Versatile Synthetic Route to Cycloheximide and Analogues That Potently Inhibit Translation Elongation

Park, Yongho; Koga, Yumi; Su, Cindy; Waterbury, Amanda L.; Johnny, Christopher L.; Liau, Brian B.

doi:10.1002/anie.201901386

Cited by 16 publications

(13 citation statements)

References 39 publications

(37 reference statements)

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“…They also evaluated alterations of the However, it is currently possible to access the structure-guided design of cycloheximide analogues. Consequently, Liau's group has been able to initiate rational design by modifying CHX [132] from the structure published by [42,132]. Important total synthesis work has been performed providing 11 CHX analogues.…”

Section: Cryo-em-based Drug Design Of Cycloheximidementioning

confidence: 99%

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Targeting the Human 80S Ribosome in Cancer: From Structure to Function and Drug Design for Innovative Adjuvant Therapeutic Strategies

Gilles

Fréchin

Natchiar

et al. 2020

Cells

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The human 80S ribosome is the cellular nucleoprotein nanomachine in charge of protein synthesis that is profoundly affected during cancer transformation by oncogenic proteins and provides cancerous proliferating cells with proteins and therefore biomass. Indeed, cancer is associated with an increase in ribosome biogenesis and mutations in several ribosomal proteins genes are found in ribosomopathies, which are congenital diseases that display an elevated risk of cancer. Ribosomes and their biogenesis therefore represent attractive anti-cancer targets and several strategies are being developed to identify efficient and specific drugs. Homoharringtonine (HHT) is the only direct ribosome inhibitor currently used in clinics for cancer treatments, although many classical chemotherapeutic drugs also appear to impact on protein synthesis. Here we review the role of the human ribosome as a medical target in cancer, and how functional and structural analysis combined with chemical synthesis of new inhibitors can synergize. The possible existence of oncoribosomes is also discussed. The emerging idea is that targeting the human ribosome could not only allow the interference with cancer cell addiction towards protein synthesis and possibly induce their death but may also be highly valuable to decrease the levels of oncogenic proteins that display a high turnover rate (MYC, MCL1). Cryo-electron microscopy (cryo-EM) is an advanced method that allows the visualization of human ribosome complexes with factors and bound inhibitors to improve our understanding of their functioning mechanisms mode. Cryo-EM structures could greatly assist the foundation phase of a novel drug-design strategy. One goal would be to identify new specific and active molecules targeting the ribosome in cancer such as derivatives of cycloheximide, a well-known ribosome inhibitor.

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Section: Cryo-em-based Drug Design Of Cycloheximidementioning

confidence: 99%

“…(A) Earlier structure activity relationship studies on cycloheximide. (B) Cycloheximide derivatives: in red, modifications leading to a loss of activity, in blue, conservation or slight enhancement of activity for compound 5[132].…”

mentioning

confidence: 99%

Targeting the Human 80S Ribosome in Cancer: From Structure to Function and Drug Design for Innovative Adjuvant Therapeutic Strategies

Gilles

Fréchin

Natchiar

et al. 2020

Cells

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“…This suggested that the presence of a hydroxy group at C13 dramatically reduced the binding affinity of HCH in true fungi and oomycetes. On the other hand, HCH inhibited protein synthesis much more efficiently than CH in a human cell line ( Park et al, 2019 ), with 50% inhibition concentration (IC 50 ) values of 0.97 μM for HCH and 2.64 μM for CH. These results suggested that the binding affinity of the three CHs to the target site may be different according to the target organism.…”

Section: Resultsmentioning

confidence: 99%

“…The appropriate numbers of hydrogen atoms were added, and protein was neutralized as per the Schrodinger standard procedure. Conversely, structures of CH, HCH, and ACH and two positive controls (lactimidomycin, and phyllanthoside; Park et al, 2019 ) were drawn by Chemdraw 12.0. For further optimization of the chemical structures of targeted molecules, the DFT method was adopted ( El-Azhary and Suter, 1996 ).…”

