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Article ; Online: Short synthesis of a broadly Reactive, cell permeable serine hydrolase Fluorophosphonate-Alkyne probe.

Konduri, Srihari / Schweer, Joshua / Siegel, Dionicio

Bioorganic & medicinal chemistry letters

2023 Volume 95, Page(s) 129434

Abstract: An abbreviated synthesis of the cell permeable fluorophosphonate-alkyne probe (FP-alkyne) for the broad assessment of serine hydrolase activity has been developed. While FP-alkyne has proven pivotal in numerous chemical biology studies access has relied ... ...

Abstract	An abbreviated synthesis of the cell permeable fluorophosphonate-alkyne probe (FP-alkyne) for the broad assessment of serine hydrolase activity has been developed. While FP-alkyne has proven pivotal in numerous chemical biology studies access has relied on a lengthy preparation over nine steps. We have developed a four-step synthesis, starting from commercially available compounds, with three purification steps to provide a new expedited route allowing easy access to a useful tool compound for exploring serine hydrolases chemistry and biology. This route was used in our own studies to generate FP-alkyne which in turn was used to identify the enzyme responsible for Fatty Acid Esters of Hydroxy Fatty Acids (FAHFA) biosynthesis. The use of this route can enable the syntheses of new tool compounds in addition to improving accessibility to FP-alkyne.
Language	English
Publishing date	2023-08-07
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2023.129434
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Article ; Online: Targeting of REST with rationally-designed small molecule compounds exhibits synergetic therapeutic potential in human glioblastoma cells.

Panina, Svetlana B / Schweer, Joshua V / Zhang, Qian / Raina, Gaurav / Hardtke, Haley A / Kim, Seungjin / Yang, Wanjie / Siegel, Dionicio / Zhang, Y Jessie

BMC biology

2024 Volume 22, Issue 1, Page(s) 83

Abstract: Background: Glioblastoma (GBM) is an aggressive brain cancer associated with poor prognosis, intrinsic heterogeneity, plasticity, and therapy resistance. In some GBMs, cell proliferation is fueled by a transcriptional regulator, repressor element-1 ... ...

Abstract	Background: Glioblastoma (GBM) is an aggressive brain cancer associated with poor prognosis, intrinsic heterogeneity, plasticity, and therapy resistance. In some GBMs, cell proliferation is fueled by a transcriptional regulator, repressor element-1 silencing transcription factor (REST). Results: Using CRISPR/Cas9, we identified GBM cell lines dependent on REST activity. We developed new small molecule inhibitory compounds targeting small C-terminal domain phosphatase 1 (SCP1) to reduce REST protein level and transcriptional activity in glioblastoma cells. Top leads of the series like GR-28 exhibit potent cytotoxicity, reduce REST protein level, and suppress its transcriptional activity. Upon the loss of REST protein, GBM cells can potentially compensate by rewiring fatty acid metabolism, enabling continued proliferation. Combining REST inhibition with the blockade of this compensatory adaptation using long-chain acyl-CoA synthetase inhibitor Triacsin C demonstrated substantial synergetic potential without inducing hepatotoxicity. Conclusions: Our results highlight the efficacy and selectivity of targeting REST alone or in combination as a therapeutic strategy to combat high-REST GBM.
MeSH term(s)	Humans ; Transcription Factors ; Glioblastoma/drug therapy ; Gene Expression Regulation ; Brain ; Aggression
Chemical Substances	Transcription Factors
Language	English
Publishing date	2024-04-12
Publishing country	England
Document type	Journal Article
ZDB-ID	2133020-7
ISSN	1741-7007 ; 1741-7007
ISSN (online)	1741-7007
ISSN	1741-7007
DOI	10.1186/s12915-024-01879-0
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Article ; Online: Tracking Inhibition of Human Small C-Terminal Domain Phosphatase 1 Using 193 nm Ultraviolet Photodissociation Mass Spectrometry.

Escobar, Edwin E / Yang, Wanjie / Lanzillotti, Michael B / Juetten, Kyle J / Shields, Samuel / Siegel, Dionicio / Zhang, Y Jessie / Brodbelt, Jennifer S

Journal of the American Society for Mass Spectrometry

2024

Abstract: Working in tandem with kinases via a dynamic interplay of phosphorylation and dephosphorylation of proteins, phosphatases regulate many cellular processes and thus represent compelling therapeutic targets. Here we leverage ultraviolet photodissociation ... ...

