Biochemistry Commons^™

Regulation And Modulation Of Human Dna Polymerase Δ Activity And Function, Marietta Y W T Lee, Xiaoxiao Wang, Sufang Zhang, Zhongtao Zhang, Ernest Y C Lee

NYMC Faculty Publications

This review focuses on the regulation and modulation of human DNA polymerase δ (Pol δ). The emphasis is on the mechanisms that regulate the activity and properties of Pol δ in DNA repair and replication. The areas covered are the degradation of the p12 subunit of Pol δ, which converts it from a heterotetramer (Pol δ4) to a heterotrimer (Pol δ3), in response to DNA damage and also during the cell cycle. The biochemical mechanisms that lead to degradation of p12 are reviewed, as well as the properties of Pol δ4 and Pol δ3 that provide insights into their functions …

Cellular And Molecular Targets Of Menthol Actions, Murat Oz, Eslam El Nebrisi, Keun-Hang Susan Yang, Frank Christopher Howarth, Lina T. Al Kury

Mathematics, Physics, and Computer Science Faculty Articles and Research

Menthol belongs to monoterpene class of a structurally diverse group of phytochemicals found in plant-derived essential oils. Menthol is widely used in pharmaceuticals, confectionary, oral hygiene products, pesticides, cosmetics, and as a flavoring agent. In addition, menthol is known to have antioxidant, anti-inflammatory, and analgesic effects. Recently, there has been renewed awareness in comprehending the biological and pharmacological effects of menthol. TRP channels have been demonstrated to mediate the cooling actions ofmenthol. There has been new evidence demonstrating thatmenthol can significantly influence the functional characteristics of a number of different kinds of ligand and voltage-gated ion channels, indicating that at …

B7h6: A Cancer Biomarker For The Development Of Novel Immunotherapy Approaches, Mariana Phillips

Seton Hall University Dissertations and Theses (ETDs)

Cancer-based immunotherapy has led the evolution of biologics that can stimulate immune responses towards tumor eradication. The synthesis of small to intermediate size molecules with the targeting and effector functions of mAb may represent a novel class of immunotherapeutics that may overcome the limitations of their biological counterparts.Towards this objective, B7H6 has been identified as a protein ligand localized on the cell surface of transformed tumor cells. B7H6 binds specifically to the activating receptor NKp30, constitutively expressed on all resting and active NK cells. Upon ligand:receptor binding, B7H6 triggers NK cell activation and release of chemokines and pro-inflammatory cytokines such …

Gene 33/Mig6 Regulates Apoptosis And The Dna Damage Response Through Independent Mechanisms, Cen Li, Soyoung Park, Leonard M. Eisenberg, Hong Zhao, Zbigniew Darzynkiewicz, Dazhong Xu

NYMC Faculty Posters

Gene 33 (Mig6, ERRFI1) is an inducible adaptor/scaffold protein whose expression can be induced by both stress and mitogenic signals. It contains multiple domains for protein-protein interaction and is involved in a broad spectrum of cellular functions. Gene 33 promotes apoptosis in a cell type-dependent manner. A recent study has linked Gene 33 to the DNA damage response (DDR) induced by hexavalent chromium [Cr(VI)]. Here we show that Gene 33 induces apoptosis via both c-Abl/p73 and EGFR/AKT-dependent pathways in lung epithelial and lung carcinoma cells. Ectopic expression of Gene 33 also triggers DDR in an ATM-dependent fashion and through pathways …

Role Of Inflammation In 20-Hete Regulation Of Ischemia-Induced Angiogenesis, Elizabeth Berry, Rachel John, Samantha Tang, Austin M. Guo

NYMC Faculty Posters

Objective: 20-Hydroxyeicosatetraenoic acid (20-HETE), an important bioactive lipid metabolite, has recently been identified to be a novel contributor of angiogenesis secondary to ischemia. Moreover, an inflammatory response is required for the initiation of ischemic angiogenesis, in response to ischemic tissue injury. The goal of this study is to investigate the role of inflammation in 20-HETE regulation of ischemia-induced angiogenesis.