Section: Methodsmentioning

confidence: 99%

“…Both chemicals bind to the site between C3993 at the base of hairpin 88 of the 28S rRNA, between the 38th amino acid of L27a, and proline 54 of L36a in yeast, resulting in the blockage of eEF2-mediated tRNA translocation ( Schneider-Poetsch et al, 2010 ). A previous study ( Park et al, 2019 ) pointed out that an additional substituent at C13 of HCH enhanced translation inhibition compared to CH in human cells. Although a previous study ( Schneider-Poetsch et al, 2010 ) postulated a mechanism of action of CH in human tumors, the precise reason why CH and its derivatives show different protein synthesis inhibition abilities in fungi and plants remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Deciphering the Relationship Between Cycloheximides Structures and Their Different Biological Activities

et al. 2021

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Streptomyces species are the most important sources of antibacterial, antifungal, and phytotoxic metabolites. In this study, cycloheximide (CH) and acetoxycycloheximide (ACH) were isolated from the fermentation broth of Streptomyces sp. JCK-6092. The antifungal and phytotoxic activities of the two compounds (CH and ACH) and a cycloheximide derivative, hydroxycycloheximide (HCH), were compared. CH exhibited the strongest antagonistic activity against all the true fungi tested, followed by ACH and HCH. However, both CH and ACH displayed similar mycelial growth inhibitory activities against several phytopathogenic oomycetes, and both were more active than that of HCH. Disparate to antifungal ability, ACH showed the strongest phytotoxic activity against weeds and crops, followed by HCH and CH. ACH caused chlorophyll content loss, leaf electrolytic leakage, and lipid peroxidation in a dose-dependent manner. Its phytotoxicity was stronger than that of glufosinate-ammonium but weaker than that of paraquat in the in vitro experiments. CH and its derivatives are well-known protein synthesis inhibitors; however, the precise differences between their mechanism of action remain undiscovered. A computational study revealed effects of CHs on the protein synthesis of Pythium ultimum (oomycetes), Magnaporthe oryzae (true fungus), and Capsicum annum (plant) and deciphered the differences in their biological activities on different targets. The binding energies and conformation stabilities of each chemical molecule correlated with their biological activities. Thus, molecular docking study supported the experimental results. This is the first comparative study to suggest the ribosomal protein alteration mechanisms of CHs in plants and fungi and to thus show how the protein inhibitory activities of the different derivatives are altered using molecular docking. The correlation of structures features of CHs in respect to bond formation with desired protein was revealed by density functional theory. Overall collective results suggested that CHs can be used as lead molecules in the development of more potent fungicides and herbicides molecules.

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Synthetic Strategy towards a Carbocyclic N‐Acetylneuraminic Acid

et al. 2022

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In the study of glycosidases, a class of activity-based probes (ABPs), that are carbocyclic mimics of natural carbohydrates and can covalently bind the enzyme, have proven to be useful tools. This type of ABP has however not yet been reported for sialidases, glycosidases involved in various important biological processes in both health and disease, which hydrolyse terminal sialic acids. Here we present our study towards the synthesis of a carbocyclic sialic acid suitable for conversion into ABPs. We developed a route starting from a chiral furanone that includes a key early stage nitrone [3 + 2] cycloaddition to install most of the chiral centres present in N-acetylneuraminic acid. The final stereocentre is installed via a Barbier alkylation, after which a ring closing metathesis forms the pivotal carbocyclic intermediate. Due to challenges in the final stretch, we were not able to convert this intermediate into an N-acetylneuraminic acid ABP. However, the work presented here still represents a versatile route to potential future carbocyclic sialic acid derivatives.

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Versatile Synthetic Route to Cycloheximide and Analogues That Potently Inhibit Translation Elongation

Cited by 16 publications

References 39 publications

Targeting the Human 80S Ribosome in Cancer: From Structure to Function and Drug Design for Innovative Adjuvant Therapeutic Strategies

Targeting the Human 80S Ribosome in Cancer: From Structure to Function and Drug Design for Innovative Adjuvant Therapeutic Strategies

Deciphering the Relationship Between Cycloheximides Structures and Their Different Biological Activities

Synthetic Strategy towards a Carbocyclic N‐Acetylneuraminic Acid

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