stable secondary structures of β-peptoid oligomers, and instead, these residues were either incorporated in cyclic structures or in combination with other types of residues to give peptidomimetic constructs with heterogeneous backbones. Amphiphilic architectures with various membrane-targeting activities, such as mimics of antimicrobial peptides or cell-penetrating peptides, have thus been particularly successful. Introduction of β-peptoid residues in histone deacetylase inhibitors mimicking nonribosomal cyclotetrapeptides have also been reported. In the present Account, we will sketch the scientific journey that ultimately delivered robustly folded β-peptoid oligomers. Contributions involving biological evaluation of peptidomimetic constructs containing β-peptoid residues, as mentioned above, which were investigated leading up to these recently reported high-resolution helical structures, will thus be discussed. On the basis of the work described in this Account, we envision that β-peptoids will find future utility as peptidomimetics for biomedical investigation containing both heterogeneous and homogeneous backbones. The recent demonstration of control over the secondary structure of a homogeneous β-peptoid backbone now enables structure-based design of scaffolds with predictable display of desired functionalities in three dimensions.

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“…[13] Starting materials for the synthesis of polyamine building blocks, methyl 3-(2-nitrophenylsulfonamido)-propanoate, [18] 3-((tert-butoxycarbonyl)amino)propyl methanesulfonate, [19] tert-butyl (3-(N-(4-bromobutyl)-2-nitrophenylsulfonamido)-propyl)carbamate, [20] 2-(trimethylsilyl)ethyl (5-aminopentyl)carbamate, [13] and allyl (5-aminopentyl)carbamate [21] were prepared according to published procedures.…”

Section: Methodsmentioning

confidence: 99%

“…> 1000 24 (16- [13] 19 (17)(18)(19)(20)(21) [ with a methylene, as in 7, 12, and 17, the degree of inhibition at AMPA receptors is essentially unchanged, whereas inhibition at NMDA receptors is significantly lowered, resulting in an increased selectivity. When the other secondary amine is replaced with methylene, as in 8, 13, and 18, activity at both AMPA and NMDA receptors is drastically decreased.…”

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confidence: 99%

Structure–Activity Relationship Study of Spider Polyamine Toxins as Inhibitors of Ionotropic Glutamate Receptors

et al. 2014

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The spider polyamine toxins Joro spider toxin-3 (JSTX-3) and Nephila polyamine toxins-1 and -8 (NPTX-1 and NPTX-8) are isolated from the venom of the orb-weaver spider Nephila clavata (Joro spider). They share a high degree of structural resemblance, their aromatic head groups being the only difference, and were recently found to be very potent open-channel blockers of ionotropic glutamate (iGlu) receptors. In this study we designed and synthesized a collection of 24 analogues of these toxins using a recently developed solid-phase synthetic methodology. Systematic variation in two regions of the toxins and subsequent evaluation of biological activity at AMPA and NMDA subtypes of iGlu receptors provided succinct information on structure-activity relationships. In particular, one set of analogues were found to display exquisite selectivity and potency for AMPA receptors relative to the natural products. Thus, this systematic SAR study has provided new pharmacological tools for studies of iGlu receptors.

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Macrocyclic Peptoid–Peptide Hybrids as Inhibitors of Class I Histone Deacetylases

Cited by 37 publications

References 39 publications

An azumamide C analogue without the zinc-binding functionality

An azumamide C analogue without the zinc-binding functionality

β-Peptoid Foldamers at Last

Structure–Activity Relationship Study of Spider Polyamine Toxins as Inhibitors of Ionotropic Glutamate Receptors

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