Abstract	Working in tandem with kinases via a dynamic interplay of phosphorylation and dephosphorylation of proteins, phosphatases regulate many cellular processes and thus represent compelling therapeutic targets. Here we leverage ultraviolet photodissociation to shed light on the binding characteristics of two covalent phosphatase inhibitors, T65 and rabeprazole, and their respective interactions with the human small C-terminal domain phosphatase 1 (SCP1) and its single-point mutant C181A, in which a nonreactive alanine replaces one key reactive cysteine. Top-down MS/MS analysis is used to localize the binding of T65 and rabeprazole on the two proteins and estimate the relative reactivities of each cysteine residue.
Language	English
Publishing date	2024-04-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	1073671-2
ISSN	1879-1123 ; 1044-0305
ISSN (online)	1879-1123
ISSN	1044-0305
DOI	10.1021/jasms.4c00098
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Article ; Online: Vinaxanthone inhibits Semaphorin3A induced axonal growth cone collapse in embryonic neurons but fails to block its growth promoting effects on adult neurons.

Ivakhnitskaia, Evguenia / Chin, Matthew R / Siegel, Dionicio / Guaiquil, Victor H

Scientific reports

2021 Volume 11, Issue 1, Page(s) 13019

Abstract: Semaphorin3A is considered a classical repellent molecule for developing neurons and a potent inhibitor of regeneration after nervous system trauma. Vinaxanthone and other Sema3A inhibitors are currently being tested as possible therapeutics to promote ... ...

Abstract	Semaphorin3A is considered a classical repellent molecule for developing neurons and a potent inhibitor of regeneration after nervous system trauma. Vinaxanthone and other Sema3A inhibitors are currently being tested as possible therapeutics to promote nervous system regeneration from injury. Our previous study on Sema3A demonstrated a switch in Sema3A's function toward induction of nerve regeneration in adult murine corneas and in culture of adult peripheral neurons. The aim of the current study is to determine the direct effects of Vinaxanthone on the Sema3A induced adult neuronal growth. We first demonstrate that Vinaxanthone maintains its anti-Sema3A activity in embryonic dorsal root ganglia neurons by inhibiting Sema3A-induced growth cone collapse. However, at concentrations approximating its IC50 Vinaxanthone treatment does not significantly inhibit neurite formation of adult peripheral neurons induced by Sema3A treatment. Furthermore, Vinaxanthone has off target effects when used at concentrations above its IC50, and inhibits neurite growth of adult neurons treated with either Sema3A or NGF. Our results suggest that Vinaxanthone's pro-regenerative effects seen in multiple in vivo models of neuronal injury in adult animals need further investigation due to the pleiotropic effect of Sema3A on various non-neuronal cell types and the possible effect of Vinaxanthone on other neuroregenerative signals.
MeSH term(s)	Animals ; Ganglia, Spinal/drug effects ; Ganglia, Spinal/metabolism ; Growth Cones/drug effects ; Growth Cones/metabolism ; Mice ; Neurogenesis/drug effects ; Neurons/drug effects ; Neurons/metabolism ; Semaphorin-3A/metabolism ; Signal Transduction/drug effects ; Trigeminal Nerve/drug effects ; Trigeminal Nerve/metabolism ; Xanthones/pharmacology
Chemical Substances	Semaphorin-3A ; Xanthones ; vinaxanthone (133293-89-7)
Language	English
Publishing date	2021-06-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-92375-w
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Article ; Online: Directing Stem Cell Fate: The Synthetic Natural Product Connection.

Johnson, Trevor C / Siegel, Dionicio

Chemical reviews

2017 Volume 117, Issue 18, Page(s) 12052–12086

Abstract: Stem cells possess remarkable potential for the treatment of a broad array of diseases including many that lack therapeutic options. However, the use of cell-based products derived from stem cells as therapeutics has limitations including rejection, ... ...

Abstract	Stem cells possess remarkable potential for the treatment of a broad array of diseases including many that lack therapeutic options. However, the use of cell-based products derived from stem cells as therapeutics has limitations including rejection, sufficient availability, and lack of appropriate engraftment. Chemical control of stem cells provides potential solutions for overcoming many of the current limitations in cell-based therapeutics. The development of exogenous molecules to control stem cell self-renewal or differentiation has arrived at natural product-based agents as an important class of modulators. The ex vivo production of cryopreserved cellular products for use in tissue repair is a relatively new area of medicine in which the conventional hurdles to implementing chemicals to effect human health are changed. Translational challenges centered on chemistry, such as pharmacokinetics, are reduced. Importantly, in many cases the desired human tissues can be evaluated against new chemicals, and approaches to cellular regulation can be validated in the clinically applicable system. As a result linking new and existing laboratory syntheses of natural products with findings of the compounds' unique abilities to regulate stem cell fate provides opportunities for developing improved methods for tissue manufacture, accessing probe compounds, and generating new leads that yield manufactured cells with improved properties. This review provides a summary of natural products that have shown promise in controlling stem cell fate and which have also been fully synthesized thereby providing chemistry platforms for further development.
MeSH term(s)	Biological Products/chemical synthesis ; Biological Products/chemistry ; Biological Products/pharmacology ; Humans ; Molecular Conformation ; Stem Cells/drug effects ; Stem Cells/metabolism
Chemical Substances	Biological Products
Language	English
Publishing date	2017-09-27
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	207949-5
ISSN	1520-6890 ; 0009-2665
ISSN (online)	1520-6890
ISSN	0009-2665
DOI	10.1021/acs.chemrev.7b00015
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Article: Directing Stem Cell Fate: The Synthetic Natural Product Connection

