112 results on '"Jennette A. Sakoff"'
Search Results
2. Supplementary Video 1 from The Dynamin Inhibitors MiTMAB and OcTMAB Induce Cytokinesis Failure and Inhibit Cell Proliferation in Human Cancer Cells
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Megan Chircop, Antony W. Braithwaite, Phillip J. Robinson, Adam McCluskey, Jennette A. Sakoff, Christopher P. Gordon, Anna Mariana, Charlotte M. Smith, Jayne Gilbert, Swetha Perera, and Sanket Joshi
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Supplementary Video 1 from The Dynamin Inhibitors MiTMAB and OcTMAB Induce Cytokinesis Failure and Inhibit Cell Proliferation in Human Cancer Cells
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- 2023
3. Supplementary Figures 1-5 and Legends from The Dynamin Inhibitors MiTMAB and OcTMAB Induce Cytokinesis Failure and Inhibit Cell Proliferation in Human Cancer Cells
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Megan Chircop, Antony W. Braithwaite, Phillip J. Robinson, Adam McCluskey, Jennette A. Sakoff, Christopher P. Gordon, Anna Mariana, Charlotte M. Smith, Jayne Gilbert, Swetha Perera, and Sanket Joshi
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Supplementary Figures 1-5 and Legends from The Dynamin Inhibitors MiTMAB and OcTMAB Induce Cytokinesis Failure and Inhibit Cell Proliferation in Human Cancer Cells
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- 2023
4. Data from The Dynamin Inhibitors MiTMAB and OcTMAB Induce Cytokinesis Failure and Inhibit Cell Proliferation in Human Cancer Cells
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Megan Chircop, Antony W. Braithwaite, Phillip J. Robinson, Adam McCluskey, Jennette A. Sakoff, Christopher P. Gordon, Anna Mariana, Charlotte M. Smith, Jayne Gilbert, Swetha Perera, and Sanket Joshi
- Abstract
The endocytic protein dynamin II (dynII) participates in cell cycle progression and has roles in centrosome cohesion and cytokinesis. We have described a series of small-molecule inhibitors of dynamin [myristyl trimethyl ammonium bromides (MiTMAB)] that competitively interfere with the ability of dynamin to bind phospholipids and prevent receptor-mediated endocytosis. We now report that dynII functions specifically during the abscission phase of cytokinesis and that MiTMABs exclusively block this step in the cell cycle. Cells treated with MiTMABs (MiTMAB and octadecyltrimethyl ammonium bromide) and dyn-depleted cells remain connected via an intracellular bridge for a prolonged period with an intact midbody ring before membrane regression and binucleate formation. MiTMABs are the first compounds reported to exclusively block cytokinesis without affecting progression through any other stage of the cell cycle. Thus, MiTMABs represent a new class of antimitotic compounds. We show that MiTMABs are potent inhibitors of cancer cell growth and have minimal effect on nontumorigenic fibroblast cells. Thus, MiTMABs have toxicity and antiproliferative properties that preferentially target cancer cells. This suggests that dynII may be a novel target for pharmacologic intervention for the treatment of cancer. Mol Cancer Ther; 9(7); 1995–2006. ©2010 AACR.
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- 2023
5. Preliminary Study on Major Phenolic Groups, Antioxidant and Cytotoxic Capacity of Tuckeroo (Cupaniopsis Anacardioides) Fruit Extracts
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Quan V. Vuong, Christopher J. Scarlett, Ngoc Minh Quynh Pham, Jennette A. Sakoff, and Michael C. Bowyer
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Cultural Studies ,Linguistics and Language ,History ,Antioxidant ,Traditional medicine ,Chemistry ,Fruit extracts ,Anthropology ,medicine.medical_treatment ,medicine ,Cytotoxic T cell ,Language and Linguistics - Abstract
Background: Tuckeroo (Cupaniopsis anacardioides) is one of eleven species that belongs to the Sapindaceae family, which is native to Australia. Objective: This study screened major phenolic groups from fresh or dried whole fruits, or just their skin. Methods: Using optimal ultrasound assisted extraction conditions with either acetone (50%) or methanol (50%) as extraction solvents. This study further tested their antioxidant capacity and cytotoxic activity against a panel of ten cancer cell lines for their potential health benefits. Results: The results showed that levels of major phenolic groups were significantly different with solvents used or types of materials (whole fruit or skin). The extract from dried skin fruit using acetone 50 % (SD-A50) had the highest level of total phenolic content(112.47 mg GAE/g) and total flavonoid content (101.89 mg CAE/g); however, the extract from fresh skin (SF-A50) had the greatest proanthocyanidin content (124.22 mg CAE/g). This SF-A50 extract also showed the strongest antioxidant activity and had the highest growth inhibition and the lower dose response (GI50 values of 20-145 μg/mL) against the HT29 (colon); U87, SJ-G2 (glioblastoma); MCF-7 (Breast); A2780 (ovarian); H460 (lung); A431 (skin); Du145 (prostate); BE2-C (neuroblastoma); and MIA PaCa-2 (pancreas) cancer cell line, revealing its therapeutic potential. Conclusions: Fourteen major compounds, including catechin were detected from the Tuckeroo fruit extract; future studies are recommended to further isolate, identify and test the health potentials from group and individual compounds of the Tuckeroo fruit extract.
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- 2021
6. Novel Platinum(II) and Platinum(IV) Antitumor Agents that Exhibit Potent Cytotoxicity and Selectivity
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Aleen Khoury, Elias Elias, Stephanie Mehanna, Wassim Shebaby, Krishant M. Deo, Najwa Mansour, Christian Khalil, Katia Sayyed, Jennette A. Sakoff, Jayne Gilbert, Costantine F. Daher, Christopher P. Gordon, Robin I. Taleb, and Janice R. Aldrich-Wright
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A549 Cells ,Cell Line, Tumor ,Drug Discovery ,Molecular Medicine ,Humans ,Antineoplastic Agents ,Apoptosis ,Cisplatin ,Platinum - Abstract
A novel platinum(II) complex
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- 2022
7. Determination of bioactive compounds, antioxidant and anticancer activities of Tuckeroo (Cupaniopsis anacardioides) fruits
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Ngoc Minh Quynh Pham, Quan V. Vuong, Jennette A. Sakoff, Michael C. Bowyer, Van Anh Le, and Christopher J. Scarlett
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Environmental Science (miscellaneous) ,Agricultural and Biological Sciences (miscellaneous) ,Biotechnology - Abstract
This study aimed to determine the phytochemical, antioxidant, and anticancer activities of the crude extract and its fractions of Cupaniopsis anacardioides. The results showed that total phenolic content (TPC), their secondary metabolites (flavonoids—TFC; proanthocyanidins—TPro), and antioxidant activity were significantly different between the crude extract and its fractions. The butanol fraction (F3) had the highest levels of TPC, TFC, and TPro, followed by the crude extract, aqueous fraction (F4), dichloromethyl fraction (F2), and hexane fraction (F1). High-Pressure Liquid Chromatography (HPLC) analysis revealed 14 major bioactive compounds were identified in the C. anacardioides extract. Further analysis showed F3 fraction contained the highest levels of the major bioactive compounds, while F1 fraction had the lowest. A similar pattern was observed for antioxidant activities. The crude extract, F3 and F4 fractions were further tested for cytotoxicity against 10 cancer cell lines, including HT29 (colon); U87, SJG2 (glioblastoma); MCF-7 (Breast); A2780 (ovarian); H460 (lung); A431 (skin); Du145 (prostate); BE2-C (neuroblastoma); MIA PaCa-2 (pancreas); and one non-tumour-derived normal breast cell line (MCF10A). Except for Du145 (prostate), the crude extract, F3 and F4 fractions inhibited the cancer cell lines at 100 µg/mL, with F3 possessing greater activity against these cancer cell lines. Future studies are recommended to isolate and identify the major bioactive compounds of the F3 fraction, and further tested their impact against cancer cell lines. This could identify the potential of anticancer agents from C. anacardioides.
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- 2022
8. Targeting the S100A2‐p53 Interaction with a Series of 3,5‐ Bis (trifluoromethyl)benzene Sulfonamides: Synthesis and Cytotoxicity
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Jennifer R. Baker, Jennette A. Sakoff, Cecilia C. Russell, Peter J. Cossar, Jufeng Sun, Christopher J. Scarlett, Adam McCluskey, Joey I. Ambrus, and Melanie J. Pirinen
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Cell Survival ,Stereochemistry ,In silico ,Triazole ,Antineoplastic Agents ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Pancreatic cancer ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,Cytotoxicity ,Cell Proliferation ,Pharmacology ,Trifluoromethyl ,Chemotactic Factors ,Dose-Response Relationship, Drug ,Molecular Structure ,S100 Proteins ,Organic Chemistry ,Cancer ,medicine.disease ,Molecular Docking Simulation ,chemistry ,Docking (molecular) ,Cell culture ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Tumor Suppressor Protein p53 - Abstract
In silico approaches identified 1, N-(6-((4-bromo- benzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzene sulfonamide, as a potential inhibitor of the S100A2-p53 protein-protein interaction, a validated pancreatic cancer drug target. Subsequent cytotoxicity screening revealed it to be a 2.97 μM cell growth inhibitor of the MiaPaCa-2 pancreatic cell line. This is in keeping with our hypothesis that inhibiting this interaction would have an anti-pancreatic cancer effect with S100A2, the validated PC drug target. A combination of focused library synthesis (three libraries, 24 compounds total) and cytotoxicity screening identified a propyl alkyl diamine spacer as optimal; the nature of the terminal phenyl substituent had limited impact on observed cytotoxicity, whereas N-methylation was detrimental to activity. In total 15 human cancer cell lines were examined, with most analogues showing broad-spectrum activity. Near uniform activity was observed against a panel of six pancreatic cancer cell lines: MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, HPAC and PANC-1. In all cases there was good to excellent correlation between the predicted docking pose in the S100A2-p53 binding groove and the observed cytotoxicity, especially in the pancreatic cancer cell line with high endogenous S100A2 expression. This supports S100A2 as a pancreatic cancer drug target.
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- 2021
9. Cytotoxic 1,2,3‐Triazoles as Potential Leads Targeting the S100A2‐p53 Complex: Synthesis and Cytotoxicity
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Jennette A. Sakoff, Christopher J. Scarlett, Peter J. Cossar, Adam McCluskey, Hong Ngoc Thuy Pham, Jennifer R. Baker, Jufeng Sun, and Cecilia C. Russell
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Cell Survival ,Stereochemistry ,Triazole ,Antineoplastic Agents ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Pancreatic cancer ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,Cytotoxicity ,Cell Proliferation ,Pharmacology ,chemistry.chemical_classification ,Sulfonyl ,Chemotactic Factors ,Dose-Response Relationship, Drug ,Molecular Structure ,S100 Proteins ,Organic Chemistry ,Triazoles ,medicine.disease ,Sulfonamide ,Molecular Docking Simulation ,chemistry ,Cell culture ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Tumor Suppressor Protein p53 ,Growth inhibition ,Acetamide - Abstract
In silico screening predicted 1 (N-(4-((4-(3-(4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)propyl)piperazin-1-yl) sulfonyl)-phenyl)acetamide) as an inhibitor of the S100A2-p53 protein-protein interaction. S100A2 is a validated pancreatic cancer drug target. In the MiaPaCa-2 pancreatic cell line, 1 was a ∼50 μM growth inhibitor. Synthesis of five focused compound libraries and cytotoxicity screening revealed increased activity from the presence of electron withdrawing moieties on the sulfonamide aromatic ring, with the 3,5-bis-CF3 Library 3 analogues the most active, with GI50 values of 0.91 (3-ClPh; 13 i; BxPC-3, Pancreas) to 9.0 μM (4-CH3 ; 13 d; PANC-1, Pancreas). Activity was retained against an expanded pancreatic cancer cell line panel (MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, PANC-1 and HPAC) and the normal cell line MCF10A (breast). Bulky 4-disposed substituents on the terminal phenyl ring enhanced broad spectrum activity with growth inhibition values spanning 1.1 to 3.1 μM (4-C(CH3 )3 ; 13 e; BxPC-3 and AsPC-1 (pancreas), respectively). Central alkyl spacer contraction from propyl to ethyl proved detrimental to activity with Library 4 and 5.5- to 10-fold less cytotoxic than the propyl linked Library 2 and Library 3. The data herein was consistent with the predicted binding poses of the compounds evaluated. The highest levels of cytotoxicity were observed with those analogues best capable of adopting a near identical pose to the p53-peptide in the S100A2-p53 binding groove.
