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1.
ACS Environ Au ; 4(2): 126, 2024 Mar 20.
Article in English | MEDLINE | ID: mdl-38525019

ABSTRACT

[This corrects the article DOI: 10.1021/acsenvironau.3c00023.].

2.
Environ Sci Technol ; 57(49): 20813-20821, 2023 Dec 12.
Article in English | MEDLINE | ID: mdl-38032317

ABSTRACT

The photochemical degradation pathways of 6PPD-quinone (6PPDQ, 6PPD-Q), a toxic transformation product of the tire antiozonant 6PPD, were determined under simulated sunlight conditions typical of high-latitude surface waters. Direct photochemical degradation resulted in 6PPDQ half-lives ranging from 17.5 h at 20 °C to no observable degradation over 48 h at 4 °C. Sensitization of excited triplet-state pathways using Cs+ and Ar purging demonstrated that 6PPDQ does not decompose significantly from a triplet state relative to a singlet state. However, assessment of processes involving reactive oxygen species (ROS) quenchers and sensitizers indicated that singlet oxygen and hydroxyl radical do significantly contribute to the degradation of 6PPDQ. Investigation of these processes in natural lake waters indicated no difference in attenuation rates for direct photochemical processes at 20 °C. This suggests that direct photochemical degradation will dominate in warm waters, while indirect photochemical pathways will dominate in cold waters, involving ROS mediated by chromophoric dissolved organic matter (CDOM). Overall, the aquatic photodegradation rate of 6PPDQ will be strongly influenced by the compounding effects of environmental factors such as light screening and temperature on both direct and indirect photochemical processes. Transformation products were identified via UHPLC-Orbitrap mass spectrometry, revealing four major processes: (1) oxidation and cleavage of the quinone ring in the presence of ROS, (2) dealkylation, (3) rearrangement, and (4) deamination. These data indicate that 6PPDQ can photodegrade in cool, sunlit waters under the appropriate conditions: t1/2 = 17.4 h tono observable decrease (direct); t1/2 = 5.2-11.2 h (indirect, CDOM).


Subject(s)
Benzoquinones , Dissolved Organic Matter , Lakes , Phenylenediamines , Photolysis , Reactive Oxygen Species , Water Pollutants, Chemical , Benzoquinones/chemistry , Benzoquinones/radiation effects , Dissolved Organic Matter/chemistry , Reactive Oxygen Species/chemistry , Reactive Oxygen Species/metabolism , Water Pollutants, Chemical/analysis , Water Pollutants, Chemical/radiation effects , Phenylenediamines/chemistry , Phenylenediamines/radiation effects , Lakes/analysis , Lakes/chemistry
3.
Environ Sci Technol ; 56(4): 2421-2431, 2022 02 15.
Article in English | MEDLINE | ID: mdl-35099932

ABSTRACT

Tire road wear particles (TRWPs) are one of the largest sources of microplastics to the urban environment with recent concerns as they also provide a pathway for additive chemicals to leach into the environment. Stormwater is a major source of TRWPs and associated additives to urban surface water, with additives including the antioxidant derivative N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-quinone) demonstrating links to aquatic toxicity at environmentally relevant concentrations. The present study used complementary analysis methods to quantify both TRWPs and a suite of known tire additive chemicals (including 6PPD-quinone) to an urban tributary in Australia during severe storm events. Concentrations of additives increased more than 40 times during storms, with a maximum concentration of 2760 ng/L for ∑15additives, 88 ng/L for 6PPD-quinone, and a similar profile observed in each storm. TRWPs were detected during storm peaks with a maximum concentration between 6.4 and 18 mg/L, and concentrations of TRWPs and all additives were highly correlated. Contaminant mass loads to this catchment were estimated as up to 100 g/storm for ∑15additives, 3 g/storm for 6PPD-quinone, and between 252 and 730 kg of TRWPs/storm. While 6PPD-quinone concentrations in this catchment were lower than previous studies, elevated concentrations post storm suggest prolonged aquatic exposure.