Johnson, Trevor C / Siegel Dionicio

Chemical Reviews. 2017 Sept. 27, v. 117, no. 18

2017

Abstract	Stem cells possess remarkable potential for the treatment of a broad array of diseases including many that lack therapeutic options. However, the use of cell-based products derived from stem cells as therapeutics has limitations including rejection, sufficient availability, and lack of appropriate engraftment. Chemical control of stem cells provides potential solutions for overcoming many of the current limitations in cell-based therapeutics. The development of exogenous molecules to control stem cell self-renewal or differentiation has arrived at natural product-based agents as an important class of modulators. The ex vivo production of cryopreserved cellular products for use in tissue repair is a relatively new area of medicine in which the conventional hurdles to implementing chemicals to effect human health are changed. Translational challenges centered on chemistry, such as pharmacokinetics, are reduced. Importantly, in many cases the desired human tissues can be evaluated against new chemicals, and approaches to cellular regulation can be validated in the clinically applicable system. As a result linking new and existing laboratory syntheses of natural products with findings of the compoundsâ unique abilities to regulate stem cell fate provides opportunities for developing improved methods for tissue manufacture, accessing probe compounds, and generating new leads that yield manufactured cells with improved properties. This review provides a summary of natural products that have shown promise in controlling stem cell fate and which have also been fully synthesized thereby providing chemistry platforms for further development.
Keywords	chemical control ; chemistry ; cryopreservation ; human health ; humans ; manufacturing ; medicine ; pharmacokinetics ; stem cells ; therapeutics ; tissue repair ; tissues ; translation (genetics)
Language	English
Dates of publication	2017-0927
Size	p. 12052-12086.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	207949-5
ISSN	1520-6890 ; 0009-2665
ISSN (online)	1520-6890
ISSN	0009-2665
DOI	10.1021%2Facs.chemrev.7b00015
Database	NAL-Catalogue (AGRICOLA)

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Article: Synthesis of the 26-Membered Core of Thiopeptide Natural Products by Scalable Thiazole-Forming Reactions of Cysteine Derivatives and Nitriles

Johnson, Trevor C. / Christy, Mitchell P. / Siegel, Dionicio

Synthesis

2020 Volume 53, Issue 03, Page(s) 498–508

Abstract: The increased resistance of bacteria to clinical antibiotics is one of the major dilemmas facing human health and without solutions the problem will grow exponentially worse. Thiopeptide natural products have shown promising antibiotic activities and ... ...

Abstract	The increased resistance of bacteria to clinical antibiotics is one of the major dilemmas facing human health and without solutions the problem will grow exponentially worse. Thiopeptide natural products have shown promising antibiotic activities and provide an opportunity for the development of a new class of antibiotics. Attempts to directly translate these compounds into human medicine have been limited due to poor physiochemical properties. The synthesis of the core structure of the 26-membered class of thiopeptide natural products is reported using chemistry that enables the synthesis of large quantities of synthetic intermediates and the common core structure. The use of cysteine/nitrile condensation reactions followed by oxidation to generate thiazoles has been key in enabling large academic scale reactions that in many instances avoided chromatography further aiding in accessing large amounts of key synthetic intermediates.
Keywords	thiopeptide ; natural product ; thiazole ; scalable ; antibiotic ; pharmacophore
Language	English
Publishing date	2020-10-15
Publisher	Georg Thieme Verlag KG
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	2033062-5
ISSN	1437-210X ; 0039-7881
ISSN (online)	1437-210X
ISSN	0039-7881
DOI	10.1055/s-0040-1706478
Database	Thieme publisher's database

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Article: Synthetic Route Development for the Laboratory Preparation of Eupalinilide E

Johnson, Trevor C / Chin Matthew R / Siegel Dionicio

Journal of organic chemistry. 2017 May 05, v. 82, no. 9

2017

Abstract: Following the discovery that the guaianolide natural product eupalinilide E promotes the expansion of hematopoietic stem and progenitor cells; the development of a synthetic route to provide laboratory access to the natural product became a priority. ... ...

