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243 results on '"Sakoff, Jennette"'

5. Next-generation of BBQ analogues that selectively target breast cancer.

Author

Baker, Jennifer R., Gilbert, Jayne, O'Brien, Nicholas S., Russell, Cecilia C., McCluskey, Adam, Sakoff, Jennette A., Wang, Wesley, Shen, Wenqi, and Afratis, Nikolaos A.

Subjects
BREAST cancer, ARYL hydrocarbon receptors, QUINOLINE, SUBSTITUENTS (Chemistry), IMIDAZOLES
Abstract

We previously reported on the interaction of 10-chloro-7H-benzo[de]benzo[4,5] imidazo[2,1-a]isoquinolin-7-one (10-Cl-BBQ) with the Aryl hydrocarbon Receptor (AhR) and selective growth inhibition in breast cancer cell lines. We now report on a library of BBQ analogues with substituents on the phenyl and naphthyl rings for biological screening. Herein, we show that absence of the phenyl Cl of 10-Cl-BBQ to produce the simple BBQ molecule substantially enhanced the growth inhibitory effect with GI50 values of 0.001-2.1 ^iM in select breast cancer cell lines MCF-7, T47D, ZR-75-1, SKBR3, MDA-MB-468, BT20, BT474 cells, while having modest effects of 2.1-7 ^iM in other cell lines including HT29, U87, SJ-G2, A2780, DU145, BE2-C, MIA, MDA-MB-231 or normal breast cells, MCF10A (3.2 ^iM). The most potent growth inhibitory effect of BBQ was observed in the triple negative cell line, MDA-MB-468 with a GI50 value of 0.001 ^M, presenting a 3,200-fold greater response than in the normal MCF10A breast cells. Additions of Cl, CH3, CN to the phenyl ring and ring expansion from benzoimidazole to dihydroquinazoline hindered the growth inhibitory potency of the BBQ analogues by blocking potential sites of CYP1 oxidative metabolism, while addition of Cl or NO2 to the naphthyl rings restored potency. In a cell-based reporter assay all analogues induced 1.2 to 10-fold AhR transcription activation. Gene expression analysis confirmed the induction of CYP1 oxygenases by BBQ. The CYP1 inhibitor a-naphthoflavone, and the SULT1A1 inhibitor quercetin significantly reduced the growth inhibitory effect of BBQ, confirming the importance of both phase I and II metabolic activation for growth inhibition. Conventional molecular modelling/docking revealed no significant differences between the binding poses of the most and least active analogues. More detailed DFT analysis at the DSD-PBEP86/Def-TZVPP level of theory could not identify significant geometric or electronic changes which would account for this varied AhR activation. Generation of Fukui functions at the same level of theory showed that CYP1 metabolism will primarily occur at the phenyl head group of the analogues, and substituents within this ring lead to lower cytotoxicity. [ABSTRACT FROM AUTHOR]

Published
2024
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15. Platinum(IV) Prodrugs Incorporating an Indole-Based Derivative, 5-Benzyloxyindole-3-Acetic Acid in the Axial Position Exhibit Prominent Anticancer Activity.

Author

Aputen, Angelico D., Elias, Maria George, Gilbert, Jayne, Sakoff, Jennette A., Gordon, Christopher P., Scott, Kieran F., and Aldrich-Wright, Janice R.

Subjects
ANTINEOPLASTIC agents, CARBOPLATIN, PRODRUGS, PLATINUM, HISTONE deacetylase, REACTIVE oxygen species, OXALIPLATIN, INDOLE
Abstract

Kinetically inert platinum(IV) complexes are a chemical strategy to overcome the impediments of standard platinum(II) antineoplastic drugs like cisplatin, oxaliplatin and carboplatin. In this study, we reported the syntheses and structural characterisation of three platinum(IV) complexes that incorporate 5-benzyloxyindole-3-acetic acid, a bioactive ligand that integrates an indole pharmacophore. The purity and chemical structures of the resultant complexes, P-5B3A, 5-5B3A and 56-5B3A were confirmed via spectroscopic means. The complexes were evaluated for anticancer activity against multiple human cell lines. All complexes proved to be considerably more active than cisplatin, oxaliplatin and carboplatin in most cell lines tested. Remarkably, 56-5B3A demonstrated the greatest anticancer activity, displaying GI50 values between 1.2 and 150 nM. Enhanced production of reactive oxygen species paired with the decline in mitochondrial activity as well as inhibition of histone deacetylase were also demonstrated by the complexes in HT29 colon cells. [ABSTRACT FROM AUTHOR]

Published
2024
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19. Data from Inhibition of Dynamin by Dynole 34-2 Induces Cell Death following Cytokinesis Failure in Cancer Cells

Author

Chircop, Megan, primary, Perera, Swetha, primary, Mariana, Anna, primary, Lau, Hui, primary, Ma, Maggie P.C., primary, Gilbert, Jayne, primary, Jones, Nigel C., primary, Gordon, Christopher P., primary, Young, Kelly A., primary, Morokoff, Andrew, primary, Sakoff, Jennette, primary, O'Brien, Terence J., primary, McCluskey, Adam, primary, and Robinson, Phillip J., primary