Methods: We first established a mouse hind limb ischemia model for immunocompetent Balb/C mice and immunodeficient NOD-SCID mice by femoral artery ligation. Groups of Balb/C and NOD-SCID mice were administered a 20-HETE synthesis inhibitor, DDMS, or saline as a solvent control. …

Docking Studies Of Isoform-Selectivity Of Phosphatidylinositol 3-Kinase (Pi3k) Inhibitors, Kaitlin Goettsch

UNO Student Research and Creative Activity Fair

Phosphatidylinositol 3-kinases (PI3Ks) and their related pathways are reputed targets for drug-based anticancer therapies. Mutations in PI3K genes, expression, and pathways are frequent among multiple cancer types. Four isoforms of PI3Ks exist: α, β, γ, & δ and studies have identified several ligands for each isoform which are capable of serving as inhibitory therapeutic compounds. However, the biochemical efficacy of these molecules varies and the isoform selectivity is not well understood. In this study, we applied in silico docking methods and free energy calculation methods to estimate the binding of reported PI3K ligands against 5 PI3K structures: PI3Kα (PBD ID: …

Pdip46 Is Involved In Replication Timing Control, Hsiao H. Chao, Hong Zhao, Sufang Zhang

NYMC Faculty Posters

No abstract provided.

Editing Of Misaminoacylated Trna Controls The Sensitivity Of Amino Acid Stress Responses In Saccharomyces Cerevisiae, Kyle Mohler, Rebecca Mann, Tammy J. Bullwinkle, Kyle W. Hopkins, Lin Hwang, Noah M. Reynolds, Brandon Gassaway, Hans-Rudolph Aerni, Jesse Rinehart, Michael Polymenis, Kym F. Faull, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Amino acid starvation activates the protein kinase Gcn2p, leading to changes in gene expression and translation. Gcn2p is activated by deacylated tRNA, which accumulates when tRNA aminoacylation is limited by lack of substrates or inhibition of synthesis. Pairing of amino acids and deacylated tRNAs is catalyzed by aminoacyl-tRNA synthetases, which use quality control pathways to maintain substrate specificity. Phenylalanyl-tRNA synthetase (PheRS) maintains specificity via an editing pathway that targets non-cognate Tyr-tRNA^Phe. While the primary role of aaRS editing is to prevent misaminoacylation, we demonstrate editing of misaminoacylated tRNA is also required for detection of amino acid starvation by …

Quality Control By Isoleucyl-Trna Synthetase Of Bacillus Subtilis Is Required For Efficient Sporulation, Elizabeth Kermgard, Zhou Yang, Annika-Marisa Michel, Rachel Simari, Jacqueline Wong, Michael Ibba, Beth A. Lazazzera

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Isoleucyl-tRNA synthetase (IleRS) is an aminoacyl-tRNA synthetase whose essential function is to aminoacylate tRNA^Ile with isoleucine. Like some other aminoacyl-tRNA synthetases, IleRS can mischarge tRNA^Ile and correct this misacylation through a separate post-transfer editing function. To explore the biological significance of this editing function, we created a ileS(T233P) mutant of Bacillus subtilis that allows tRNA^Ile mischarging while retaining wild-type Ile-tRNA^Ile synthesis activity. As seen in other species defective for aminoacylation quality control, the growth rate of the ileS(T233P) strain was not significantly different from wild-type. When the ileS(T233P) strain was assessed for its ability to promote …

Ms-Read: Quantitative Measurement Of Amino Acid Incorporation, Kyle Mohler, Hans-Rudolph Aerni, Brandon Gassaway, Jiqiang Ling, Michael Ibba, Jesse Rinehart

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Ribosomal protein synthesis results in the genetically programmed incorporation of amino acids into a growing polypeptide chain. Faithful amino acid incorporation that accurately reflects the genetic code is critical to the structure and function of proteins as well as overall proteome integrity. Errors in protein synthesis are generally detrimental to cellular processes yet emerging evidence suggest that proteome diversity generated through mistranslation may be beneficial under certain conditions. Cumulative translational error rates have been determined at the organismal level, however codon specific error rates and the spectrum of misincorporation errors from system to system remain largely unexplored. In particular, until …

Maysin And Its Flavonoid Derivative From Centipedegrass Attenuates Amyloid Plaques By Inducting Humoral Immune Response With Th2 Skewed Cytokine Response In The Tg (Appswe, Ps1de9) Alzheimer's Mouse Model, Yuno Song, Hong-Duck Kim, Min-Kwon Lee, Il-Hwa Hong, Chung-Kil Won, Seung Sik Lee, Jae-Hyeon Cho