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- 2021
10. Potent Chlorambucil-Platinum(IV) Prodrugs
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Angelico D. Aputen, Maria George Elias, Jayne Gilbert, Jennette A. Sakoff, Christopher P. Gordon, Kieran F. Scott, and Janice R. Aldrich-Wright
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Male ,Ovarian Neoplasms ,Organoplatinum Compounds ,Organic Chemistry ,Antineoplastic Agents ,General Medicine ,Catalysis ,PHENSS ,5MESS ,56MESS ,DNA ,chlorambucil ,platinum(II) ,platinum(IV) ,cytotoxicity ,ROS ,Computer Science Applications ,Carboplatin ,Inorganic Chemistry ,Oxaliplatin ,Cell Line, Tumor ,Humans ,Chlorambucil ,Female ,Prodrugs ,Physical and Theoretical Chemistry ,Cisplatin ,Reactive Oxygen Species ,Molecular Biology ,Spectroscopy ,Platinum - Abstract
The DNA-alkylating derivative chlorambucil was coordinated in the axial position to atypical cytotoxic, heterocyclic, and non-DNA coordinating platinum(IV) complexes of type, [PtIV(HL)(AL)(OH)2](NO3)2 (where HL is 1,10-phenanthroline, 5-methyl-1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, AL is 1S,2S-diaminocyclohexane). The resultant platinum(IV)-chlorambucil prodrugs, PCLB, 5CLB, and 56CLB, were characterized using high-performance liquid chromatography, nuclear magnetic resonance, ultraviolet-visible, circular dichroism spectroscopy, and electrospray ionization mass spectrometry. The prodrugs displayed remarkable antitumor potential across multiple human cancer cell lines compared to chlorambucil, cisplatin, oxaliplatin, and carboplatin, as well as their platinum(II) precursors, PHENSS, 5MESS, and 56MESS. Notably, 56CLB was exceptionally potent in HT29 colon, Du145 prostate, MCF10A breast, MIA pancreas, H460 lung, A2780, and ADDP ovarian cell lines, with GI50 values ranging between 2.7 and 21 nM. Moreover, significant production of reactive oxygen species was detected in HT29 cells after treatment with PCLB, 5CLB, and 56CLB up to 72 h compared to chlorambucil and the platinum(II) and (IV) precursors.
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- 2022
11. Determination of bioactive compounds, antioxidant and anticancer activities of Tuckeroo (
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Ngoc Minh Quynh, Pham, Quan V, Vuong, Jennette A, Sakoff, Michael C, Bowyer, Van Anh, Le, and Christopher J, Scarlett
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This study aimed to determine the phytochemical, antioxidant, and anticancer activities of the crude extract and its fractions of
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- 2022
12. Versatile Platinum(IV) Prodrugs of Naproxen and Acemetacin as Chemo-Anti-Inflammatory Agents
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Angelico D. Aputen, Maria George Elias, Jayne Gilbert, Jennette A. Sakoff, Christopher P. Gordon, Kieran F. Scott, and Janice R. Aldrich-Wright
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Cancer Research ,Oncology ,platinum(II) ,cisplatin ,chemotherapy ,platinum(IV) ,naproxen ,acemetacin ,cytotoxicity ,ROS ,mitochondria ,cyclooxygenase-2 - Abstract
Developing new and versatile platinum(IV) complexes that incorporate bioactive moieties is a rapidly evolving research strategy for cancer drug discovery. In this study, six platinum(IV) complexes (1–6) that are mono-substituted in the axial position with a non-steroidal anti-inflammatory molecule, naproxen or acemetacin, were synthesised. A combination of spectroscopic and spectrometric techniques confirmed the composition and homogeneity of 1–6. The antitumour potential of the resultant complexes was assessed on multiple cell lines and proved to be significantly improved compared with cisplatin, oxaliplatin and carboplatin. The platinum(IV) derivatives conjugated with acemetacin (5 and 6) were determined to be the most biologically potent, demonstrating GI50 values ranging between 0.22 and 250 nM. Remarkably, in the Du145 prostate cell line, 6 elicited a GI50 value of 0.22 nM, which is 5450-fold more potent than cisplatin. A progressive decrease in reactive oxygen species and mitochondrial activity was observed for 1–6 in the HT29 colon cell line, up to 72 h. The inhibition of the cyclooxygenase-2 enzyme was also demonstrated by the complexes, confirming that these platinum(IV) complexes may reduce COX-2-dependent inflammation and cancer cell resistance to chemotherapy.
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- 2023
13. Borylated 2,3,4,5-Tetrachlorophthalimide and Their 2,3,4,5-Tetrachlorobenzamide Analogues: Synthesis, Their Glycosidase Inhibition and Anticancer Properties in View to Boron Neutron Capture Therapy
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David M. Campkin, Yuna Shimadate, Barbara Bartholomew, Paul V. Bernhardt, Robert J. Nash, Jennette A. Sakoff, Atsushi Kato, and Michela I. Simone
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Boron Compounds ,boron ,phthalimide ,benzamide ,glycosidase ,cancer ,boron neutron capture therapy ,Glycoside Hydrolases ,Organic Chemistry ,Pharmaceutical Science ,Boron Neutron Capture Therapy ,Analytical Chemistry ,Rats ,Chemistry (miscellaneous) ,Neoplasms ,Drug Discovery ,Molecular Medicine ,Animals ,Cattle ,Physical and Theoretical Chemistry ,Boron - Abstract
Tetrachlorinated phthalimide analogues bearing a boron-pinacolate ester group were synthesised via two synthetic routes and evaluated in their glycosidase modulating and anticancer properties, with a view to use them in boron neutron capture therapy (BNCT), a promising radiation type for cancer, as this therapy does little damage to biological tissue. An unexpected decarbonylation/decarboxylation to five 2,3,4,5-tetrachlorobenzamides was observed and confirmed by X-ray crystallography studies, thus, giving access to a family of borylated 2,3,4,5-tetrachlorobenzamides. Biological evaluation showed the benzamide drugs to possess good to weak potencies (74.7–870 μM) in the inhibition of glycosidases, and to have good to moderate selectivity in the inhibition of a panel of 18 glycosidases. Furthermore, in the inhibition of selected glycosidases, there is a core subset of three animal glycosidases, which is always inhibited (rat intestinal maltase α-glucosidase, bovine liver β-glucosidase and β-galactosidase). This could indicate the involvement of the boron atom in the binding. These glycosidases are targeted for the management of diabetes, viral infections (via a broad-spectrum approach) and lysosomal storage disorders. Assays against cancer cell lines revealed potency in growth inhibition for three molecules, and selectivity for one of these molecules, with the growth of the normal cell line MCF10A not being affected by this compound. One of these molecules showed both potency and selectivity; thus, it is a candidate for further study in this area. This paper provides numerous novel aspects, including expedited access to borylated 2,3,4,5-tetrachlorophthalimides and to 2,3,4,5-tetrachlorobenzamides. The latter constitutes a novel family of glycosidase modulating drugs. Furthermore, a greener synthetic access to such structures is described.
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- 2022
14. Amino Alcohol Acrylonitriles as Activators of the Aryl Hydrocarbon Receptor Pathway: An Unexpected MTT Phenotypic Screening Outcome
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Jayne Gilbert, Adam McCluskey, Jennette A. Sakoff, Jennifer R. Baker, and Cecilia C. Russell
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Cell Survival ,Stereochemistry ,Phenotypic screening ,Drug Evaluation, Preclinical ,Sulforhodamine B ,Antineoplastic Agents ,01 natural sciences ,Biochemistry ,Cell Line ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,Basic Helix-Loop-Helix Transcription Factors ,Humans ,Moiety ,MTT assay ,General Pharmacology, Toxicology and Pharmaceutics ,Cell Proliferation ,Pharmacology ,Acrylonitrile ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Aryl hydrocarbon receptor ,Amino Alcohols ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Phenotype ,Receptors, Aryl Hydrocarbon ,Cell culture ,biology.protein ,Molecular Medicine ,Female ,Piperidine ,Drug Screening Assays, Antitumor ,Acetamide - Abstract
Lead (Z)-N-(4-(2-cyano-2-(3,4-dichlorophenyl)vinyl)phenyl)acetamide, 1 showed MCF-7 GI50 =30 nM and 400-fold selective c.f. MCF10A (normal breast tissue). Acetamide moiety modification (13 a-g) to introduce additional hydrophobicity was favoured with MCF-7 breast cancer cell activity enhanced at 1.3 nM. Other analogues were potent against the HT29 colon cancer cell line at 23 nM. Textbook SAR data was observed in the MCF-7 cell line, in an MTT assay, via the ortho (17 a), meta (17 b) and para (13 f). The amino alcohol -OH moiety was pivotal, but no stereochemical preference noted. But, these data did not fit our homology modelling expectations. Aberrant MTT ((3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) screening results and metabolic interference confirmed by sulforhodamine B (SRB) screening. Interfering analogues resulted in 120 and 80-fold CYP1A1 and CYP1A2 amplification, with no upregulation of SULT1A1. This is consistent with activation of the AhR pathway. Piperidine per-deuteration reduced metabolic inactivation. 3-OH / 4-OH piperidine analogues showed differential MTT and SRB activity supporting MTT assay metabolic inactivation. Data supports piperidine 3-OH, but not the 4-OH, as a CYP substrate. This family of β-amino alcohol substituted 3,4-dichlorophenylacetonitriles show broad activity modulated via the AhR pathway. By SRB analysis the most potent analogue was 23 b, (Z)-3-(4-(3-(4-phenylpiperidin-1-yl)-2-hydroxypropoxy)phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile.
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- 2020
15. Selective cytotoxicity of organotin(IV) compounds with 2,3-dihydroxybenzyldithiocarbazate Schiff bases
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Nurul N. M. Ishak, Mohamed Ibrahim Mohamed Tahir, Thahira Begum S. A. Ravoof, Enis Nadia Md Yusof, Jennette A. Sakoff, Alister J. Page, Edward R. T. Tiekink, and Muhammad Alif Mohammad Latif
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010405 organic chemistry ,Hydrogen bond ,Chemistry ,Imine ,Molar conductivity ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Medicinal chemistry ,Square pyramidal molecular geometry ,0104 chemical sciences ,Trigonal bipyramidal molecular geometry ,chemistry.chemical_compound ,Molecular geometry ,Molecule ,Absorption (chemistry) - Abstract
A series of tridentate ONS Schiff bases were synthesised via condensation by reacting 2,3-dihydroxybenzaldehyde with S-2-methylbenzyldithiocarbazate (S2MBDTC) (1), S-4-methylbenzyldithiocarbazate (S4MBDTC) (2) and S-benzyldithiocarbazate (SBDTC) (3) in an equimolar ratio (10 mmol). The Schiff bases were then reacted with diphenyltin(IV) and dimethyltin(IV) dichloride in an equimolar ratio (1 mmol) yielding six new organotin(IV) compounds (4–9). All the compounds were successfully characterised by elemental analysis, FT-IR, multinuclear NMR, UV–Vis, mass spectroscopy and molar conductivity. The molecular geometries for five compounds, 3, 5, 6, 8 and 9, have been established by X-ray crystallography. The five-coordinate geometry for each of the diorganotin molecules was defined by two carbon atoms from the tin-bound substituents as well as three donor atoms derived from the dinegative, tridentate dithiocarbazate ligands, namely thiolate-S, phenoxide-O and imine-N atoms. The resultant five-coordinate C2NOS geometries were intermediate between ideal square pyramidal and trigonal bipyramidal geometries. The diphenyltin(IV) compounds (4–6) exhibited particularly promising and selective cytotoxicity against the A2780 (ovarian), BE2-C (neuroblastoma), SJ-G2 (glioblastoma) and MIA (pancreas) cancer cell lines. The interactions of the compounds (4–9) with calf thymus (CT-DNA) were evaluated using an electronic absorption method, and 7, 8, 9 were found to have good DNA binding affinity. The molecular docking studies of compounds (4–9) with DNA revealed that the compounds interacted with duplex DNA via hydrogen bonding, hydrophobic and electrostatic interactions.