Published
2023
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20. Supplementary Figure 2 from Inhibition of Dynamin by Dynole 34-2 Induces Cell Death following Cytokinesis Failure in Cancer Cells

Author

Chircop, Megan, primary, Perera, Swetha, primary, Mariana, Anna, primary, Lau, Hui, primary, Ma, Maggie P.C., primary, Gilbert, Jayne, primary, Jones, Nigel C., primary, Gordon, Christopher P., primary, Young, Kelly A., primary, Morokoff, Andrew, primary, Sakoff, Jennette, primary, O'Brien, Terence J., primary, McCluskey, Adam, primary, and Robinson, Phillip J., primary

Published
2023
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21. Supplementary Figure 1 from Inhibition of Dynamin by Dynole 34-2 Induces Cell Death following Cytokinesis Failure in Cancer Cells

Author

Chircop, Megan, primary, Perera, Swetha, primary, Mariana, Anna, primary, Lau, Hui, primary, Ma, Maggie P.C., primary, Gilbert, Jayne, primary, Jones, Nigel C., primary, Gordon, Christopher P., primary, Young, Kelly A., primary, Morokoff, Andrew, primary, Sakoff, Jennette, primary, O'Brien, Terence J., primary, McCluskey, Adam, primary, and Robinson, Phillip J., primary

Published
2023
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22. Supplementary Methods, Table 1, Figure Legends 1-2 from Inhibition of Dynamin by Dynole 34-2 Induces Cell Death following Cytokinesis Failure in Cancer Cells

Author

Chircop, Megan, primary, Perera, Swetha, primary, Mariana, Anna, primary, Lau, Hui, primary, Ma, Maggie P.C., primary, Gilbert, Jayne, primary, Jones, Nigel C., primary, Gordon, Christopher P., primary, Young, Kelly A., primary, Morokoff, Andrew, primary, Sakoff, Jennette, primary, O'Brien, Terence J., primary, McCluskey, Adam, primary, and Robinson, Phillip J., primary

Published
2023
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25. 2,3-Dihydroquinazolin-4(1H)-ones and quinazolin-4(3H)-ones as broad-spectrum cytotoxic agents and their impact on tubulin polymerisationElectronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3md00600j

Author

O'Brien, Nicholas S., Gilbert, Jayne, McCluskey, Adam, and Sakoff, Jennette A.

Abstract

Tubulin plays a central role in mitosis and has been the target of multiple anticancer drugs, including paclitaxel. Herein two separate families of 2,3-dihydroquinazoline-4(1H)-ones and quinazoline-4(3H) ones, comprising 57 compounds in total, were synthesised. Screening against a broad panel of human 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) reveals these analogues to be broad spectrum cytotoxic compounds. Of particular note, 2-styrylquinazolin-4(3H)-one 51, 2-(4-hydroxystyryl)quinazolin-4(3H)-one 63, 2-(2-methoxystyryl)quinazolin-4(3H)-one 64and 2-(3-methoxystyryl)quinazolin-4(3H)-one 65and 2-(naphthalen-1-yl)-2,3-dihydroquinazolin-4(1H)-one 39exhibited sub-μM potency growth inhibition values. Of these 1-naphthyl 39has activity <50 nM against the HT29, U87, A2780, H460 and BE2-C cell lines. Molecular modelling of these compounds, e.g.2-(naphthalen-1-yl)-2,3-dihydroquinazolin-4(1H)-one 39, 2-(2-methoxystyryl)quinazolin-4(3H)-one 64, 2-(3-methoxystyryl)quinazolin-4(3H)-one 65, and 2-(4-methoxystyryl)quinazolin-4(3H)-one 50docked to the known tubulin polymerisation inhibitor sites highlighted well conserved interactions within the colchicine binding pocket. These compounds were examined in a tubulin polymerisation assay alongside the known tubulin polymerisation promotor, paclitaxel (69), and tubulin inhibitor, nocodazole (68). Of the analogues examined, indoles 43and 47were modest promotors of tubulin polymerisation, but less effective than paclitaxel. Analogues 39, 64, and 65showed reduced microtubule formation consistent with tubulin inhibition. The variation in ring methoxy substituent with 50, 64and 65, from o- to m- to p-, results in a concomitant reduction in cytotoxicity and a reduction in tubulin polymerisation, with p-OCH350being the least active in this series of analogues. This presents 64as a tubulin polymerisation inhibitor possessing novel chemotype and sub micromolar cytotoxicity. Naphthyl 39, with complete inhibition of tubulin polymerisation, gave rise to a sub 0.2 μM cell line cytotoxicity. Compounds 39and 64induced G2+ M cell cycle arrest indicative of inhibition of tubulin polymerisation, with 39inducing an equivalent effect on cell cycle arrest as nocodazole (68).