Subject(s)
Plastics , Water , Australia , Environmental Monitoring , Quinones
4.
Biosci Rep ; 42(2)2022 02 25.
Article in English | MEDLINE | ID: mdl-35088066

ABSTRACT

Proteasome-addicted neoplastic malignancies present a considerable refractory and relapsed phenotype with patients exhibiting drug resistance and high mortality rates. To counter this global problem, novel proteasome-based therapies are being developed. In the current study, we extensively characterize TIR-199, a syrbactin-class proteasome inhibitor derived from a plant virulence factor of bacterium Pseudomonas syringae pv syringae. We report that TIR-199 is a potent constitutive and immunoproteasome inhibitor, capable of inducing cell death in multiple myeloma, triple-negative breast cancer, (TNBC) and non-small cell lung cancer lines. TIR-199 also effectively inhibits the proteasome in primary myeloma cells of patients, and bypasses the PSMB5 A49T+A50V bortezomib-resistant mutant. TIR-199 treatment leads to accumulation of canonical proteasome substrates in cells, it is specific, and does not inhibit 50 other enzymes tested in vitro. The drug exhibits synergistic cytotoxicity in combination with proteasome-activating kinase DYRK2 inhibitor LDN192960. Furthermore, low-doses of TIR-199 exhibits in vivo activity by delaying myeloma-mediated bone degeneration in a mouse xenograft model. Together, our data indicates that proteasome inhibitor TIR-199 could indeed be a promising next-generation drug within the repertoire of proteasome-based therapeutics.


Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Multiple Myeloma , Amides , Animals , Antineoplastic Agents/pharmacology , Azoles , Carcinoma, Non-Small-Cell Lung/drug therapy , Cell Line, Tumor , Drug Resistance, Neoplasm , Humans , Lung Neoplasms/drug therapy , Mice , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Proteasome Endopeptidase Complex/genetics , Proteasome Endopeptidase Complex/metabolism , Proteasome Inhibitors/pharmacology
5.
J Org Chem ; 86(12): 8036-8040, 2021 06 18.
Article in English | MEDLINE | ID: mdl-34078070

ABSTRACT

Cannabichromene (CBC) is unusual among cannabinoids in having been described as both a racemic and a scalemic compound from natural Cannabis sources. Several explanations are available for this circumstance, including facile racemization. Cannabichromene was resolved chromatographically, and the enantiomer matching CBC from local Cannabis was identified. To preclude racemization, CBC was converted to cannabicyclol for further stereochemical analysis. This permitted the (R) absolute stereochemistry to be assigned to natural CBC based on chiroptical data for related natural products and the absolute configuration of a cannabicyclol analog determined by X-ray crystallography. The racemization of CBC was found to be rather slow in the laboratory, but handling practices for natural cannabis products can be inferred to promote the process.


Subject(s)
Cannabinoids , Cannabis
6.
J Med Chem ; 63(21): 12131-12136, 2020 11 12.
Article in English | MEDLINE | ID: mdl-32531156

ABSTRACT

Cannabinoids have surely been one of the most widely self-administered drugs other than caffeine. The U.S. FDA recently approved one cannabinoid-based drug whose active pharmaceutical ingredient (API) is cannabidiol (CBD). The long history of individual use of cannabis for a wide range of conditions has sparked great interest in other uses of CBD, in ethical drugs and botanical supplements as well as in foods and nonprescription wellness products. CBD may be sourced from cannabis plants but can also be prepared synthetically, the topic of this review.


Subject(s)
Cannabidiol/analogs & derivatives , Cannabidiol/chemical synthesis , Cannabidiol/metabolism , Cannabinoids/chemistry , Cannabis/chemistry , Cannabis/metabolism , Plant Roots/chemistry , Plant Roots/metabolism , Stereoisomerism , Terpenes/chemistry , Yeasts/chemistry , Yeasts/metabolism
7.
Leuk Res ; 88: 106271, 2020 01.
Article in English | MEDLINE | ID: mdl-31778912