NYMC Faculty Publications

Alzheimer's disease (AD) is a slow, progressive neurodegenerative disease and the most common type of dementia in the elderly. The etiology of AD and its underlying mechanism are still not clear. In a previous study, we found that an ethyl acetate extract of Centipedegrass (CG) (i.e., EA-CG) contained 4 types of Maysin derivatives, including Luteolin, Isoorientin, Rhamnosylisoorientin, and Derhamnosylmaysin, and showed protective effects against Amyloid beta (Aβ) by inhibiting oligomeric Aβ in cellular and in vitro models. Here, we examined the preventative effects of EA-CG treatment on the Aβ burden in the Tg (Mo/Hu APPswe PS1dE9) AD mouse model. We …

Myeloperoxidase-Mediated Protein Lysine Oxidation Generates 2- Aminoadipic Acid And Lysine Nitrile In Vivo, Hongqiao Lin, Bruce S. Levison, Jennifer A. Buffa, Ying Huang, Xiaoming Fu, Zeneng Wang, Valentin Gogonea, Joseph A. Didonato, Stanley L. Hazen

Chemistry Faculty Publications

Recent studies reveal 2-aminoadipic acid (2-AAA) is both elevated in subjects at risk for diabetes and mechanistically linked to glucose homeostasis. Prior studies also suggest enrichment of protein-bound 2-AAA as an oxidative post-translational modification of lysyl residues in tissues associated with degenerative diseases of aging. While in vitro studies suggest redox active transition metals or myeloperoxidase (MPO) generated hypochlorous acid (HOCl) may produce protein-bound 2-AAA, the mechanism(s) responsible for generation of 2- AAA during inflammatory diseases are unknown. In initial studies we observed that traditional acid- or basecatalyzed protein hydrolysis methods previously employed to measure tissue 2-AAA can artificially generate …

Toward Biochemical Conversion Of Lignocellulose On-Farm: Pretreatment And Hydrolysis Of Corn Stover In Situ, Alicia A. Modenbach, Sue E. Nokes, Michael D. Montross, Barbara L. Knutson

Biosystems and Agricultural Engineering Faculty Publications

High-solids lignocellulosic pretreatment using NaOH followed by high-solids enzymatic hydrolysis was evaluated for an on-farm biochemical conversion process. Increasing the solids loadings for these processes has the potential for increasing glucose concentrations and downstream ethanol production; however, sequential processing at high-solids loading similar to an on-farm cellulose conversion system has not been studied. This research quantified the effects of high-solids pretreatment with NaOH and subsequent high-solids enzymatic hydrolysis on cellulose conversion. As expected, conversion efficiency was reduced; however, the highest glucose concentration (40.2 g L^-1), and therefore the highest potential ethanol concentration, resulted from the high-solids combined pretreatment …

Synthesis Of Rhamnosylated Arginine Glycopeptides And Determination Of The Glycosidic Linkage In Bacterial Elongation Factor P, Siyao Wang, Leo Corcilius, Phillip B. Sharp, Andrei Rajkovic, Michael Ibba, Benjamin L. Parker, Richard J. Payne

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

A new class of N-linked protein glycosylation – arginine rhamnosylation – has recently been discovered as a critical modification for the function of bacterial elongation factor P (EF-P). Herein, we describe the synthesis of suitably protected α- and β-rhamnosylated arginine amino acid “cassettes” that can be directly installed into rhamnosylated peptides. Preparation of a proteolytic fragment of Pseudomonas aeruginosa EF-P bearing both α- and β-rhamnosylated arginine enabled the unequivocal determination of the native glycosidic linkage to be α through 2D NMR and nano-UHPLC-tandem mass spectrometry studies.