Published
2024
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27. Supplementary Figures 1-5 and Legends from The Dynamin Inhibitors MiTMAB and OcTMAB Induce Cytokinesis Failure and Inhibit Cell Proliferation in Human Cancer Cells

Author

Joshi, Sanket, primary, Perera, Swetha, primary, Gilbert, Jayne, primary, Smith, Charlotte M., primary, Mariana, Anna, primary, Gordon, Christopher P., primary, Sakoff, Jennette A., primary, McCluskey, Adam, primary, Robinson, Phillip J., primary, Braithwaite, Antony W., primary, and Chircop, Megan, primary

Published
2023
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31. Novel Platinum(II) and Platinum(IV) Antitumor Agents that Exhibit Potent Cytotoxicity and Selectivity

Author

Khoury, Aleen, primary, Elias, Elias, additional, Mehanna, Stephanie, additional, Shebaby, Wassim, additional, Deo, Krishant M., additional, Mansour, Najwa, additional, Khalil, Christian, additional, Sayyed, Katia, additional, Sakoff, Jennette A., additional, Gilbert, Jayne, additional, Daher, Costantine F., additional, Gordon, Christopher P., additional, Taleb, Robin I., additional, and Aldrich-Wright, Janice R., additional

Published
2022
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34. Potent Chlorambucil-Platinum(IV) Prodrugs

Author

Aputen, Angelico D., primary, Elias, Maria George, additional, Gilbert, Jayne, additional, Sakoff, Jennette A., additional, Gordon, Christopher P., additional, Scott, Kieran F., additional, and Aldrich-Wright, Janice R., additional

Published
2022
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35. Pyrimidyn‐Based Dynamin Inhibitors as Novel Cytotoxic Agents

Author

Odell, Luke R., Chau, Ngoc, Russell, Cecilia C., Young, Kelly A., Gilbert, Jayne, Robinson, Phillip J., Sakoff, Jennette A., McCluskey, Adam, Odell, Luke R., Chau, Ngoc, Russell, Cecilia C., Young, Kelly A., Gilbert, Jayne, Robinson, Phillip J., Sakoff, Jennette A., and McCluskey, Adam

Published
2022
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44. Novel piperazine-1,2,3-triazole leads for the potential treatment of pancreatic cancerElectronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d2md00289b

Author

Sun, Jufeng, Baker, Jennifer R., Russell, Cecilia C., Pham, Hong N. T., Goldsmith, Chloe D., Cossar, Peter J., Sakoff, Jennette A., Scarlett, Christopher J., and McCluskey, Adam

Abstract

From lead 1, (N-(4-((4-(3-(4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)propyl)piperazin-1-yl)sulfonyl)-phenyl)acetamide), a S100A2–p53 protein–protein interaction inhibitor based on an in silicomodelling driven hypothesis, four focused libraries were designed and synthesised. Growth inhibition screening was performed against 16 human cancer cell lines including the pancreatic cell lines MiaPaCa2, BxPC3, AsPC-1, Capan-2, HPAC, PANC-1 and the drug resistant CFPAC1. Modification of 1’s phenylacetamide moiety, gave Library 1with only modest pancreatic cancer activity. Modification of the 3-OCH3Ph moiety (Library 2) gave 4-CH3(26), 4-CH2CH3(27), 4-CF3(31) and 4-NO2(32) with sterically bulky groups more active. A 4-CF3acetamide replacement enhanced cytotoxicity (Library 3). The 4-C(CH3)336resulted in a predicted steric clash in the S100A2–p53 binding groove, with a potency decrease. Alkyl moieties afforded more potent analogues, 34(4-CH3) and 35(CH2CH3), a trend evident against pancreatic cancer: GI503.7 (35; BxPC-3) to 18 (40; AsPC-1) μM. Library 4analogues with a 2-CF3and 3-CF3benzenesulfonamide moiety were less active than the corresponding Library 3analogues. Two additional analogues were designed: 51(4-CF3; 4-OCH3) and 52(4-CF3; 2-OCH3) revealed 52to be 10–20 fold more active than 51, against the pancreatic cancer cell lines examined with sub-micromolar GI50values 0.43 (HPAC) to 0.61 μM (PANC-1). MOE calculated binding scores for each pose are also consistent with the observed biological activity with 52. The obtained SAR data is consistent with the proposed interaction within the S100A2–p53 bonding groove.

Published
2023
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45. Selective cytotoxicity of organotin(IV) compounds with 2,3-dihydroxybenzyldithiocarbazate Schiff bases

Author

Md Yusof, Enis Nadia, Mohamad Ishak, Nurul Nabihah, Mohammad Latif, Muhammad Alif, Mohamed Tahir, Mohamed Ibrahim, Sakoff, Jennette A., Page, Alister J., Tiekink, Edward R. T., Ravoof, Thahira B. S. A., Md Yusof, Enis Nadia, Mohamad Ishak, Nurul Nabihah, Mohammad Latif, Muhammad Alif, Mohamed Tahir, Mohamed Ibrahim, Sakoff, Jennette A., Page, Alister J., Tiekink, Edward R. T., and Ravoof, Thahira B. S. A.

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.

Published
2020

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