ABSTRACT

Multiple myeloma (MM) and mantle cell lymphoma (MCL) are blood cancers that respond to proteasome inhibitors. Three FDA-approved drugs that block the proteasome are currently on the market, bortezomib, carfilzomib, and ixazomib. While these proteasome inhibitors have demonstrated clinical efficacy against refractory and relapsed MM and MCL, they are also associated with considerable adverse effects including peripheral neuropathy and cardiotoxicity, and tumor cells often acquire drug resistance. TIR-199 belongs to the syrbactin class, which constitutes a novel family of irreversible proteasome inhibitors. In this study, we compare TIR-199 head-to-head with three FDA-approved proteasome inhibitors. We demonstrate that TIR-199 selectively inhibits to varying degrees the sub-catalytic proteasomal activities (C-L/ß1, T-L/ß2, and CT-L/ß5) in three actively dividing MM cell lines, with Ki50 (CT-L/ß5) values of 14.61 ±â€¯2.68 nM (ARD), 54.59 ±â€¯10.4 nM (U266), and 26.8 ±â€¯5.2 nM (MM.1R). In most instances, this range was comparable with the activity of ixazomib. However, TIR-199 was more effective than bortezomib, carfilzomib, and ixazomib in killing bortezomib-resistant MM and MCL cell lines, as judged by a low resistance index (RI) between 1.7 and 2.2, which implies that TIR-199 indiscriminately inhibits both bortezomib-sensitive and bortezomib-resistant MM and MCL cells at similar concentrations. Importantly, TIR-199 reduced the tumor burden in a MM mouse model (p < 0.01) confirming its potency in vivo. Given the fact that there is still no cure for MM, the further development of TIR-199 or similar molecules that belong to the syrbactin class of proteasome inhibitors is warranted.


Subject(s)
Amides/pharmacology , Azoles/pharmacology , Bortezomib/therapeutic use , Cell Proliferation/drug effects , Drug Resistance, Neoplasm/drug effects , Multiple Myeloma/pathology , Proteasome Inhibitors/pharmacology , Tumor Burden/drug effects , Amides/administration & dosage , Amides/chemistry , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Azoles/administration & dosage , Azoles/chemistry , Bortezomib/administration & dosage , Cell Line, Tumor , Drug Synergism , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, SCID , Mice, Transgenic , Multiple Myeloma/drug therapy , Peptides, Cyclic/chemistry , Proteasome Inhibitors/administration & dosage , Proteasome Inhibitors/chemistry , Xenograft Model Antitumor Assays
8.
Bioorg Med Chem Lett ; 29(19): 126591, 2019 10 01.
Article in English | MEDLINE | ID: mdl-31471166

ABSTRACT

The firefly luciferin analog thioluciferin (S-luc) was synthesised as a key element of bioluminescent reporters for oxidation state and thiol/disulfide equilibria. It shows blue-shifts in absorption and fluorescence compared to luciferin, and is a modest luciferase substrate. These features are attributed to a π-system that is less conjugated than luciferin.


Subject(s)
Disulfides/chemistry , Firefly Luciferin/chemistry , Luciferases, Firefly/metabolism , Luminescence , Sulfhydryl Compounds/chemistry , Animals , Luminescent Measurements
9.
Anticancer Res ; 38(10): 5607-5613, 2018 Oct.
Article in English | MEDLINE | ID: mdl-30275178

ABSTRACT

BACKGROUND/AIM: Proteasome inhibition is a validated therapeutic strategy for the treatment of refractory and relapsed multiple myeloma (MM) and mantle cell lymphoma. We previously showed that thiasyrbactins (NAM compounds) are inhibitors with an affinity for the trypsin-like (T-L, ß2) site of the constitutive proteasome, and more profoundly for the T-L site of the immunoproteasome. MATERIALS AND METHODS: In this study, the biological activity of three NAM compounds was evaluated using four MM cell lines (ARD, U266, MM1R, and MM1S). We assessed the effect of (NAM-93, NAM-95, and NAM-105 on cell viability, as well as cell-based proteasomal activities, and determined the EC50 and Ki50 values, respectively. RESULTS: MM cells were most sensitive to NAM-93 with EC50 values <0.75 µM after 48 h of treatment. NAM-105 had a similar profile in most of the MM cells with EC50 values ranging between 0.42 and 3.02 µM. The level of inhibition of the proteasome T-L sub-catalytic activity in actively-growing MM cells was similar for NAM-93 and NAM-105. However, in each cell line, NAM-93 was more effective than NAM-105 at inhibiting overall trypsin-like sub-catalytic activity while NAM-105 was typically more effective at inhibiting overall chymotrypsin-like (CT-L, ß5) sub-catalytic activity. CONCLUSION: These results show for the first time the proteasome-targeted biological activity of thiasyrbactins in MM tumor cells.