The Complex Evolutionary History Of Aminoacyl-Trna Synthetases, Anargyros Chaliotis, Panayotis Vlastaridis, Dimitris Mossialos, Michael Ibba, Hubert D. Becker, Constantinos Stathopoulos, Grigorios D. Amoutzias

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Aminoacyl-tRNA synthetases (AARSs) are a superfamily of enzymes responsible for the faithful translation of the genetic code and have lately become a prominent target for synthetic biologists. Our large-scale analysis of >2500 prokaryotic genomes reveals the complex evolutionary history of these enzymes and their paralogs, in which horizontal gene transfer played an important role. These results show that a widespread belief in the evolutionary stability of this superfamily is misconceived. Although AlaRS, GlyRS, LeuRS, IleRS, ValRS are the most stable members of the family, GluRS, LysRS and CysRS often have paralogs, whereas AsnRS, GlnRS, PylRS and SepRS are often absent …

Isoacceptor Specific Characterization Of Trna Aminoacylation And Misacylation In Vivo, Kyle Mohler, Rebecca Mann, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Amino acid misincorporation during protein synthesis occurs due to misacylation of tRNAs or defects in decoding at the ribosome. While misincorporation of amino acids has been observed in a variety of contexts, less work has been done to directly assess the extent to which specific tRNAs are misacylated in vivo, and the identity of the misacylated amino acid moiety. Here we describe tRNA isoacceptor specific aminoacylation profiling (ISAP), a method to identify and quantify the amino acids attached to a tRNA species in vivo. ISAP allows compilation of aminoacylation profiles for specific isoacceptors tRNAs. To demonstrate the efficacy and …

Maintenance Of Transcription-Translation Coupling By Elongation Factor P, Sara Elgamal, Irina Artsimovitch, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Under conditions of tight coupling between translation and transcription, the ribosome enables synthesis of full-length mRNAs by preventing both formation of intrinsic terminator hairpins and loading of the transcription termination factor Rho. While previous studies have focused on transcription factors, we investigated the role of Escherichia coli elongation factor P (EF-P), an elongation factor required for efficient translation of mRNAs containing consecutive proline codons, in maintaining coupled translation and transcription. In the absence of EF-P, the presence of Rho utilization (rut) sites led to an ~30-fold decrease in translation of polyproline-encoding mRNAs. Coexpression of the Rho inhibitor Psu …

Sweetening Of Glutamine Metabolism In Cancer Cells By Rho Gtpases Through Convergence Of Multiple Oncogenic Signaling Pathways, Thambi Dorai, John T. Pinto, Arthur J. L. Cooper

NYMC Faculty Publications

Comment on: Lukey MJ, Greene KS, Erickson JW, et al. The oncogenic transcription factor c-Jun regulates glutaminase expression and sensitizes cells to glutaminase-targeted therapy. Nat Commun 2016;7:11321.

Analysis Of The Intricacies Of Substrate Recognition Of High Mobility Group Proteins And Aminoacyl-Trna Synthetases Using Non-Cognate Substrates, Douglas Van Iverson Ii

Dissertations

The studies presented in section 1 (Chapters I-IV) focus on the design and development of nucleic acid four-way junctions (4WJs) to target a member of the high mobility group (HMG) proteins, the proinflammatory cytokine high mobility group box 1 protein (HMGB1). In the present study, hybrid PNA-DNA 4WJs based on a model DNA 4WJ were constructed to improve the thermal stability of 4WJs while maintaining strong binding affinity toward HMGB1. An electrophoretic mobility shift assay (EMSA) was used to examine the binding affinity of an isolated DNA binding domain of HMGB1, the HMGB1 b-box (HMGB1b), toward a set of PNA-DNA …

Translation Control Of Swarming Proficiency In Bacillus Subtilis By 5-Amino-Pentanolylated Elongation Factor P, Andrei Rajkovic, Katherine R. Hummels, Anne Witzky, Sarah Erickson, Philip R. Gafken, Julian P. Whitelegge, Kym F. Faull, Daniel B. Kearns, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Elongation factor P (EF-P) accelerates diprolyl synthesis and requires a posttranslational modification to maintain proteostasis. Two phylogenetically distinct EF-P modification pathways have been described and are encoded in the majority of Gram-negative bacteria, but neither is present in Gram-positive bacteria. Prior work suggested that the EF-P-encoding gene (efp) primarily supports Bacillus subtilis swarming differentiation, whereas EF-P in Gram-negative bacteria has a more global housekeeping role, prompting our investigation to determine whether EF-P is modified and how it impacts gene expression in motile cells. We identified a 5-aminopentanol moiety attached to Lys³² of B. subtilis EF-P that is …