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- 2020
16. The aryl hydrocarbon receptor (AhR) as a breast cancer drug target
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Jennifer R. Baker, Jennette A. Sakoff, and Adam McCluskey
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Molecular Conformation ,Apoptosis ,Breast Neoplasms ,Disease ,Crystallography, X-Ray ,Ligands ,03 medical and health sciences ,chemistry.chemical_compound ,Cytosol ,0302 clinical medicine ,Breast cancer ,Protein Domains ,Cell Line, Tumor ,Drug Discovery ,Basic Helix-Loop-Helix Transcription Factors ,Animals ,Humans ,Medicine ,Cell Proliferation ,030304 developmental biology ,Cell Nucleus ,Flavonoids ,Pharmacology ,0303 health sciences ,biology ,business.industry ,Cancer ,Oncogenes ,Aryl hydrocarbon receptor ,medicine.disease ,Metastatic breast cancer ,Gene Expression Regulation, Neoplastic ,Pharmaceutical Preparations ,Receptors, Aryl Hydrocarbon ,chemistry ,Biological target ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Molecular Medicine ,Female ,Growth inhibition ,Xenobiotic ,business - Abstract
Breast cancer is the most common cancer in women, with more than 1.7 million diagnoses worldwide per annum. Metastatic breast cancer remains incurable, and the presence of triple-negative phenotypes makes targeted treatment impossible. The aryl hydrocarbon receptor (AhR), most commonly associated with the metabolism of xenobiotic ligands, has emerged as a promising biological target for the treatment of this deadly disease. Ligands for the AhR can be classed as exogenous or endogenous and may have agonistic or antagonistic activity. It has been well reported that agonistic ligands may have potent and selective growth inhibition activity in a number of oncogenic cell lines, and one (aminoflavone) has progressed to phase I clinical trials for breast cancer sufferers. In this study, we examine the current state of the literature in this area and elucidate the promising advances that are being made in hijacking the cytosolic-to-nuclear pathway of the AhR for the possible future treatment of breast cancer.
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- 2019
17. Pyrimidyn-Based Dynamin Inhibitors as Novel Cytotoxic Agents
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Cecilia C. Russell, Kelly A. Young, Phillip J. Robinson, Jennette A. Sakoff, Luke R. Odell, Ngoc Chau, Jayne Gilbert, and Adam McCluskey
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Dynamins ,Pyrimidine ,Antineoplastic Agents ,Biochemistry ,chemistry.chemical_compound ,Structure-Activity Relationship ,DU145 ,Prostate ,Neuroblastoma ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,Enzyme Inhibitors ,Cytotoxicity ,Mitosis ,Dynamin ,Cell Proliferation ,Pharmacology ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Cytotoxins ,Organic Chemistry ,medicine.disease ,Molecular biology ,medicine.anatomical_structure ,Pyrimidines ,Cell culture ,Molecular Medicine ,Drug Screening Assays, Antitumor - Abstract
Five focused libraries of pyrimidine-based dynamin GTPase inhibitors, in total 69 compounds were synthesised, and their dynamin inhibition and broad-spectrum cytotoxicity examined. Dynamin plays a crucial role in mitosis, and as such inhibition of dynamin was expected to broadly correlate with the observed cytotoxicity. The pyrimidines synthesised ranged from mono-substituted to trisubstituted. The highest levels of dynamin inhibition were noted with di- and tri- substituted pyrimidines, especially those with pendent amino alkyl chains. Short chains and simple heterocyclic rings reduced dynamin activity. There were three levels of dynamin activity noted: 1-10, 10-25 and 25-60 μM. Screening of these compounds in a panel of cancer cell lines: SW480 (colon), HT29 (colon), SMA (spontaneous murine astrocytoma), MCF-7 (breast), BE2-C (glioblastoma), SJ-G2 (neuroblastoma), MIA (pancreas), A2780 (ovarian), A431 (skin), H460 (lung), U87 (glioblastoma) and DU145 (prostate) cell lines reveal a good correlation between the observed dynamin inhibition and the observed cytotoxicity. The most active analogues ( 31a , b ) developed returned average GI 50 values of 1.0 and 0.78 μM across the twelve cell lines examined. These active analogues were: N 2 -(3-dimethylaminopropyl)- N 4 -dodecyl-6-methylpyrimidine-2,4-diamine ( 31a ) and N 4 -(3-dimethylaminopropyl)- N 2 -dodecyl-6-methylpyrimidine-2,4-diamine ( 31b ).
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- 2021
18. A methanol and protic ionic liquid Ugi multicomponent reaction path to cytotoxic α-phenylacetamido amides
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Ahmed Al Otaibi, Adam McCluskey, Cecilia C. Russell, Lacey Hizartzidis, Fiona M. Deane, Jennette A. Sakoff, and Siobhann N. McCluskey
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chemistry.chemical_classification ,General Chemical Engineering ,Isocyanide ,02 engineering and technology ,General Chemistry ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,Medicinal chemistry ,Aldehyde ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Ionic liquid ,Moiety ,Structure–activity relationship ,Amine gas treating ,Ethylammonium nitrate ,Methanol ,0210 nano-technology - Abstract
The Ugi four component reaction of an aldehyde, amine, isocyanide and an ethanoic acid was effected smoothly in protic ionic liquids ethylammonium nitrate (EAN) and propylammonium nitrate (PAN) to afford analogues of α-phenylacetamido amides in good to excellent isolated yields. The corresponding reactions in [BMIM][PF6] and the protic ionic liquid ethanolammonium nitrate (ETAN) failed. Microwave irradiation in EAN facilitated rapid access to three focused libraries, based on the parent isocyanide: cyclohexyl isocyanide, benzyl isocyanide and ethyl isocyanoacetate. Analysis of the structure activity relationship data suggested the presence of a bulky moiety originating from the isocyanide (cyclohexyl and benzyl) enhanced cytotoxicity. Removal of the acetylenic H-atom from the ethanoic acid moiety was detrimental to cytotoxicity. The most active analogues produced, N-(2-cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl-N-(3,5-dimethoxyphenyl)propiolamide, returned average GI50 values of ≤1 μM across the cancer cell lines evaluated. Combined, these data suggest that analogues of this nature are interesting potential anti-cancer development leads.
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- 2019
19. Comparative cytotoxic activity between kaempferol and gallic acid against various cancer cell lines
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Christopher J. Scarlett, Hong Ngoc Thuy Pham, Jennette A. Sakoff, Michael C. Bowyer, and Quan V. Vuong
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0301 basic medicine ,Antioxidant ,endocrine system diseases ,medicine.medical_treatment ,Pharmacology ,lcsh:Computer applications to medicine. Medical informatics ,03 medical and health sciences ,chemistry.chemical_compound ,DU145 ,Biochemistry, Genetics and Molecular Biology ,Neuroblastoma ,medicine ,Gallic acid ,lcsh:Science (General) ,neoplasms ,Multidisciplinary ,biology ,Chemistry ,Catharanthus roseus ,Antimicrobial ,medicine.disease ,biology.organism_classification ,030104 developmental biology ,Phytochemical ,lcsh:R858-859.7 ,Kaempferol ,lcsh:Q1-390 - Abstract
This data article indicates the in vitro cytotoxicity of kaempferol and gallic acid across different cancer cell lines including A2780 (ovarian), H460 (lung), A431 (skin), MIA PaCa-2 (pancreas), Du145 (prostate), HT29 (colon), MCF-7 (breast), BE2-C (neuroblastoma), SJ-G2, U87 and SMA (glioblastoma). The dataset showed that the inhibitory activity of kaempferol was comparatively stronger than gallic acid. Thereby, kaempferol is offered as a potent anticancer agent for further investigation and beneficial as a dietary supplement. The data within this article relates to the research article entitled “Screening phytochemical content, antioxidant, antimicrobial and cytotoxic activities of Catharanthus roseus (L.) G. Don stem extract and its fractions” (Pham et al., 2018).
- Published
- 2018
20. Borylated methyl cinnamates: Expedited synthesis, characterization, crystallographic analysis and biological activities in glycosidase inhibition and in cancer cells lines
- Author
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Jennette A. Sakoff, Atsushi Kato, William J Legge, Paul V. Bernhardt, Mahdi Ghorbani, Todd Ashley Houston, Michela I. Simone, and Yuna Shimadate
- Subjects
Crystallography ,chemistry.chemical_compound ,Recrystallization (geology) ,chemistry ,Pinacol ,Wittig reaction ,Cinnamates ,Biological activity ,Pharmacophore ,Selectivity ,IC50 - Abstract
Three cinnamate derivatives bearing a boronate pinacol ester group para, meta and ortho to the a,b-unsaturated ester group have been synthesized via a solventless, expedited Wittig protocol in the best stereoisomeric ratios yet reported, purified by recrystallization, characterized and analyzed by X-ray crystallography. These are valuable building blocks to biologically active derivatives and are themselves biologically active drug leads, displaying excellent selectivities as glycosidase modulators and for future testing as boron neutron capture therapy (BNCT) agents. In a panel of 15 glycosidases, IC50 values of 351 mM and 374 mM were shown for para 2 against almond b-glucosidase and bovine liver b-galactosidase, respectively. For meta 2 the selectivity profile is improved with only inhibition of bovine liver b-galactosidase with an IC50 of 780 mM. These borylated derivatives also possess the capability to be used as BNCT agents. This occurs via irradiation with slow neutrons, thus granting them a switch-on/switch-off toxicity. This is an important new capability imbued into anticancer drugs, too many of which are too toxic in their therapeutic window. BNCT drugs bearing the organic boron pharmacophore have the potential to fine-tune the timing of toxicity delivery.
- Published
- 2021
21. Modelling and Phenotypic Screening of NAP-6 and 10-Cl-BBQ, AhR Ligands Displaying Selective Breast Cancer Cytotoxicity in Vitro
- Author
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Jennette A. Sakoff, Jennifer R. Baker, Brett L. Pollard, Adam McCluskey, Jayne Gilbert, Andrew J. S. Lin, Xiao Zhu, and Stefan Paula
- Subjects
Phenotypic screening ,Antineoplastic Agents ,Breast Neoplasms ,Ligands ,Biochemistry ,Structure-Activity Relationship ,Breast cancer ,Protein Domains ,Cell Line, Tumor ,Drug Discovery ,medicine ,Cytotoxic T cell ,Humans ,MTT assay ,General Pharmacology, Toxicology and Pharmaceutics ,skin and connective tissue diseases ,Cell Proliferation ,Pharmacology ,Binding Sites ,biology ,Chemistry ,Organic Chemistry ,Aryl hydrocarbon receptor ,medicine.disease ,Isoquinolines ,Molecular biology ,Molecular Docking Simulation ,Phenotype ,Receptors, Aryl Hydrocarbon ,Cell culture ,Docking (molecular) ,SKBR3 ,biology.protein ,Molecular Medicine ,Benzimidazoles ,Female ,Drug Screening Assays, Antitumor - Abstract
To exploit the interaction of the aryl hydrocarbon receptor (AhR) pathway in developing breast cancer specific cytotoxic compounds, we examined the breast cancer selectivity and the docking pose of the AhR ligands (Z)-2-(2-aminophenyl)-1 H -benzo[ de ]isoquinoline-1,3(2 H )-dione (NAP-6; 5 ) and 10-chloro-7 H -benzo[ de ]benzo[4,5]imidazo[2,1- a ]isoquinolin-7-one (10-Cl-BBQ; 6 ). While the breast cancer selectivity of 5 in vitro is known, we discuss the SAR around this lead, and show for the first time using phenotypic cell line screening and the MTT assay that 6 also presents with breast cancer selectivity , notably in the triple negative (TN) receptor breast cancer cell line MDA-MB-468, the ER+ breast cancer cell lines T47D, ZR-75-1 and the HER2+ breast cancer cell line SKBR3 (GI 50 values of 0.098, 0.97, 0.13 and 0.21 µ M, respectively). Indeed, 6 is 55-fold more potent in MDA-MB-468 cells than the normal MCF10A breast cells (GI 50 of 0.098 vs 5.4 µ M) and more than 130-fold more potent than in cell lines derived from pancreas, brain and prostate (GI 50 of 0.098 vs 10-13 µ M). Molecular docking poses of 5 and 6 together with analogue synthesis and phenotypic screening show the importance of the naphthalene moiety, and an ortho-disposed substituent on the N -phenyl moiety for biological activity.