Subject(s)
Apoptosis/drug effects , Cell Proliferation/drug effects , Multiple Myeloma/pathology , Peptides/pharmacology , Proteasome Endopeptidase Complex/chemistry , Proteasome Inhibitors/pharmacology , Antimicrobial Cationic Peptides , Dose-Response Relationship, Drug , Humans , Multiple Myeloma/drug therapy , Multiple Myeloma/enzymology , Tumor Cells, Cultured
10.
Bioorg Med Chem ; 26(2): 401-412, 2018 01 15.
Article in English | MEDLINE | ID: mdl-29269255

ABSTRACT

A family of macrodilactam natural products, the syrbactins, are known proteasome inhibitors. A small group of syrbactin analogs was prepared with a sulfur-for-carbon substitution to enhance synthetic accessibility and facilitate modulation of their solubility. Two of these compounds surprisingly proved to be inhibitors of the trypsin-like catalytic site, including of the immunoproteasome. Their bound and free conformations suggest special properties of the thiasyrbactin ring are responsible for this unusual preference, which may be exploited to develop drug-like immunoproteasome inhibitors. These compounds show greater selectivity than earlier compounds used to infer phenotypes of immunoproteasome inhibition, like ONX-0914.


Subject(s)
Biological Products/pharmacology , Lactams/pharmacology , Proteasome Endopeptidase Complex/metabolism , Proteasome Inhibitors/pharmacology , Biological Products/chemical synthesis , Biological Products/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Lactams/chemical synthesis , Lactams/chemistry , Molecular Structure , Proteasome Inhibitors/chemical synthesis , Proteasome Inhibitors/chemistry , Structure-Activity Relationship
11.
ChemistryOpen ; 6(6): 697-700, 2017 12.
Article in English | MEDLINE | ID: mdl-29226056

ABSTRACT

A 5,5-d2 -luciferin was prepared to measure isotope effects on reactions of two intermediates in firefly bioluminescence: emission by oxyluciferin and elimination of a putative luciferyl adenylate hydroperoxide to dehydroluciferin. A negligible isotope effect on bioluminescence provides further support for the belief that the emitting species is the keto-phenolate of oxyluciferin and rules out its excited-state tautomerization, one potential contribution to a bioluminescence quantum yield less than unity. A small isotope effect on dehydroluciferin formation supports a single-electron-transfer mechanism for reaction of the luciferyl adenylate enolate with oxygen to form the hydroperoxide or dehydroluciferin. Partitioning between the dioxetanone intermediate (en route to oxyluciferin) and dehydroluciferin is determined, not by the fate of the hydroperoxide, but by that of the radical formed from luciferyl adenylate, and the kinetic isotope effect (KIE) reflects H-atom abstraction by superoxide.

12.
Org Biomol Chem ; 14(38): 9159, 2016 09 26.
Article in English | MEDLINE | ID: mdl-27714303

ABSTRACT

Correction for 'Total synthesis of fellutamides, lipopeptide proteasome inhibitors. More sustainable peptide bond formation' by Michael C. Pirrung, et al., Org. Biomol. Chem., 2016, 14, 8367-8375.

13.
Org Biomol Chem ; 14(35): 8367-75, 2016 Sep 21.
Article in English | MEDLINE | ID: mdl-27533920

ABSTRACT

Solution-phase syntheses of three bioactive natural products of mixed polypeptide-polyketide biogenesis, fellutamides A, B, and C, have been achieved. Three peptide bonds are generated without the use of coupling reagents in each synthesis of the fellutamides, which act against proteasomes.