Multiple Quality Control Pathways Limit Non-Protein Amino Acid Use By Yeast Cytoplasmic Phenylalanyl-Trna Synthetase, Adil Moghal, Lin Hwang, Kym F. Faull, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Non-protein amino acids, particularly isomers of the proteinogenic amino acids, present a threat to proteome integrity if they are mistakenly inserted into proteins. Quality control during aminoacyl-tRNA synthesis reduces non-protein amino acid incorporation by both substrate discrimination and proofreading. For example phenylalanyl-tRNA synthetase (PheRS) proofreads the non-protein hydroxylated phenylalanine derivative m-Tyr after its attachment to tRNA^Phe. We now show in Saccharomyces cerevisiae that PheRS misacylation of tRNA^Phe with the more abundant Phe oxidation product o-Tyr is limited by kinetic discrimination against o-Tyr-AMP in the transfer step followed by o-Tyr-AMP release from the synthetic …

Non-Canonical Roles Of Trnas And Trna Mimics In Bacterial Cell Biology, Assaf Katz, Sara Elgamal, Andrei Rajkovic, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Transfer RNAs (tRNAs) are the macromolecules that transfer activated amino acids from aminoacyl‐tRNA synthetases to the ribosome, where they are used for the mRNA guided synthesis of proteins. Transfer RNAs are ancient molecules, perhaps even predating the existence of the translation machinery. Albeit old, these molecules are tremendously conserved, a characteristic that is well illustrated by the fact that some bacterial tRNAs are efficient and specific substrates of eukaryotic aminoacyl‐tRNA synthetases and ribosomes. Considering their ancient origin and high structural conservation, it is not surprising that tRNAs have been hijacked during evolution for functions outside of translation. These roles beyond …

Zn(Ii), Cu(Ii), Sn(Ii), And Ni(Ii) And Other Metal Cations Do Not Prevent The Aggregation Of Hiapp, Charles Hoying

Honors Thesis

The Zn(II) metal ion has been shown to interact with Islet Amyloid Polypeptide (IAPP), a protein implicated in the progression of Type II Diabetes Mellitus, in such a way as to prevent the protein from aggregating into toxic fibers. We set out to find whether other metal ions might similarly prevent IAPP aggregation. Using Thioflavin T (ThT) spectroscopic assays, which measure fluorescence of ThT upon binding to aggregated IAPP, we observed a decrease in aggregation when incubated with Zn(II), Cu(II), Ni(II), and Sn(II). Atomic Force Microscopy (AFM), which can visualize fibril formation, revealed that the metals were not inhibiting IAPP …

Engineering A Mutation In The Heparin Binding Pocket Of The Human Fibroblast Growth Factor, Roshni Patel

Chemistry & Biochemistry Undergraduate Honors Theses

Fibroblast growth factors (FGFs) are family of proteins that belong to a group of growth factors that are found in mammals and play an important role in angiogenesis, differentiation, organogenesis, and tissue repair. In summary, their main functionality is involved in cell division and proliferation. Because FGFs plays such a vital role in cell proliferation, they are mainly involved in the process of wound healing and injuries. FGF binds to its ligand, heparin—a heavily sulfated glycosaminoglycan. The binding of heparin to FGF occurs through electrostatic interactions, specifically between the negatively charged sulfate groups on heparin and positively charged residues such …

Comparing The Quantitation Of Opiates From Possible Drug Overdose Cases Using Results Of Blood Analysis And Liver Analysis, Lee Ann Garozzo

Forensic Science Theses

Currently the quantitation of opiates at the Erie County Medical Examiner’s Office Toxicology Laboratory is conducted through whole blood analysis. The objective of this thesis project was to determine if the analysis of opiates could be conducted through liver analysis, and if the analysis of opiates would provide a more accurate quantitation compared to the blood analysis. The quantitation of opiates was conducted from the livers of sixty-four possible overdose cases that were brought into the Erie County Medical Examiner’s Office between 2013 and 2015. Results showed that the opiate drugs could successfully be quantitated using the liver analysis. Generally …

Characterization And Target Identification Of Ak301: A Novel Mitotic Arrest Agent, Michael J. Bond, Avijeet S. Chopra, Marina Bleiler, Michelle Yeagley, Eric Scocchera