- Published
- 2020
22. 3,5-Bis(trifluoromethyl)phenylsulfonamides, a novel pancreatic cancer active lead. Investigation of the terminal aromatic moiety
- Author
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Jufeng, Sun, Joey I, Ambrus, Jennifer R, Baker, Cecilia C, Russell, Peter J, Cossar, Jennette A, Sakoff, Christopher J, Scarlett, and Adam, McCluskey
- Subjects
Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,Antineoplastic Agents ,Biochemistry ,Pancreatic Neoplasms ,Structure-Activity Relationship ,Cell Line, Tumor ,Drug Discovery ,Humans ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Molecular Biology ,Cell Proliferation - Abstract
Virtual screening identified N-(6-((4-bromobenzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzenesulfonamide (1) a lead compound that bound to the S100A2-p53 binding groove. S100A2 is a Ca
- Published
- 2022
23. Cover Image, Volume 40, Issue 3
- Author
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Jennifer R. Baker, Jennette A. Sakoff, and Adam McCluskey
- Subjects
Pharmacology ,Drug Discovery ,Molecular Medicine - Published
- 2020
24. Synthesis, Characterisation, and Biological Activity of the Ruthenium Complexes of the N4-Tetradentate (N4-TL), 1,6-Di(2′-pyridyl)-2,5-dimethyl-2,5-diazahexane (picenMe2)
- Author
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Janice R. Aldrich-Wright, Aleksandra Bjelosevic, Jennette A. Sakoff, Christopher P. Gordon, Yingjie Zhang, and Jayne Gilbert
- Subjects
Green chemistry ,chemistry.chemical_compound ,Quinoxaline ,chemistry ,Biocatalysis ,Phenanthroline ,Phenazine ,Supramolecular chemistry ,chemistry.chemical_element ,General Chemistry ,High-performance liquid chromatography ,Medicinal chemistry ,Ruthenium - Abstract
A series of complexes of the type rac-[Ru(N4-TL)(PL)]2+ (where N4-TL = 1,6-di(2′-pyridyl)-2,5-dimethyl-2,5-diazahexane (picenMe2, N4-TL-2) and PL = 1,10-phenanthroline (phen, Ru-2), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq, Ru-3), 7,8-dimethyl-dipyrido[3,2-a:2′,3′-c]phenazine (dppzMe2, Ru-4), 2-phenyl-1H-imidazo[4,5-f][1,10]phenanthroline (phenpyrBz, Ru-5), 2-(p-tolyl)-1H-imidazo[4,5-f][1,10]phenanthroline (phenpyrBzMe, Ru-6), and 2-(4-nitrophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline (phenpyrBzNO2, Ru-7), were synthesised. All structures were confirmed using NMR, electrospray ionisation mass spectrometry (ESI-MS), high-performance liquid chromatography (HPLC), and UV analysis and for four complexes X-ray crystallography. The in vitro cytotoxicity assays revealed that Ru-6 was 5, 10, and 40-fold more potent than oxaliplatin, cisplatin, and carboplatin, respectively.
- Published
- 2020
25. Synthesis, characterisation and biological activity of the ruthenium(II) complexes of the N4-tetradentate (N4-TL), 1,6-di(2′-pyridyl)-2,5-dibenzyl-2,5-diazahexane (picenBz2)
- Author
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Christopher J. Gordon, Aleksandra Bjelosevic, Janice R. Aldrich-Wright, Jennette A. Sakoff, Jayne Gilbert, Yingjie Zhang, and Brondwyn McGhie
- Subjects
Cisplatin ,Phenanthroline ,In vitro cytotoxicity ,Phenazine ,chemistry.chemical_element ,Biological activity ,Biochemistry ,Medicinal chemistry ,Ruthenium ,Inorganic Chemistry ,chemistry.chemical_compound ,Quinoxaline ,chemistry ,medicine ,Cancer cell lines ,medicine.drug - Abstract
A series of complexes of the type rac-cis-β-[Ru(N4-TL)(N2-bidentates)]2+ (where N4-TL = 1,6-di(2′-pyridyl)-2,5-dibenzyl-2,5-diazahexane (picenBz2, N4-TL-2) and N2-bidentates = 1,10-phenanthroline (phen, Ru-2), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq, Ru-3), 7,8-dimethyl-dipyrido[3,2-a:2′,3′-c] phenazine (dppzMe2, Ru-4), 2-phenyl-1H-imidazo[4,5-f][1,10]phenanthroline (phenpyrBz, Ru-5), 2-(p-tolyl)-1H-imidazo[4,5-f][1,10]phenanthroline (phenpyrBzMe, Ru-6), 2-(4-nitrophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline (phenpyrBzNO2, Ru-7), were synthesised and characterised and X-ray crystallography of Ru-5 obtained. The in vitro cytotoxicity assays revealed that Ru-6 was 5, 2 and 19-fold more potent than oxaliplatin, cisplatin, and carboplatin, respectively displaying an average GI50 value of ≈ 0.76 μM against a panel of 11 cancer cell lines.
- Published
- 2022
26. Screening phytochemical content, antioxidant, antimicrobial and cytotoxic activities of Catharanthus roseus (L.) G. Don stem extract and its fractions
- Author
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Hong Ngoc Thuy Pham, Christopher J. Scarlett, Quan V. Vuong, Jennette A. Sakoff, and Michael C. Bowyer
- Subjects
0301 basic medicine ,Antioxidant ,medicine.medical_treatment ,Bioengineering ,01 natural sciences ,Applied Microbiology and Biotechnology ,03 medical and health sciences ,chemistry.chemical_compound ,medicine ,Gallic acid ,biology ,Traditional medicine ,Chemistry ,Extraction (chemistry) ,Catharanthus roseus ,biology.organism_classification ,Antimicrobial ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,030104 developmental biology ,Phytochemical ,Apigenin ,Kaempferol ,Agronomy and Crop Science ,Food Science ,Biotechnology - Abstract
The aims of this study were to screen the phytochemical content, antioxidant, antimicrobial and cytotoxic properties of the extract and its fractions prepared from Catharanthus roseus (L.) G. Don (C. roseus) stem. C. roseus stem was powdered and extracted with methanol using ultrasound-assisted extraction to obtain the crude extract. The crude extract was further fractioned using liquid-liquid extraction technique to obtain extracts of increasing polarity including n-butanol and residual aqueous fractions. The crude extract and its derived fractions were then subjected to phytochemical screening and assayed for antioxidant, antimicrobial and cytotoxic activities. Results showed that the n-butanol fraction contained the highest levels of saponins and phenolics (3037.54 mg ESE/g and 77.87 mg GAE/g, respectively) and possessed the strongest antioxidant capacity amongst the tested extracts. HPLC analysis revealed that this n-butanol fraction had high levels of apigenin and kaempferol, whereas the aqueous fraction contained a high level of gallic acid. The n-butanol fraction was found to effectively inhibit the activity of Escherichia coli and Staphylococccus lugdunensis. The n-butanol fraction also possessed strong cytotoxic activity in vitro against a wide range of cancer cell lines including A2780 (ovarian), H460 (lung), A431 (skin), MIA PaCa-2 (pancreas), Du145 (prostate), HT29 (colon), MCF-7 (breast), BE2-C (neuroblastoma), SJ-G2, U87 and SMA (glioblastoma) at low doses (GI50 values of 5.2−21.0 µg/mL). These results indicate that the n-butanol fraction prepared from C. roseus stem is a rich source of bioactive compounds which can be isolated for further evaluation as potential antimicrobial drugs or antitumor therapeutic agents.
- Published
- 2018
27. A simplified method to calculate telomere length from Southern blot images of terminal restriction fragment lengths
- Author
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Jayne Gilbert, Lisa F. Lincz, Fiona E. Scorgie, Jennette A. Sakoff, and Madhu B. Garg
- Subjects
Adult ,Male ,General Biochemistry, Genetics and Molecular Biology ,Restriction fragment ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Image Processing, Computer-Assisted ,Humans ,Statistical software ,030304 developmental biology ,Southern blot ,Mathematics ,Aged ,0303 health sciences ,biology ,Gold standard (test) ,Middle Aged ,Telomere ,Peripheral blood ,Healthy Volunteers ,Blotting, Southern ,Terminal (electronics) ,biology.protein ,Female ,Cancer cell lines ,Algorithm ,030217 neurology & neurosurgery ,Software ,Biotechnology - Abstract
Southern blotting of DNA terminal restriction fragment lengths is the gold standard for measuring mean telomere length. Analysis of the final image is a crucial step in this process, however, current techniques are cumbersome and prone to error. Here we present a simple and accurate method for analyzing telomere smears. Basic 2D gel imaging software was used to automatically subtract background, generate standard curves and calculate net intensity and MW at each position (i) along the telomere smear. Our method required no statistical software or major data manipulation and correctly classified >80% of 18 samples as having short, medium or long telomeres compared with 33–72% using other methods.
- Published
- 2019
28. Synthesis, characterisation and influence of lipophilicity on cellular accumulation and cytotoxicity of unconventional platinum(iv) prodrugs as potent anticancer agents
- Author
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Krishant M Deo, Janice R. Aldrich Wright, Jayne Gilbert, Yingjie Zhang, and Jennette A. Sakoff
- Subjects
Models, Molecular ,Organoplatinum Compounds ,Stereochemistry ,Molecular Conformation ,chemistry.chemical_element ,Antineoplastic Agents ,Chemistry Techniques, Synthetic ,010402 general chemistry ,01 natural sciences ,Inorganic Chemistry ,chemistry.chemical_compound ,DU145 ,medicine ,Humans ,Prodrugs ,Carboxylate ,Cytotoxicity ,Cisplatin ,010405 organic chemistry ,Prodrug ,0104 chemical sciences ,chemistry ,Lipophilicity ,Cancer cell ,Platinum ,HT29 Cells ,Hydrophobic and Hydrophilic Interactions ,medicine.drug ,Phenanthrolines - Abstract
Lipophilic platinum(IV) complexes were synthesised of the type [Pt(HL)(AL)(OH)(R)]2+ and [Pt(HL)(AL)(R)2]2+ (HL = 5,6-dimethyl-1,10-phenanthroline or 1,10-phenanthroline; AL = 1S,2S-diaminocyclohexane and R = increasingly lipophilic carboxylate axial ligands (C10–18)) from hydrophilic platinum(II) precursors that exhibit exceptional anticancer activity. The increased overall lipophilicity of the complexes suggested the formation of spontaneously self-assembled structures in an aqueous environment. The anti-proliferative properties were assessed against one non-cancerous and a panel of cancerous cell lines. Nanomolar levels of activity were observed against several cell lines, with the lowest GI50 of 3.4 nm against the Du145 prostate cancer cell line and over 1100-fold greater activity than cisplatin against HT29 colon carcinoma. RP-HPLC was utilised to establish the relative lipophilicities of each complex. While there seemed to be an increase in cellular accumulation for the lipophilic derivatives in some instances, ICP-MS studies showed no clear correlation between increasing lipophilicity, cellular accumulation and cytotoxicity.