Subject(s)
Chemistry Techniques, Synthetic/methods , Lipopeptides/chemical synthesis , Proteasome Inhibitors/chemical synthesis , Biological Products/chemistry , Molecular Structure , Oligopeptides/chemical synthesis , Solutions/chemistry
14.
J Biol Chem ; 291(16): 8350-62, 2016 Apr 15.
Article in English | MEDLINE | ID: mdl-26907687

ABSTRACT

Multiple myeloma is an aggressive hematopoietic cancer of plasma cells. The recent emergence of three effective FDA-approved proteasome-inhibiting drugs, bortezomib (Velcade®), carfilzomib (Kyprolis®), and ixazomib (Ninlaro®), confirms that proteasome inhibitors are therapeutically useful against neoplastic disease, in particular refractory multiple myeloma and mantle cell lymphoma. This study describes the synthesis, computational affinity assessment, and preclinical evaluation of TIR-199, a natural product-derived syrbactin structural analog. Molecular modeling and simulation suggested that TIR-199 covalently binds each of the three catalytic subunits (ß1, ß2, and ß5) and revealed key interaction sites. In vitro and cell culture-based proteasome activity measurements confirmed that TIR-199 inhibits the proteasome in a dose-dependent manner and induces tumor cell death in multiple myeloma and neuroblastoma cells as well as other cancer types in the NCI-60 cell panel. It is particularly effective against kidney tumor cell lines, with >250-fold higher anti-tumor activities than observed with the natural product syringolin A. In vivo studies in mice revealed a maximum tolerated dose of TIR-199 at 25 mg/kg. The anti-tumor activity of TIR-199 was confirmed in hollow fiber assays in mice. Adverse drug reaction screens in a kidney panel revealed no off-targets of concern. This is the first study to examine the efficacy of a syrbactin in animals. Taken together, the results suggest that TIR-199 is a potent new proteasome inhibitor with promise for further development into a clinical drug for the treatment of multiple myeloma and other forms of cancer.


Subject(s)
Multiple Myeloma/drug therapy , Proteasome Endopeptidase Complex/metabolism , Proteasome Inhibitors/pharmacology , Animals , Cattle , Cell Line, Tumor , HEK293 Cells , Humans , Mice , Mice, Nude , Multiple Myeloma/enzymology , Multiple Myeloma/pathology , Proteasome Inhibitors/chemistry , Xenograft Model Antitumor Assays
15.
European J Org Chem ; 2016(34): 5633-5636, 2016 Dec.
Article in English | MEDLINE | ID: mdl-28111523

ABSTRACT

This work develops serine peptide assembly (SPA), which complements and contrasts with classic native chemical ligation (NCL). Advances in reagent-less peptide bond formation have been applied to serine (and serine models) and a range of C-terminal amino acids, including bulky residues that are not amenable to NCL. The particular appeal of SPA is preparative-scale segment condensations with zero racemization risk and favourable process mass intensity (PMI). Mechanistic studies support a previously proposed reaction pathway via an initial trans-esterification step. An understanding of the factors favouring this pathway relies on hard-soft acid-base theory, where mildly activated esters with the largest carbonyl positive charge are most reactive with hydroxy amines. Novel C-terminal activators have been discovered that enhance reactivity and give harmless by-products.

16.
Bioorg Med Chem Lett ; 24(20): 4881-3, 2014 Oct 15.
Article in English | MEDLINE | ID: mdl-25239851

ABSTRACT

A new synthesis route to firefly luciferin analogs was developed via the synthesis of 5',7'-difluoroluciferin. As a luciferase substrate, it produces maximal bioluminescence at a much lower pH than is optimal for native luciferin, and at lower pH it gives much more of the red-shifted emission that is characteristic of the phenolate. These features are attributed to the enhanced acidity of the o,o-difluorophenol.