Abstract	Following the discovery that the guaianolide natural product eupalinilide E promotes the expansion of hematopoietic stem and progenitor cells; the development of a synthetic route to provide laboratory access to the natural product became a priority. Exploration of multiple synthetic routes yielded an approach that has permitted a scalable synthesis of the natural product. Two routes that failed to access eupalinilide E were triaged either as a result of providing an incorrect diastereomer or due to lack of synthetic efficiency. The successful strategy relied on late-stage allylic oxidations at two separate positions of the molecule, which significantly increased the breadth of reactions that could be used to this point. Subsequent to CâH bond oxidation, adaptations of existing chemical transformations were required to permit chemoselective reduction and oxidation reactions. These transformations included a modified Luche reduction and a selective homoallylic alcohol epoxidation.
Keywords	alcohols ; chemical bonding ; chemoselectivity ; diastereomers ; epoxidation reactions ; organic chemistry ; oxidation ; stem cells
Language	English
Dates of publication	2017-0505
Size	p. 4640-4653.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	123490-0
ISSN	1520-6904 ; 0022-3263
ISSN (online)	1520-6904
ISSN	0022-3263
DOI	10.1021%2Facs.joc.7b00266
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Article ; Online: Complanadine A, a selective agonist for the Mas-related G protein-coupled receptor X2.

Johnson, Trevor / Siegel, Dionicio

Bioorganic & medicinal chemistry letters

2014 Volume 24, Issue 15, Page(s) 3512–3515

Abstract: The first biological target for the natural product complanadine A has been determined. The pseudosymmetric alkaloid functions as a selective agonist for the Mas-related G protein-coupled receptor X2 (MrgprX2), a G protein-coupled receptor that is highly ...

Abstract	The first biological target for the natural product complanadine A has been determined. The pseudosymmetric alkaloid functions as a selective agonist for the Mas-related G protein-coupled receptor X2 (MrgprX2), a G protein-coupled receptor that is highly expressed in neurons. Given the potential of MrgprX2 to function as a modulator of pain, complanadine A represents a new chemical probe to selectively interrogate the physiological function of MrgprX2 as well as a potential lead for the development of antihyperalgesics for the treatment of persistent pain. While complanadine A possess agonistic activity the related natural product lycodine, representing half of complanadine A, lacks activity providing a cursory description of the structural requirements for agonistic activity.
MeSH term(s)	Dose-Response Relationship, Drug ; Heterocyclic Compounds, 4 or More Rings/chemical synthesis ; Heterocyclic Compounds, 4 or More Rings/chemistry ; Heterocyclic Compounds, 4 or More Rings/pharmacology ; Humans ; Molecular Structure ; Nerve Tissue Proteins/agonists ; Receptors, G-Protein-Coupled/agonists ; Receptors, Neuropeptide/agonists ; Structure-Activity Relationship
Chemical Substances	Heterocyclic Compounds, 4 or More Rings ; MRGPRX2 protein, human ; Nerve Tissue Proteins ; Receptors, G-Protein-Coupled ; Receptors, Neuropeptide ; complanadine A
Language	English
Publishing date	2014-08-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2014.05.060
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Article ; Online: Synthetic Route Development for the Laboratory Preparation of Eupalinilide E.

Johnson, Trevor C / Chin, Matthew R / Siegel, Dionicio

The Journal of organic chemistry

2017 Volume 82, Issue 9, Page(s) 4640–4653

Abstract	Following the discovery that the guaianolide natural product eupalinilide E promotes the expansion of hematopoietic stem and progenitor cells; the development of a synthetic route to provide laboratory access to the natural product became a priority. Exploration of multiple synthetic routes yielded an approach that has permitted a scalable synthesis of the natural product. Two routes that failed to access eupalinilide E were triaged either as a result of providing an incorrect diastereomer or due to lack of synthetic efficiency. The successful strategy relied on late-stage allylic oxidations at two separate positions of the molecule, which significantly increased the breadth of reactions that could be used to this point. Subsequent to C-H bond oxidation, adaptations of existing chemical transformations were required to permit chemoselective reduction and oxidation reactions. These transformations included a modified Luche reduction and a selective homoallylic alcohol epoxidation.
MeSH term(s)	Laboratories ; Oxidation-Reduction ; Sesquiterpenes/chemical synthesis
Chemical Substances	Sesquiterpenes ; eupalinilide E
Language	English
Publishing date	2017--05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	123490-0
ISSN	1520-6904 ; 0022-3263
ISSN (online)	1520-6904
ISSN	0022-3263
DOI	10.1021/acs.joc.7b00266
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