University Scholar Projects

The Giardina Laboratory has recently identified AK301 as a novel mitotic arrest agent. This work aimed to characterize the arrest state induced by AK301 (EC₅₀ ~ 150nM) and identify the cellar targets responsible for the arrest. It was found that AK301 arrest is readily reversible upon withdrawal of AK301. Cells that slip from mitosis after removal of AK301 are sensitized to apoptosis. This was found to be unique for AK301 when compared to other mitotic arrest agents like colchicine, vincristine, and BI2536. Arrested cells were found to have increased ATM activity as well as an upregulation of p53 and …

Novel Compound Heterozygous Mutations Expand The Recognized Phenotypes Of Fars2-Linked Disease, Melissa A. Walker, Kyle Mohler, Kyle W. Hopkins, Derek H. Oakley, David A. Sweetser, Michael Ibba, Matthew P. Frosch, Ronald L. Thibert

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Mutations in mitochondrial aminoacyl-tRNA synthetases are an increasingly recognized cause of human diseases, often arising in individuals with compound heterozygous mutations and presenting with system-specific phenotypes, frequently neurologic. FARS2 encodes mitochondrial phenylalanyl transfer ribonucleic acid (RNA) synthetase (mtPheRS), perturbations of which have been reported in 6 cases of an infantile, lethal disease with refractory epilepsy and progressive myoclonus. Here the authors report the case of juvenile onset refractory epilepsy and progressive myoclonus with compound heterozygous FARS2 mutations. The authors describe the clinical course over 6 years of care at their institution and diagnostic studies including electroencephalogram (EEG), brain magnetic resonance …

Development Of A Chemical Genetic Screen To Determine Synergistic Compounds With Laromustine In Treating Glioblastoma Multiforme Cultured Cells, Ryan Weeks

Honors Theses

Laromustine is a chemotherapeutic sulfonylhydrazine prodrug used in clinical trials to treat acute myeloid leukemia (AML) and glioblastoma multiforme (GBM). While treatment of AML with laromustine has more demonstrative clinical success, there are enough promising data against GBM to pursue additional pre-clinical and clinical experiments. To determine the synergistic effects caused by treating cultured GBM cells with laromustine and a library of FDA-approved compounds, a chemical genetic screen was developed. To optimize the screen, optimal cultured GBM cell seed density, growth period and maximum well capacity were determined. The treatment period for a lethal dose of laromustine in cultured GBM …

Synthesis And Biochemical Evaluation Of 3-Phenoxy-1,4-Diarylazetidin-2-Ones As Tubulin-Targeting Antitumor Agents, Thomas F. Greene, Shu Wang, Lisa M. Greene, Seema M. Nathwani, Jade K. Pollock, Azizah M. Malebari, Thomas Mccabe, Brendan Twamley, Niamh O'Boyle, Daniela M. Zisterer, Mary J. Meegan

Articles

Structure-activity relationships for a series of 3-phenoxy-1,4-diarylazetidin-2-ones were investigated leading to the discovery of a number of potent antiproliferative compounds, including trans-4-(3-hydroxy-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (78b) and trans-4-(3-amino-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (90b). X-ray crystallography studies indicate the potential importance of the torsional angle between the 1-phenyl ‘A’ ring and 4-phenyl ‘B’ ring for potent antiproliferative activity, and that a trans configuration between the 3-phenoxy and 4-phenyl rings is generally optimal. These compounds displayed IC₅₀ values of 38 nM and 19 nM respectively in MCF-7 breast cancer cells, inhibited the polymerization of isolated tubulin in vitro, disrupted the microtubular …

Piperlongumine (Piplartine) And Analogues: Antiproliferative Microtubule-Destabilising Agents, Mary J. Meegan, Seema M. Nathwani, Brendan Twamley, Daniela M. Zisterer, Niamh O'Boyle

Articles

Piperlongumine (piplartine, 1) is a small molecule alkaloid that is receiving intense interest due to its antiproliferative and anticancer activities. We investigated the effects of 1 on tubulin and microtubules. Using both an isolated tubulin assay, and a combination of sedimentation and Western blotting, we demonstrated that 1 is a tubulin-destabilising agent. This result was confirmed by immunofluorescence and confocal microscopy, which showed that microtubules in MCF-7 breast cancer cells were depolymerised when treated with 1. We synthesised a number of analogues of 1 to explore structure-activity relationships. Compound 13 had the best cytotoxic profile of this series, …