Subject(s)
Firefly Luciferin/analogs & derivatives , Luminescence , Firefly Luciferin/chemistry , Hydrogen-Ion Concentration , Luminescent Measurements , Molecular Structure
17.
Biochem Mol Biol Educ ; 42(2): 106-13, 2014.
Article in English | MEDLINE | ID: mdl-24344052

ABSTRACT

This review provides a perspective on the initial development of microarray technologies by two independent groups in the late 1980s.


Subject(s)
Microarray Analysis/history , Microarray Analysis/methods , History, 20th Century , History, 21st Century , Humans
18.
Tetrahedron Lett ; 54(29)2013 Jul 17.
Article in English | MEDLINE | ID: mdl-24187389

ABSTRACT

Allylic ethers of kojic acid undergo Claisen rearrangement with catalysis by zinc triflate to give the corresponding C-allylated kojic acids in moderate to good yields.

19.
PLoS One ; 8(6): e65695, 2013.
Article in English | MEDLINE | ID: mdl-23755268

ABSTRACT

Verrucosidin (VCD) belongs to a group of fungal metabolites that were identified in screening programs to detect molecules that preferentially kill cancer cells under glucose-deprived conditions. Its mode of action was proposed to involve inhibition of increased GRP78 (glucose regulated protein 78) expression during hypoglycemia. Because GRP78 plays an important role in tumorigenesis, inhibitors such as VCD might harbor cancer therapeutic potential. We therefore sought to characterize VCD's anticancer activity in vitro. Triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-468 were treated with VCD under different conditions known to trigger increased expression of GRP78, and a variety of cellular processes were analyzed. We show that VCD was highly cytotoxic only under hypoglycemic conditions, but not in the presence of normal glucose levels, and VCD blocked GRP78 expression only when glycolysis was impaired (due to hypoglycemia or the presence of the glycolysis inhibitor 2-deoxyglucose), but not when GRP78 was induced by other means (hypoxia, thapsigargin, tunicamycin). However, VCD's strictly hypoglycemia-specific toxicity was not due to the inhibition of GRP78. Rather, VCD blocked mitochondrial energy production via inhibition of complex I of the electron transport chain. As a result, cellular ATP levels were quickly depleted under hypoglycemic conditions, and common cellular functions, including general protein synthesis, deteriorated and resulted in cell death. Altogether, our study identifies mitochondria as the primary target of VCD. The possibility that other purported GRP78 inhibitors (arctigenin, biguanides, deoxyverrucosidin, efrapeptin, JBIR, piericidin, prunustatin, pyrvinium, rottlerin, valinomycin, versipelostatin) might act in a similar GRP78-independent fashion will be discussed.


Subject(s)
Electron Transport Chain Complex Proteins/antagonists & inhibitors , Electron Transport Chain Complex Proteins/metabolism , Electron Transport/drug effects , Heat-Shock Proteins/antagonists & inhibitors , Heat-Shock Proteins/metabolism , Pyrones/pharmacology , Adenosine Triphosphate/metabolism , Biguanides/pharmacology , Cell Line, Tumor , Endoplasmic Reticulum Chaperone BiP , Furans/pharmacology , Humans , Immunoblotting , Lignans/pharmacology , Pyridines/pharmacology , Pyrvinium Compounds/pharmacology
20.
Mol Biosyst ; 8(3): 879-87, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22241083

ABSTRACT

Using a fluorescent NBD amino acid, new protease substrates were developed that are attractive because of the excellent chemical stability and long wavelength of excitation (480 nm) of the NBD fluorophore. The fluorescent peptides are synthesized by Fmoc solid-phase peptide synthesis. An example peptide was efficiently immobilized onto a microarray surface using click chemistry, and its proteolysis was monitored by fluorescence imaging. Excellent site specificity was achieved for the protease. Fluorescent peptides are also used to monitor the conjugation efficiency onto a surface using a standard microarray scanner.


Subject(s)
Amino Acids/chemistry , Fluorescent Dyes/chemistry , Peptides/chemistry , Protein Array Analysis/methods , Fluorescence , Glass , Proteolysis , Solid-Phase Synthesis Techniques
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