- Published
- 2019
29. Dichlorophenylacrylonitriles as AhR Ligands That Display Selective Breast Cancer Cytotoxicity in vitro
- Author
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Jennifer R. Baker, Jennette A. Sakoff, Adam McCluskey, Jayne Gilbert, Xiao Zhu, and Stefan Paula
- Subjects
0301 basic medicine ,Halogenation ,Cell Survival ,Antineoplastic Agents ,Breast Neoplasms ,Crystallography, X-Ray ,Ligands ,Biochemistry ,Medicinal chemistry ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,DU145 ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Moiety ,General Pharmacology, Toxicology and Pharmaceutics ,Cytotoxicity ,Pharmacology ,Acrylonitrile ,Organic Chemistry ,Molecular Docking Simulation ,030104 developmental biology ,Receptors, Aryl Hydrocarbon ,chemistry ,SKBR3 ,030220 oncology & carcinogenesis ,Molecular Medicine ,Female ,Knoevenagel condensation ,Drug Screening Assays, Antitumor ,Growth inhibition ,Acetamide - Abstract
Knoevenagel condensation of 3,4-dichloro- and 2,6-dichlorophenylacetonitriles gave a library of dichlorophenylacrylonitriles. Our leads (Z)-2-(3,4-dichlorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile (5) and (Z)-2-(3,4-dichlorophenyl)-3-(4-nitrophenyl)acrylonitrile (6) displayed 0.56±0.03 and 0.127±0.04 μm growth inhibition (GI50 ) and 260-fold selectivity for the MCF-7 breast cancer cell line. A 2,6-dichlorophenyl moiety saw a 10-fold decrease in potency; additional nitrogen moieties (-NO2 ) enhanced activity (Z)-2-(2,6-dichloro-3-nitrophenyl)-3-(2-nitrophenyl)acrylonitrile (26) and (Z)-2-(2,6-dichloro-3-nitrophenyl)-3-(3-nitrophenyl)acrylonitrile (27), with the corresponding -NH2 analogues (Z)-2-(3-amino-2,6-dichlorophenyl)-3-(2-aminophenyl)acrylonitrile (29) and (Z)-2-(3-amino-2,6-dichlorophenyl)-3-(3-aminophenyl)acrylonitrile (30) being more potent. Despite this, both 29 (2.8±0.03 μm) and 30 (2.8±0.03 μm) were found to be 10-fold less cytotoxic than 6. A bromine moiety effected a 3-fold enhancement in solubility with (Z)-3-(5-bromo-1H-pyrrol-2-yl)-2-(3,4-dichlorophenyl)acrylonitrile 18 relative to 5 at 211 μg mL-1 . Modeling-guided synthesis saw the introduction of 4-aminophenyl substituents (Z)-3-(4-aminophenyl)-2-(3,4-dichlorophenyl)acrylonitrile (35) and (Z)-N-(4-(2-cyano-2-(3,4-dichlorophenyl)vinyl)phenyl)acetamide (38), with respective GI50 values of 0.030±0.014 and 0.034±0.01 μm. Other analogues such as 35 and 36 were found to have sub-micromolar potency against our panel of cancer cell lines (HT29, colon; U87 and SJ-G2, glioblastoma; A2780, ovarian; H460, lung; A431, skin; Du145, prostate; BE2-C, neuroblastoma; MIA, pancreas; and SMA, murine glioblastoma), except compound 38 against the U87 cell line. A more extensive evaluation of 38 ((Z)-N-(4-(2-cyano-2-(3,4-dichlorophenyl)vinyl)phenyl)acetamide) in a panel of drug-resistant breast carcinoma cell lines showed 10-206 nm potency against MDAMB468, T47D, ZR-75-1, SKBR3, and BT474. Molecular Operating Environment docking scores showed a good correlation between predicted binding efficiencies and observed MCF-7 cytotoxicity. This supports the use of this model in the development of breast-cancer-specific drugs.
- Published
- 2018
30. (Z)-2-(3,4-Dichlorophenyl)-3-(1H-Pyrrol-2-yl)Acrylonitrile Exhibits Selective Antitumor Activity in Breast Cancer Cell Lines via the Aryl Hydrocarbon Receptor Pathway
- Author
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Mark Tarleton, Jennette A. Sakoff, Geoffry N. De Iuliis, Jayne Gilbert, and Adam McCluskey
- Subjects
0301 basic medicine ,Pharmacology ,Cell cycle checkpoint ,Aryl hydrocarbon receptor nuclear translocator ,biology ,Aryl hydrocarbon receptor ,medicine.disease ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Breast cancer ,chemistry ,SKBR3 ,Cell culture ,030220 oncology & carcinogenesis ,biology.protein ,medicine ,Cancer research ,Molecular Medicine ,Growth inhibition ,skin and connective tissue diseases ,Receptor - Abstract
We have previously reported the synthesis and breast cancer selectivity of (Z)-2-(3,4-dichlorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile (ANI-7) in cancer cell lines. To further evaluate the selectivity of ANI-7, we have expanded upon the initial cell line panel to now include the breast cancer cell lines (MCF7, MCF7/VP16, BT474, T47D, ZR-75-1, SKBR3, MDA-MB-468, BT20, MDA-MB-231); normal breast cells (MCF-10A); and cell lines derived from colon (HT29), ovarian (A2780), lung (H460), skin (A431), neuronal (BE2C), glial (U87, SJG2), and pancreatic (MIA) cancers. We now show that ANI-7 is up to 263-fold more potent at inhibiting the growth of breast cancer cell lines (MCF7, MCF7/VP16, BT474, T47D, ZR-75-1, SKBR3, MDA-MB-468) than normal breast cells (MCF-10A) or cell lines derived from other tumor types. Measures of growth inhibition, cell cycle analysis, morphologic assessment, Western blotting, receptor binding, gene expression, small interfering RNA technology, reporter activity, and enzyme inhibition assays were exploited to define the mechanism of action of ANI-7. In this work, we report that ANI-7 mediates its effects via the activation of the aryl hydrocarbon receptor (AhR) pathway and the subsequent induction of CYP1-metabolizing mono-oxygenases. The metabolic conversion of ANI-7 induces DNA damage, checkpoint activation, S-phase cell cycle arrest, and cell death in sensitive breast cancer cell lines. Basal expression of AhR, the AhR nuclear translocator, and the CYP1 family members do not predict for sensitivity; however, inherent expression of the phase II-metabolizing enzyme sulfur transferase 1A1 does. For the first time, we identify (Z)-2-(3,4-dichlorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile as a new AhR ligand.
- Published
- 2017
31. Bioactive α,β-conjugated 3-keto-steroids from the Australian brown alga Cystophora xiphocarpa
- Author
-
Ian A. van Altena, Cheri Motti, Yuhanis Mhd Bakri, Diana Angélica Zaleta Pinet, Ian P. Holland, and Jennette A. Sakoff
- Subjects
0106 biological sciences ,Cystophora ,Colorectal cancer ,Plant Science ,Horticulture ,Phaeophyta ,01 natural sciences ,Biochemistry ,Cell Line, Tumor ,medicine ,Humans ,Cytotoxicity ,Molecular Biology ,Ovarian Neoplasms ,biology ,010405 organic chemistry ,Chemistry ,Cell growth ,Australia ,Diastereomer ,General Medicine ,biology.organism_classification ,medicine.disease ,0104 chemical sciences ,Brown algae ,Sargassaceae ,Female ,Steroids ,Fucales ,010606 plant biology & botany - Abstract
As part of our ongoing study of the specialised metabolites present in brown algae belonging to the Cystophora genus, eight new steroids including three pairs of diastereoisomers were isolated from Cystophora xiphocarpa (Harvey) (Sargassacea, Fucales). The metabolites identified by standard spectrometric methods are (16S,22S)-16,22-dihydroxyergosta-4,24(28)-dien-3-one and (16S,22R)-16,22-dihydroxyergosta-4,24(28)-dien-3-one, (16S,22S,24R)-16,22,24-trihydroxyporifera-4,28-dien-3-one and (16S,22S,24S)-16,22,24-trihydroxystigma-4,28-dien-3-one along with (16S,22S,24E)-16,22-dihydroxystigma-4,24(28)-dien-3-one and (16S,20S)-16,20-dihydroxyergosta-4,24(28)-dien-3-one. (16S,22S,24E)-16,22-Dihydroxystigma-4,24(28)-dien-3-one possessed the most potent cytotoxicity of the steroids in this series with cell growth inhibitions of GI50 8.7 ± 0.7 μM against colon cancer HT29, GI50 5.6 ± 0.8 μM against the breast cancer line MCF-7 and GI50 4.5 ± 0.2 μM against the ovarian cancer cell line A2780. (16S,22R)-16,22-dihydroxyergosta-4,24(28)-dien-3-one was found to be active against the ovarian cancer cell line A2780 with a GI50 of 6.2 ± 0.1 μM.
- Published
- 2021
32. Small-Molecule Inhibitors of the NusB–NusE Protein–Protein Interaction with Antibiotic Activity
- Author
-
Mohammed K. Abdel-Hamid, Christopher P. Gordon, Trieu N. Trinh, Peter J. Lewis, Jennette A. Sakoff, Adam McCluskey, Peter J. Cossar, and Cong Ma
- Subjects
biology ,010405 organic chemistry ,Chemistry ,Stereochemistry ,General Chemical Engineering ,General Chemistry ,Bacillus subtilis ,010402 general chemistry ,medicine.disease_cause ,biology.organism_classification ,01 natural sciences ,Small molecule ,Article ,In vitro ,0104 chemical sciences ,Protein–protein interaction ,lcsh:Chemistry ,chemistry.chemical_compound ,lcsh:QD1-999 ,Biochemistry ,Antitermination ,medicine ,Pharmacophore ,Growth inhibition ,Escherichia coli - Abstract
The NusB–NusE protein–protein interaction (PPI) is critical to the formation of stable antitermination complexes required for stable RNA transcription in all bacteria. This PPI is an emerging antibacterial drug target. Pharmacophore-based screening of the mini-Maybridge compound library (56 000 molecules) identified N,N′-[1,4-butanediylbis(oxy-4,1-phenylene)]bis(N-ethyl)urea 1 as a lead of interest. Competitive enzyme-linked immunosorbent assay screening validated 1 as a 20 μM potent inhibitor of NusB–NusE. Four focused compound libraries based on 1, comprising 34 compounds in total were designed, synthesized, and evaluated as NusB–NusE PPI inhibitors. Ten analogues displayed NusB–NusE PPI inhibition ≥50% at 25 μM concentration in vitro. In contrast to representative Gram-negative Escherichia coli and Gram-positive Bacillus subtilis species, these analogues showed up to 100% growth inhibition at 200 μM. 2-((Z)-4-(((Z)-4-(4-((E)-(Carbamimidoylimino)methyl)phenoxy)but-2-en-1-yl)oxy)benzylidene)hydrazine-1-carboximidamide 22 showed excellent activity against important pathogens. With minimum inhibitory concentration values of ≤3 μg/mL for Gram-positive Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus and ≤51 μg/mL for Gram-negative Pseudomonas aeruginosa and Acinetobacter baumannii, 22 is a potent lead for a novel antibacterial target. Epifluorescence studies in live bacteria were consistent with 22, inhibiting the NusB–NusE PPI as proposed.
- Published
- 2017
33. Investigating the cytotoxicity of platinum(II) complexes incorporating bidentate pyridyl-1,2,3-triazole 'click' ligands
- Author
-
Feng Li, James D. Crowley, Jennette A. Sakoff, Yingjie Zhang, Jayne Gilbert, Janice R. Aldrich-Wright, Benjamin J. Pages, and Dan Preston
- Subjects
Magnetic Resonance Spectroscopy ,1,2,3-Triazole ,Denticity ,Organoplatinum Compounds ,Stereochemistry ,Triazole ,chemistry.chemical_element ,Crystallography, X-Ray ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Medicinal chemistry ,Cell Line ,Inorganic Chemistry ,chemistry.chemical_compound ,Pyridine ,Humans ,Cytotoxins ,010405 organic chemistry ,Ligand ,Nuclear magnetic resonance spectroscopy ,Triazoles ,0104 chemical sciences ,chemistry ,MCF-7 Cells ,Click chemistry ,Click Chemistry ,Platinum - Abstract
Six platinum(II) complexes of the type [Pt(PL)(AL)]2+, where PL is a bidentate pyridyl-1,2,3-triazole "click" ligand and AL is the R,R or S,S isomer of 1.2-diaminocyclohexane, have been synthesised and characterised by several methods including elemental microanalysis, proton NMR spectroscopy and X-ray crystallography. The in vitro cytotoxicity of each complex was assessed in eleven cell lines, revealing moderate to good activity for complexes incorporating 2-(1-phenyl-1H-1,2,3-triazol-4-yl)pyridine.
