Palau’amine and Related Oroidin Alkaloids Dibromophakellin and Dibromophakellstatin Inhibit the Human 20S Proteasome

Lansdell, Theresa A.; Hewlett, Nicole M.; Skoumbourdis, Amanda P.; Fodor, Matthew D.; Seiple, Ian B.; Su, Shun; Baran, Phil S.; Feldman, Ken S.; Tepe, Jetze J.

doi:10.1021/np300231f

Cited by 48 publications

(43 citation statements)

References 52 publications

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“…35,39 We found that only compound 2 induced the activation of the chymotrypsin-like (CT-L, EC 50 4.9 μ M), tryptic-like (T-L, EC 50 10.0 μ M), and caspase-like (Casp-L, EC 50 4.8 μ M) activity (Figure S2). The parallel effects of all proteolytic sites is consistent with the induction of an open-gate conformation that allows all substrates to enter the chamber.…”

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confidence: 90%

Small Molecule Enhancement of 20S Proteasome Activity Targets Intrinsically Disordered Proteins

et al. 2017

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The 20S proteasome is the main protease for the degradation of oxidatively damaged and intrinsically disordered proteins. When accumulation of disordered or oxidatively damaged proteins exceeds proper clearance in neurons, imbalanced pathway signaling or aggregation occurs, which have been implicated in the pathogenesis of several neurological disorders. Screening of the NIH Clinical Collection and Prestwick libraries identified the neuroleptic agent chlorpromazine as a lead agent capable of enhancing 20S proteasome activity. Chemical manipulation of chlorpromazine abrogated its D2R receptor binding affinity while retaining its ability to enhance 20S mediated proteolysis at low micromolar concentrations. The resulting small molecule enhancers of 20S proteasome activity induced the degradation of intrinsically disordered proteins, α-synuclein, and tau but not structured proteins. These small molecule 20S agonists can serve as leads to explore the therapeutic potential of 20S activation or as new tools to provide insight into the yet unclear mechanics of 20S-gate regulation.

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confidence: 90%

Small Molecule Enhancement of 20S Proteasome Activity Targets Intrinsically Disordered Proteins

et al. 2017

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“…Pyrrole-containing molecules include commonly naturally produced compounds such as chlorophyll, chlorins, vitamin B12 and porphyrinogens [34][35][36]. A pyrrole ring is also a part of tryptamines including serotonin, melatonin and many other biologically important substances [37][38][39][40]. For that reason, apart from broadening our knowledge of the stacking interaction phenomenon itself, this extensive study of the intermolecular interaction in model pyrrole systems may be relevant in electronic properties of pyrrole-unit-based drugs.…”

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confidence: 99%

The intricacies of the stacking interaction in a pyrrole–pyrrole system

Sierański

2016

Struct Chem

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Extensive calculations of potential energy surfaces for parallel-displaced configurations of pyrrole-pyrrole systems have been carried out by the use of a dispersion-corrected density functional. System geometries associated with the energy minima have been found. The minimum interaction energy has been calculated as -5.38 kcal/mol. However, bonding boundaries appeared to be relatively broad, and stacking interactions can be binding even for ring centroid distances larger than 6 Å . Though the contribution of the correlation energy to intermolecular interaction in pyrrole dimers appeared to be relatively small (around 1.6 smaller than it is in a benzenebenzene system), this system's minimum interaction energy is lower than those calculated for benzene-benzene, benzene-pyridine and even pyridine-pyridine configurations. The calculation of the charges and energy decomposition analysis revealed that the specific charge distribution in a pyrrole molecule and its relatively high polarization are the significant source of the intermolecular interaction in pyrrole dimer systems.

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“…[10] In our ongoing efforts to discover proteasome inhibitors with novel modes of action, we investigated compounds from the highly diverse family of biologically active pyrroleimidazoline marine alkaloids, which differ significantly from all CP inhibitors described to date (Scheme 1). [14] The structurally related natural products dibromophakellstatin (2) and dibromophakellin (3) are synthetically more accessible, although these compounds display reduced CP inhibitory potency compared to 1 [IC 50 (b5c) = 25.3 and 11.9 mm, respectively]. [11][12][13] Compound 1 was described to bind irreversibly to the CP (IC 50 (b5c) = 2.5 mm), but its scarcity and structural complexity prevents the rapid generation of more potent synthetic or semisynthetic derivatives.…”

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“…The most important member of this class of compounds is palauamine (1), a cytotoxic and immunosuppressive hexacyclic bisguanidine that was isolated from the sea sponge Stylotella agminata. [14,15] We established a robust synthetic route towards derivatives of phakellins that share the same rigid cyclic framework [14,16] and revealed activity similar to 1. [14] The structurally related natural products dibromophakellstatin (2) and dibromophakellin (3) are synthetically more accessible, although these compounds display reduced CP inhibitory potency compared to 1 [IC 50 (b5c) = 25.3 and 11.9 mm, respectively].…”

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Indolo‐Phakellins as β5‐Specific Noncovalent Proteasome Inhibitors

et al. 2015

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The proteasome represents an invaluable target for the treatment of cancer and autoimmune disorders. The application of proteasome inhibitors, however, remains limited to blood cancers because their reactive headgroups and peptidic scaffolds convey unfavorable pharmacodynamic properties. Thus, the discovery of more drug-like lead structures is indispensable. In this study, we present the first structure of the proteasome in complex with an indolo-phakellin that exhibits a unique noncovalent binding mode unparalleled by all hitherto reported inhibitors. The natural product inspired pentacyclic alkaloid binds solely and specificially into the spacious S3 subpocket of the proteasomal β5 substrate binding channel, gaining major stabilization through halogen bonding with the protein backbone. The presented compound provides an ideal scaffold for the structure-based design of subunit-specific nonpeptidic proteasome-blockers.

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Palau’amine and Related Oroidin Alkaloids Dibromophakellin and Dibromophakellstatin Inhibit the Human 20S Proteasome

Cited by 48 publications

References 52 publications

Small Molecule Enhancement of 20S Proteasome Activity Targets Intrinsically Disordered Proteins

Small Molecule Enhancement of 20S Proteasome Activity Targets Intrinsically Disordered Proteins

The intricacies of the stacking interaction in a pyrrole–pyrrole system

Indolo‐Phakellins as β5‐Specific Noncovalent Proteasome Inhibitors

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