- Published
- 2016
34. Antioxidant and anti-proliferative properties of Davidson’s plum (Davidsonia pruriens F. Muell) phenolic-enriched extracts as affected by different extraction solvents
- Author
-
Sathira Hirun, Quan V. Vuong, Christopher J. Scarlett, Jennette A. Sakoff, Michael C. Bowyer, Tiffany L.K. Chuen, Melanie J. Predebon, and Chloe D. Goldsmith
- Subjects
0301 basic medicine ,030109 nutrition & dietetics ,Antioxidant ,ABTS ,biology ,Traditional medicine ,DPPH ,medicine.medical_treatment ,010401 analytical chemistry ,Extraction (chemistry) ,biology.organism_classification ,01 natural sciences ,0104 chemical sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Nutraceutical ,Complementary and alternative medicine ,Proanthocyanidin ,chemistry ,Polyphenol ,medicine ,Davidsonia pruriens - Abstract
The Davidson’s plum (DP; Davidsonia pruriens F. Muell) is a fruit native to Australia that is a rich source of phenolic compounds. This study investigated the effects of various extraction solvents (ethanol, methanol, acetone and water) on total phenolic content (TPC), antioxidant capacity (ABTS, DPPH, CUPRAC, FRAP assays) and anti-proliferative activity (MTT, CCK-8 assays) of DP. Our data revealed that extraction solvents significantly affected the physico-chemical, antioxidant and anti-proliferative properties of DP extracts. Within the tested solvents, ethanol was found to be the optimal solvent for extraction of bioactive compounds from DP as its extract had the greatest TPC (94.13 GAE/g), flavonoids (78.33 mg RUE/g), proanthocyanidins (5.33 mg CAE/g), anthocyanidins (2.81 mg CGE/g), as well as possessed the highest antioxidant capacity and anti-proliferative activity against a panel of cancer cell lines. This included cancers of the pancreas, breast, lung, brain, skin, colon and ovary. Therefore, further investigations should be conducted to identify key bioactive compounds to determine the potential for utilization in the nutraceutical and phytopharmaceutical industries.
- Published
- 2016
35. Synthesis and Cytotoxicity of Octahydroepoxyisoindole-7-carboxylic Acids and Norcantharidin-Amide Hybrids as Norcantharidin Analogues
- Author
-
Jayne Gilbert, Lacey Hizartzidis, Adam McCluskey, Jennette A. Sakoff, and Christopher P. Gordon
- Subjects
Stereochemistry ,Ether ,Antineoplastic Agents ,Isoindoles ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Structure-Activity Relationship ,Amide ,Cell Line, Tumor ,Drug Discovery ,Humans ,Carboxylate ,General Pharmacology, Toxicology and Pharmaceutics ,Cytotoxicity ,neoplasms ,Cell Proliferation ,Pharmacology ,Norcantharidin ,Bicyclic molecule ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,Bridged Bicyclo Compounds, Heterocyclic ,Heptene ,Amides ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry ,Molecular Medicine ,Growth inhibition ,Drug Screening Assays, Antitumor - Abstract
Octahydroepoxyisoindole analogues of norcantharidin were accessed through a Diels-Alder reaction of an amine-substituted furan with maleic anhydride and subsequent reduction of the bicyclo[2.2.1]heptene olefin. Despite retention of the carboxylate and the ether bridgehead known to impart cytotoxic activity to norcantharidin, none of these analogues displayed notable cytotoxicity against the 11 cell lines examined: HT29 (colon), MCF-7 (breast), A2780 (ovarian), H460 (lung), A431 (skin), Du145 (prostate), BE2-C (neuroblastoma), SJ-G2 and U87 (glioblastoma), MIA (pancreatic), and SMA (spontaneous murine astrocytoma). The incorporation of an amino-substituted system post-synthesis of norcantharidin afforded facile access to 14 acid/amide-substituted norcantharidin analogues. Of these, only four displayed sufficient activity at the initial 25 μm compound screening dose to warrant full evaluation of growth inhibition. Common to these analogues was the presence of a 4-biphenyl moiety, and in particular 3-(2-(furan-2-ylmethyl)-3-(4-biphenylamino)-3-oxopropylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (13 c) and 3-(2-(pyrrole-2-ylmethyl)-3-(4-biphenylamino)-3-oxopropylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (24) displayed high levels of cytotoxicity, returning GI50 values of 15 nm (HT29) to 2.9 μm (U87) and 17 nm (SMA) to 2.8 μm (U87), respectively. These are the most cytotoxic norcantharidin analogues reported to date.
- Published
- 2019
36. Quinolone-1-(2H)-ones as hedgehog signalling pathway inhibitors
- Author
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Jennette A. Sakoff, Eileen A. McLaughlin, Christopher P. Gordon, V. Pye, Peter J. Cossar, Mohammed K. Abdel-Hamid, Ilana R. Bernstein, Adam McCluskey, and Trieu N. Trinh
- Subjects
0301 basic medicine ,Stereochemistry ,Antineoplastic Agents ,Quinolones ,Biochemistry ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Downregulation and upregulation ,Cell Line, Tumor ,Humans ,Moiety ,Hedgehog Proteins ,Physical and Theoretical Chemistry ,Cytotoxicity ,Cell Proliferation ,Indole test ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,Hedgehog signaling pathway ,030104 developmental biology ,chemistry ,Cell culture ,Drug Screening Assays, Antitumor ,Pharmacophore ,Acetamide ,Signal Transduction - Abstract
A series of quinolone-2-(1H)-ones derived from the Ugi-Knoevenagel three- and four-component reaction were prepared exhibiting low micromolar cytotoxicity against a panel of eight human cancer cell lines known to possess the Hedgehog Signalling Pathway (HSP) components, as well as the seminoma TCAM-2 cell line. A focused SAR study was conducted and revealed core characteristics of the quinolone-2-(1H)-ones required for cytotoxicity. These requirements included a C3-tethered indole moiety, an indole C5-methyl moiety, an aliphatic tail or an ester, as well as an additional aromatic moiety. Further investigation in the SAG-activated Shh-LIGHT2 cell line with the most active analogues: 2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(1-methyl-1H-indol-3-yl)-N-(pentan-2-yl)acetamide (5), 2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(5-methyl-1H-indol-3-yl)-N-(pentan-2-yl)acetamide (23) and ethyl (2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(5-methyl-1H-indol-3-yl)acetyl)glycinate (24) demonstrated a down regulation of the HSP via a reduction in Gli expression, and in the mRNA levels of Ptch1 and Gli2. Analogues 5, 23 and 24 returned in cell inhibition values of 11.6, 2.9 and 3.1 μM, respectively, making this new HSP-inhibitor pharmacophore amongst the most potent non-Smo targeted inhibitors thus far reported.
- Published
- 2016
37. A facile hybrid ‘flow and batch’ access to substituted 3,4-dihydro-2H-benzo[b][1,4]oxazinones
- Author
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Shelby L. Frailey, Jennifer R. Baker, Jennette A. Sakoff, Adam McCluskey, Andrew J. S. Lin, and Cecilia C. Russell
- Subjects
Stereochemistry ,Antineoplastic Agents ,Chemistry Techniques, Synthetic ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Esterase ,Cell Line ,Small Molecule Libraries ,chemistry.chemical_compound ,Cell Line, Tumor ,Amide ,Animals ,Humans ,Potency ,Cytotoxic T cell ,Physical and Theoretical Chemistry ,Cytotoxicity ,Cell Proliferation ,010405 organic chemistry ,Organic Chemistry ,Benzoxazines ,0104 chemical sciences ,chemistry ,Cell culture ,Toxicity ,Drug Screening Assays, Antitumor ,Growth inhibition - Abstract
We describe a simple flow chemistry approach to libraries of ethyl 3-oxo-2-(substituted-phenylamino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylates (12a–l) and N-ethyl-3-oxo-2-(substituted-phenylamino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamides (13a–l) in 38–87% yields. This scaffold is poorly described in the chemical literature. Screening against a panel of 11 cancer and one normal cell line showed that the amide linked library 13a–l was devoid of toxicity. Whereas the ester linked analogues 12b, 12c, 12g, 12j and 12l were highly cytotoxic with growth inhibition (GI50) values from 0.34 to >50 μM across all cell lines, with the 2-OH-Ph substituted 12l analogue presenting with sub-micromolar potency against the A2780 (ovarian; 0.34 ± 0.04 μM), BEC-2 (glioblastoma; 0.35 ± 0.06 μM), MIA (pancreas; 0.91 ± 0.054 μM) and SMA (murine glioblastoma; 0.77 ± 0.029 μM) carcinoma cell lines. Interestingly, the U87 glioblastoma cell line showed inherent resistance to growth inhibition by all analogues (GI50 32 to >50 μM) while the A2780 cells were highly sensitive (GI50 3.8–0.34 μM), suggesting that the analogues developed herein may be valuable lead compounds for the development of ovarian carcinoma specific cytotoxic agents. The differences in amide versus ester cytotoxicity was consitent with esterase cleaveage to release the cytotoxic warhead.
- Published
- 2016
38. Oral Abstracts
- Author
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Stephen E. Rose, Michael Fay, Stuart Crozier, Jennifer H. Martin, Klaus Dittman, Jennette A. Sakoff, Andrew W. Boyd, and Hans-Peter Rodemann
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Oncology ,medicine.medical_specialty ,biology ,business.industry ,General Medicine ,medicine.disease ,EPH receptor A2 ,Internal medicine ,biology.protein ,Cancer research ,Medicine ,Sensitivity (control systems) ,Irradiation ,Antibody ,U87 ,business ,Glioblastoma - Published
- 2015
39. Tin(IV) compounds of tridentate thiosemicarbazone Schiff bases: Synthesis, characterization, in-silico analysis and in vitro cytotoxicity
- Author
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Edward R. T. Tiekink, Enis Nadia Md Yusof, Jennette A. Sakoff, Alister J. Page, Thahira Begum S. A. Ravoof, Abhi Veerakumarasivam, and Michela I. Simone
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chemistry.chemical_classification ,010405 organic chemistry ,Hydrogen bond ,Aryl ,Synthon ,Supramolecular chemistry ,010402 general chemistry ,01 natural sciences ,Medicinal chemistry ,0104 chemical sciences ,Inorganic Chemistry ,Azine ,chemistry.chemical_compound ,chemistry ,Materials Chemistry ,Amine gas treating ,Physical and Theoretical Chemistry ,Semicarbazone ,Alkyl - Abstract
Twelve tin(IV) compounds (5–16) derived from four tridentate thiosemicarbazone Schiff bases of 4-methyl-3-thiosemicarbazide with 2-hydroxy-3-methoxybenzaldehyde (1, 2) and 4-phenyl-3-thiosemicarbazide with 2,3-dihydroxybenzaldehyde (3, 4) of the general formulae [R2Sn(Ln)] and [Sn(Ln)2] (where R = Ph or Me; Ln = 1, 2, 3 and 4) were synthesized and characterized by elemental analysis, IR, UV–vis, mass spectrometry and multinuclear NMR (1H, 13C and 119Sn) spectroscopy. X-ray crystallographic data was obtained for 11′, a 2:1 co-crystal between Ph2Sn(L2) (11) and 3-methoxysalicylaldehyde azine, and Me2Sn(L2) (12) where L2H2 is 2-(2-hydroxy-3-methoxybenzylidene)-N-phenylhydrazinecarbothioamide. The analysis revealed distinct coordination geometries for 11 and 12 approaching trigonal–bipyramidal. In the crystal of 11′, supramolecular dimers arising from amine N H…S(thiolate) hydrogen bonding and {…HNCS}2 synthons are evident; π(chelate ring)…π(oxidobenzylidene) stacking is also apparent. In the crystal of 12, supramolecular, helical chains are generated by a combination of amine N H…O(phenoxide) hydrogen bonding and Sn…S secondary bonding. The cytotoxic activity of the compounds against a panel of ten cancer cell lines, [HT29 (colon), U87 and SJ-G2 (glioblastoma), MCF-7 (breast), A2780 (ovarian), H460 (lung), A431 (skin), DU145 (prostate), BE2-C (neuroblastoma) and MIA (pancreas), and one normal cell line, MCF-10A (normal breast)] were investigated. The thiosemicarbazone Schiff bases 1 and 4 as well as the diphenyltin(IV) compounds showed a strong ability to inhibit the growth of cancer cells, with particular selectivity against HT29, MCF-7, A2780, A431, BE2-C, SJ-G2 and MIA cell lines. The structure–activity relationship of all these compounds were studied by evaluating the effect of alkyl and aryl groups attached on the thiosemicarbazone backbone, the methoxy/hydroxyl groups present at the meta-position of the phenyl ring and alkyl or aryl groups bound to the tin center.
- Published
- 2020
40. Homoleptic tin(IV) compounds containing tridentate ONS dithiocarbazate Schiff bases: Synthesis, X-ray crystallography, DFT and cytotoxicity studies
- Author
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Mohamed Ibrahim Mohamed Tahir, Thahira Begum S. A. Ravoof, Jennette A. Sakoff, Alister J. Page, Edward R. T. Tiekink, Muhammad Alif Mohammad Latif, Abhi Veerakumarasivam, and Enis Nadia Md Yusof
- Subjects
Schiff base ,010405 organic chemistry ,Organic Chemistry ,Imine ,chemistry.chemical_element ,Crystal structure ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,Analytical Chemistry ,Inorganic Chemistry ,chemistry.chemical_compound ,Crystallography ,Molecular geometry ,chemistry ,Octahedron ,X-ray crystallography ,Homoleptic ,Tin ,Spectroscopy - Abstract
Six new tin(IV) compounds derived from tridentate dinegatively charged ONS dithiocarbazate Schiff bases derived from 2-hydroxy-3-methoxybenzaldehyde (H2L1, H2L2 and H2L3) and 2,3-dihydroxybenzaldehyde (H2L4, H2L5 and H2L6) (where H2Ln = di-acids of Schiff base) are reported. The compounds were characterised by elemental analysis, FT-IR and multinuclear NMR (1H, 13C and 119Sn) spectroscopy. The crystal structures of tin(IV) [S-4-methybenzyl-β-N-(2-hydroxy-3-methoxybenzylmethylene)dithiocarbazate] (2) and tin(IV) [S-benzyl-β-N-(2-hydroxy-3-methoxy benzylmethylene)dithiocarbazate] (3) were determined by X-ray single crystal diffraction analysis. X-ray crystallography showed the molecular geometries in homoleptic 2 and 3 to be quite similar in which the dinegative tridentate ligand coordinated the tin atoms via thiolate-S, phenoxide-O and imine-N atoms. The coordination geometries are based on an octahedron with like-atoms mutually trans. The experimental findings were validated by density functional theory (DFT) calculations at the B3LYP/LanL2DZ/6-311G(d,p) level of theory. All the tin(IV) compounds, except the insoluble compound 2 were screened for their in vitro cytotoxicity against a panel ten of cancer cell lines and one normal breast cell line (MCF-10 A) by MTT assay. Interestingly, the cytotoxicity of five tin(IV) compounds against HT29, MCF7 and MIA was higher than the reference drug, cisplatin.
- Published
- 2020
41. Phytochemical, antioxidant, anti-proliferative and antimicrobial properties of Catharanthus roseus root extract, saponin-enriched and aqueous fractions
- Author
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Quan V. Vuong, Christopher J. Scarlett, Hong Ngoc Thuy Pham, Jennette A. Sakoff, and Michael C. Bowyer
- Subjects
0301 basic medicine ,Catharanthus ,Phytochemicals ,Saponin ,Plant Roots ,Antioxidants ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Alkaloids ,Anti-Infective Agents ,Phenols ,Cell Line, Tumor ,Genetics ,Humans ,Gallic acid ,Molecular Biology ,Cell Proliferation ,chemistry.chemical_classification ,Flavonoids ,Plants, Medicinal ,Traditional medicine ,biology ,Plant Extracts ,Aspergillus niger ,General Medicine ,Catharanthus roseus ,Saponins ,biology.organism_classification ,Antimicrobial ,Anti-Bacterial Agents ,030104 developmental biology ,chemistry ,Phytochemical ,030220 oncology & carcinogenesis ,Apigenin ,Kaempferol - Abstract
Catharanthus roseus (L.) G. Don (C. roseus) is a well-known medicinal plant for its source of alkaloids solely found in the leaves. Other parts including the root are usually discarded after the alkaloid extraction. This study sought to investigate phytochemical profiles, antioxidant, antimicrobial and cytotoxic properties of the C. roseus root extract (RE) and its two sub-fractions including saponin-enriched (SE) and aqueous (AQ) fractions. The results showed that the RE was a rich source of saponins (1744.44 mg ESE/g) and phenolics (51.27 mg GAE/g), which comprised of gallic acid (25.74 mg/g), apigenin (1.45 mg/g) and kaempferol (1.58 mg/g). The SE fraction was enriched with 31% of saponins and 63% of phenolics higher than those of the RE; whereas the concentrations of saponins and phenolics of the AQ fraction were lower than those of the RE by 40% and 74%, respectively. The content of gallic acid in the SE fraction was 1.4-fold and 1.5-fold higher than those of the RE or AQ fraction, respectively. The SE fraction demonstrated potent antioxidant capacity, which was significantly higher than the RE or AQ fraction, and also exhibited strong anti-proliferative activity against 11 cancer cell lines including A2780 (ovarian), H460 (lung), A431 (skin), MIA PaCa-2 (pancreas), Du145 (prostate), HT29 (colon), MCF-7 (breast), BE2-C (neuroblastoma), SJ-G2, U87 and SMA (glioblastoma) with low GI50 values (≤ 2.00 µg/mL). The SE fraction was also shown to effectively inhibit the growth of both bacteria (Escherichia coli, Enterobacter aerogenes and Staphylococccus lugdunensis) and fungi (Candida albicans and Aspergillus niger). These findings warrant further investigation to isolate major compounds from the SE fraction and further test their antioxidant, anticancer and antimicrobial activities.
- Published
- 2018
42. In vitro antibacterial and anticancer properties of Helicteres hirsuta Lour. leaf and stem extracts and their fractions
- Author
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Jennette A. Sakoff, Michael C. Bowyer, Hong Ngoc Thuy Pham, Christopher J. Scarlett, Quan V. Vuong, and Danielle R. Bond
- Subjects
0301 basic medicine ,Microbial Sensitivity Tests ,Antioxidants ,03 medical and health sciences ,Minimum inhibitory concentration ,0302 clinical medicine ,DU145 ,Neuroblastoma ,Cell Line, Tumor ,Helicteres hirsuta ,Genetics ,medicine ,Escherichia coli ,Cytotoxic T cell ,Anticarcinogenic Agents ,Humans ,Molecular Biology ,Malvaceae ,Plants, Medicinal ,Traditional medicine ,Plant Stems ,Chemistry ,Plant Extracts ,Staphylococcus lugdunensis ,Cancer ,General Medicine ,medicine.disease ,In vitro ,Anti-Bacterial Agents ,Plant Leaves ,030104 developmental biology ,030220 oncology & carcinogenesis ,Antibacterial activity ,Phytotherapy - Abstract
Helicteres hirsuta Lour. (H. hirsuta) has been considered as a herbal medicine for the treatment of malaria and diabetes but limited studies have been conducted on its anticancer and antibacterial properties. In this study, the in vitro antibacterial and anticancer properties of the leaf and stem extracts and their two sub-fractions (aqueous and saponin-enriched butanol fractions) prepared from H. hirsuta were elucidated. MTT and CCK-8 assays were employed to assess their in vitro anticancer properties against various cancer cell lines. The antibacterial activity was assessed using the disc diffusion method and minimum inhibitory concentration (MIC) values were determined. The results revealed that the saponin-enriched fractions from H. hirsuta leaves and stems showed the highest antibacterial activity against E. coli (MIC values of 2.50 and 5.00 mg/mL, respectively) and S. lugdunensis (MIC values of 0.35 and 0.50 mg/mL, respectively). Importantly, these saponin-enriched fractions possessed strong anticancer activity in vitro towards a range of cancer cell lines including MIA PaCa-2 (pancreas); A2780 (ovarian); H460 (lung); A431 (skin); Du145 (prostate); HT29 (colon); MCF-7 (breast); SJ-G2, U87, SMA (glioblastoma) and BE2-C (neuroblastoma) at low doses (GI50 values of 0.36–11.17 µg/mL). They especially revealed potent anti-pancreatic cancer activity in vitro against MIA PaCa-2, BxPC-3 and CFPAC-1 cells with IC50 values of 1.80–6.43 µg/mL. This finding provides scientific evidence of the cytotoxic activity of the extracts prepared from H. hirsuta leaves and stems, and suggests further studies to isolate active compounds for development of new anticancer agents from these plant extracts.
- Published
- 2018
43. Supporting Data from A focused library synthesis and cytotoxicity of quinones derived from the natural product bolinaquinone
- Author
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Azadeh Ghods, Gilbert, Jayne, Baker, Jennifer R., Cecilia C, Russell, Jennette A. Sakoff, and McCluskey, Adam
- Subjects
Condensed Matter::Strongly Correlated Electrons - Abstract
Compound characterisation and spectra
- Published
- 2018
- Full Text
- View/download PDF
44. Physicochemical, antioxidant and anti-cancer activity of a Eucalyptus robusta (Sm.) leaf aqueous extract
- Author
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Benjamin R. Munro, Quan V. Vuong, Christopher J. Scarlett, Jennette A. Sakoff, Michael C. Bowyer, Phoebe A. Phillips, Tiffany L.K. Chuen, Sathira Hirun, Anita C. Chalmers, and Chloe D. Goldsmith
- Subjects
Antioxidant ,Chemistry ,medicine.medical_treatment ,Cancer ,Water extraction ,Biological activity ,Ascorbic acid ,medicine.disease ,chemistry.chemical_compound ,Polyphenol ,Botany ,Toxicity ,medicine ,Food science ,alpha-Tocopherol ,Agronomy and Crop Science - Abstract
Eucalyptus robusta (Sm.) (ER) is a widely distributed tree native to the east coast of Australia, which has also been established in numerous other countries. ER leaves contain high levels of essential oils and are rich in total phenolic compounds (TPC), which have been linked with health benefits; however, there is limited information on the bioactivity of ER leaf extracts. This study aimed to optimise water extraction conditions for TPC, prepare a spray-dried powdered extract and test its physicochemical, antioxidant and anti-proliferative properties. The results showed that optimal water extraction conditions for TPC were 85 °C, 15 min and a water-to-leaf ratio of 20:1 mL/g. Under these conditions, spray-dried powdered extract was prepared with a recovery yield of 85%. The extract was water-soluble and had a TPC level of 407 mg GAE/g. It also possessed potent antioxidant capacity, comparable to pure ascorbic acid, but higher than pure α-tocopherol. In addition, the powdered extract demonstrated significant activity against a panel of cancer cell lines, which included cancers of the pancreas, breast, lung, brain, skin, colon and ovary. Of note, the ER extract exerted a more significant toxic effect on pancreatic cancer (PC) cells compared to gemcitabine, the first line chemotherapeutic agent for PC. We suggest that future studies should purify individual bioactive compounds from ER for further investigation of its potential health promoting and anti-cancer activity.
- Published
- 2015
45. Synthesis and anticancer activity of focused compound libraries from the natural product lead, oroidin
- Author
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Anthony D. Wright, Adam McCluskey, Kelly A. Young, Lauren Dyson, and Jennette A. Sakoff
- Subjects
Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,DU145 ,Neuroblastoma ,Drug Discovery ,medicine ,Animals ,Cytotoxic T cell ,Pyrroles ,Molecular Biology ,Cell Proliferation ,Biological Products ,Molecular Structure ,Chemistry ,Cell growth ,Alkaloid ,Organic Chemistry ,Cancer ,medicine.disease ,Combinatorial chemistry ,Molecular biology ,digestive system diseases ,Cell culture ,Molecular Medicine ,Growth inhibition - Abstract
Oroidin (1), (E)-N-(3-(2-amino-1H-imidazol-4-yl)allyl)-4,5-dibromo-1H-pyrrole-2-carboxamide, is a pyrrole alkaloid isolated from the marine sponge Agelas oroides. Routine screening in a panel of twelve cancer cell lines revealed 1 to be poorly cytotoxic with the 50% growth inhibition concentration (GI50) of 42 μM in MCF-7 (breast) cells and 24 μM in A2780 (ovarian) cells and >50 μM in all other cell lines tested. The development of eight focused libraries comprising thirty compounds total identified N-(biphenyl-4-ylmethyl)-1H-pyrrole-2-carboxamide (4l), N-benzyl-4,5-dibromo-1H-pyrrole-2-carboxamide (5a) and N-(biphenyl-4-ylmethyl)-4,5-dibromo-1H-pyrrole-2-carboxamide (5l) as potent inhibitors of cell growth in our panel of cell lines. Of these compounds GI50 values of
- Published
- 2014
46. Discovery of acrylonitrile-based small molecules active against Haemonchus contortus
- Author
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Christopher P. Gordon, Lacey Hizartzidis, Jennette A. Sakoff, Bronwyn E. Campbell, Robin B. Gasser, Jayne Gilbert, Mark Tarleton, and Adam McCluskey
- Subjects
Pharmacology ,Programmed cell death ,biology ,Stereochemistry ,Organic Chemistry ,Pharmaceutical Science ,biology.organism_classification ,Biochemistry ,Small molecule ,chemistry.chemical_compound ,chemistry ,Cell culture ,Amide ,Drug Discovery ,medicine ,Molecular Medicine ,Anthelmintic ,Acrylonitrile ,Cytotoxicity ,Haemonchus contortus ,medicine.drug - Abstract
We report the discovery of a series of acrylonitrile-containing molecules and α-amino amides which cause 99–100% lethality in H. contortus. Of the 22 acrylonitrile analogues investigated, the most active were 2-cyano-3-[1-(3-dimethylaminopropyl)-2-methyl-1H-indol-3-yl]-N-hexylacrylamide (13a), 2-cyano-3-[1(2-dimethylaminoethyl)-2-methyl-1H-indol-3-yl]-N-hexylacrylamide (13b), 2-cyano-3-{4-[3-(dimethylamino)propoxy]phenyl}-N-octylacrylamide (21), and 2-cyano-3-{1-[3-(dimethylamino)propyl]-1H-pyrrol-2-yl}-N-octylacrylamide (22) with each displaying LD50 values
- Published
- 2014
47. Cytotoxicity of a Series of Norcantharidin-Inspired Tetrahydroepoxyisoindole Carboxamides
- Author
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Janice R. Aldrich-Wright, Jack K. Clegg, Jayne Gilbert, Adam McCluskey, Lawson K. Spare, Mark Baker, Christopher P. Gordon, Feng Li, Pasquale Falsetta, David G. Harman, and Jennette A. Sakoff
- Subjects
medicine.drug_class ,Stereochemistry ,Molecular Conformation ,Carboxamide ,Antineoplastic Agents ,Isoindoles ,Crystallography, X-Ray ,01 natural sciences ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,0302 clinical medicine ,Isomerism ,Neuroblastoma ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,Cytotoxicity ,Pharmacology ,Cisplatin ,Norcantharidin ,010405 organic chemistry ,Organic Chemistry ,medicine.disease ,Bridged Bicyclo Compounds, Heterocyclic ,Amides ,0104 chemical sciences ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,Molecular Medicine ,Ugi reaction ,Drug Screening Assays, Antitumor ,Cis–trans isomerism ,medicine.drug - Abstract
A series of 28 norcantharidin (NorC)-inspired analogues were accessed via a robust two-step Ugi intramolecular Diels–Alder (IMDA) sequence. Four analogues displayed whole-cell cytotoxicity equipotent to that of NorC and cisplatin against a number of cancer cell lines and a normal breast cell line (MCF10A). Notably, (3S,3aS,6R)-2-benzyl-7-methyl-N-(naphthalen-2-yl)-1-oxo-1,2,3,6-tetrahydro-3a,6-epoxyisoindole-3-carboxamide (trans-27) displayed superior whole-cell activity against breast (MCF-7, GI=2.9 μm) and colon (HT29, GI=6.4 μm) cancer cell lines relative to the control (cisplatin), which elicited respective GIvalues of 6.5 and 11.3 μm against the aforementioned cell lines. This analogue also displayed improved activity relative to NorC across the breast (MCF-7, GI=2.9 μm; NorC GI=7.5 μm), ovarian (A2780, GI=2.2 μm; NorC GI=4.4 μm), and neuroblastoma (BE2-C, GI=2.2 μm; NorC GI=3.7 μm) cancer cell lines. Structure–activity relationship (SAR) investigations demonstrated that retention of sphybridized connections within the tetrahydroepoxyisoindole carboxamide scaffold is crucial, as aromatization to a phenolic functionality decreased activity, whereas removal of a single olefin bond abolished cytotoxicity. Nonetheless, with respect to the latter, use of crotonic acid as opposed 2-butynoic acid in the Ugi-IMDA sequence imparted a significant improvement to diastereoselectivity, with the cis/trans isomer ratio shifting from ≈1:1.2 to ≈0.5:9.5.
- Published
- 2016
48. Synthesis and characterisation of platinum(IV) polypyridyl complexes with halide axial ligands
- Author
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Jayne Gilbert, Brondwyn McGhie, Janice R. Aldrich-Wright, and Jennette A. Sakoff
- Subjects
Ethanol ,010405 organic chemistry ,Ligand ,Halide ,chemistry.chemical_element ,010402 general chemistry ,01 natural sciences ,Peroxide ,Medicinal chemistry ,Microanalysis ,0104 chemical sciences ,Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Reagent ,Oxidizing agent ,Materials Chemistry ,Physical and Theoretical Chemistry ,Platinum - Abstract
A series of complexes of the type [Pt(PL)(AL)(X)2]2+ (where PL = 1,10-phenanthroline, 5-methyl-1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline; AL = 1S,2S-diaminocyclohexane and, X = Cl, Br or I) with anticancer potency, were synthesised in a one pot reaction using N-halogensuccinimide (NXS) as both the source of the ligand and the oxidizing reagent. It was determined that 2.4 equivalents of NXS resulted in 100% oxidation of Pt(II) in a solution of equal parts H2O, ethanol and 1 M HCl. This method of oxidation was 24 times faster than the established peroxide method resulting in the acceleration of the complete synthesis of [Pt(PL)(AL)(X)2]2+. All structures were confirmed using NMR, ESI-MS, CD and UV, while the purity was confirmed by microanalysis. The in vitro cytotoxicity assays revealed that they were more active than analogous complexes with hydroxido axial ligands, and share comparable activity with the corresponding Pt(II) complex.
- Published
- 2019
49. Pyrimidyn Compounds: Dual-Action Small Molecule Pyrimidine-Based Dynamin Inhibitors
- Author
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Anna Mariana, Jennette A. Sakoff, Kelly A. Young, Luke R. Odell, Jayne Gilbert, Timothy A. Hill, Damien J. Keating, Aimee E. Novelle, Nick N. Gorgani, Phillip J. Robinson, Ngoc Chau, Megan Chircop, Ellen M. van Dam, James A. Daniel, Fiona M. Deane, Michael A. Cousin, Ainslie Whiting, Adam McCluskey, Annie Quan, Swetha Perera, and Andrew B. McGeachie
- Subjects
Dynamins ,endocrine system ,GTP' ,Blotting, Western ,macromolecular substances ,GTPase ,Biology ,Endocytosis ,Biochemistry ,Dynamin II ,Small Molecule Libraries ,Chlorocebus aethiops ,medicine ,Animals ,Dynamin ,Synaptic vesicle endocytosis ,Molecular Structure ,General Medicine ,Flow Cytometry ,Cell biology ,Pyrimidines ,Mechanism of action ,Drug Design ,COS Cells ,Phospholipid Binding ,Molecular Medicine ,Biological Assay ,biological phenomena, cell phenomena, and immunity ,medicine.symptom ,Protein Binding - Abstract
Dynamin is required for clathrin-mediated endocytosis (CME). Its GTPase activity is stimulated by phospholipid binding to its PH domain, which induces helical oligomerization. We have designed a series of novel pyrimidine-based "Pyrimidyn" compounds that inhibit the lipid-stimulated GTPase activity of full length dynamin I and II with similar potency. The most potent analogue, Pyrimidyn 7, has an IC50 of 1.1 μM for dynamin I and 1.8 μM for dynamin II, making it among the most potent dynamin inhibitors identified to date. We investigated the mechanism of action of the Pyrimidyn compounds in detail by examining the kinetics of Pyrimidyn 7 inhibition of dynamin. The compound competitively inhibits both GTP and phospholipid interactions with dynamin I. While both mechanisms of action have been previously observed separately, this is the first inhibitor series to incorporate both and thereby to target two distinct domains of dynamin. Pyrimidyn 6 and 7 reversibly inhibit CME of both transferrin and EGF in a number of non-neuronal cell lines as well as inhibiting synaptic vesicle endocytosis (SVE) in nerve terminals. Therefore, Pyrimidyn compounds block endocytosis by directly competing with GTP and lipid binding to dynamin, limiting both the recruitment of dynamin to membranes and its activation. This dual mode of action provides an important new tool for molecular dissection of dynamin's role in endocytosis.
- Published
- 2013
50. Focused library development of 2-phenylacrylamides as broad spectrum cytotoxic agents
- Author
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Mark Tarleton, Adam McCluskey, Lauren Dyson, Jennette A. Sakoff, and Jayne Gilbert
- Subjects
Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cell Line, Tumor ,Neoplasms ,Furan ,Drug Discovery ,Humans ,Potency ,Moiety ,Cytotoxicity ,Molecular Biology ,Cell Proliferation ,Acrylamides ,Cytotoxins ,Organic Chemistry ,chemistry ,Acrylamide ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Growth inhibition ,Acrylonitrile ,Lead compound - Abstract
With our lead compound (E)-3-(4-chlorophenyl)-2-(1H-pyrrole-2-carbonyl)acrylonitrile (1) inducing 50% growth inhibition of 11 cancer cell lines at 27–61 μM, potency enhancements were rapidly established through the synthesis of a series of focused compound libraries. Six highly focused libraries (46 compounds in total) were synthesised. Each library allowed the identification of a new lead compound, viz Library A identified (E)-3-(pentafluorophenyl)-2-(1H-pyrrole-2-carbonyl)acrylonitrile (11) and (E)-3-(1H-indol-3-yl)-2-(1H-pyrrole-2-carbonyl)acrylonitrile (13) as inhibitors with improved cytotoxicity. Synthesis of discrete libraries of amidoacrylamide analogues (Ar–C C(CN)–Ar✠Ar–C C(CN)–C( O)NH)–Ar) resulted in a series of analogues significantly more potent that the lead, 1. Three furan three analogues: (E)-3-(5-chlorofuran-2-yl)-2-cyano-N-(4-methoxybenzyl)acrylamide (33), (E)-3-(5-bromofuran-2-yl)-2-cyano-N-(4-methoxybenzyl)acrylamide (34) and (E)-2-cyano-3-(furan-3-yl)-N-(4-methoxybenzyl)acrylamide (37) returned broad spectrum growth inhibition (GI50 values of 5–16 μM). Replacement of the furan moiety with simple aromatics gave an additional three analogues: (E)-2-cyano-N-(4-methoxybenzyl)-3-phenylacrylamide (39), (E)-3-(4-chlorophenyl)-2-cyano-N-(4-methoxybenzyl)acrylamide (41) and (E)-2-cyano-N-(4-methoxyphenyl)-3-(naphthalen-1-yl)acrylamide (45) with GI50 values of 7–24 μM. The final library retained the aromatic substituents but introduced a 3,4-dichlorbenzylamine moiety to afford the 1-naphthyl substituted 52, which was the most potent broad spectrum cytotoxic analogue produced here in with an average GI50 = 8.6 μM. This represents a fivefold potency enhancement relative to 1 and a new cytotoxic scaffold suitable for further development.
- Published
- 2013
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