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13 results on '"Keely, Niall O."'

6. Novel Selective Estrogen Receptor Ligand Conjugates Incorporating Endoxifen-Combretastatin and Cyclofenil-Combretastatin Hybrid Scaffolds: Synthesis and Biochemical Evaluation.

Author

Kelly, Patrick M., Keely, Niall O., Bright, Sandra A., Yassin, Bassem, Ana, Gloria, Fayne, Darren, Zisterer, Daniela M., and Meegan, Mary J.

Subjects
*SELECTIVE estrogen receptor modulators, *NUCLEAR receptors (Biochemistry), *LIGANDS (Biochemistry), *BREAST cancer treatment, *OSTEOPOROSIS treatment
Abstract

Nuclear receptors such as the estrogen receptors (ERα and ERβ) modulate the effects of the estrogen hormones and are important targets for design of innovative chemotherapeutic agents for diseases such as breast cancer and osteoporosis. Conjugate and bifunctional compounds which incorporate an ER ligand offer a useful method of delivering cytotoxic drugs to tissue sites such as breast cancers which express ERs. A series of novel conjugate molecules incorporating both the ER ligands endoxifen and cyclofenil-endoxifen hybrids covalently linked to the antimitotic and tubulin targeting agent combretastatin A-4 were synthesised and evaluated as ER ligands. A number of these compounds demonstrated pro-apoptotic effects, with potent antiproliferative activity in ER-positive MCF-7 breast cancer cell lines and low cytotoxicity. These conjugates displayed binding affinity towards ERα and ERβ isoforms at nanomolar concentrations e.g., the cyclofenil-amide compound 13e is a promising lead compound of a clinically relevant ER conjugate with IC50 in MCF-7 cells of 187 nM, and binding affinity to ERα (IC50 = 19 nM) and ERβ (IC50 = 229 nM) while the endoxifen conjugate 16b demonstrates antiproliferative activity in MCF-7 cells (IC50 = 5.7 nM) and binding affinity to ERα (IC50 = 15 nM) and ERβ (IC50 = 115 nM). The ER binding effects are rationalised in a molecular modelling study in which the disruption of the ER helix-12 in the presence of compounds 11e, 13e and 16b is presented These conjugate compounds have potential application for further development as antineoplastic agents in the treatment of ER positive breast cancers [ABSTRACT FROM AUTHOR]

Published
2017
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8. The Vascular Targeting Agent Combretastatin-A4 and a Novelcis-Restricted β-Lactam Analogue, CA-432, Induce Apoptosis in Human Chronic Myeloid Leukemia Cells and Ex Vivo Patient Samples Including Those Displaying Multidrug Resistance

Author

Greene, Lisa M., primary, Nathwani, Seema M., additional, Bright, Sandra A., additional, Fayne, Darren, additional, Croke, Aisling, additional, Gagliardi, Maria, additional, McElligott, Anthony M., additional, O'Connor, Lisa, additional, Carr, Miriam, additional, Keely, Niall O., additional, O'Boyle, Niamh M., additional, Carroll, Peig, additional, Sarkadi, Balazs, additional, Conneally, Eibhlin, additional, Lloyd, David G., additional, Lawler, Mark, additional, Meegan, Mary J., additional, and Zisterer, Daniela M., additional

Published
2010
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9. The Vascular Targeting Agent Combretastatin-A4 and a Novel cis-Restricted β-Lactam Analogue, CA-432, Induce Apoptosis in Human Chronic Myeloid Leukemia Cells and Ex Vivo Patient Samples Including Those Displaying Multidrug Resistance

Author

Greene, Lisa M., Nathwani, Seema M., Bright, Sandra A., Fayne, Darren, Croke, Aisling, Gagliardi, Maria, McElligott, Anthony M., O’Connor, Lisa, Carr, Miriam, Keely, Niall O., O’Boyle, Niamh M., Carroll, Peig, Sarkadi, Balazs, Conneally, Eibhlin, Lloyd, David G., Lawler, Mark, Meegan, Mary J., and Zisterer, Daniela M.

Abstract

Combretastatin-A4 (CA-4) is a natural derivative of the African willow tree Combretum caffrum. CA-4 is one of the most potent antimitotic components of natural origin, but it is, however, intrinsically unstable. A novel series of CA-4 analogs incorporating a 3,4-diaryl-2-azetidinone (β-lactam) ring were designed and synthesized with the objective to prevent cis -transisomerization and improve the intrinsic stability without altering the biological activity of CA-4. Evaluation of selected β-lactam CA-4 analogs demonstrated potent antitubulin, antiproliferative, and antimitotic effects in human leukemia cells. A lead β-lactam analog, CA-432, displayed comparable antiproliferative activities with CA-4. CA-432 induced rapid apoptosis in HL-60 acute myeloid leukemia cells, which was accompanied by depolymerization of the microtubular network, poly(ADP-ribose) polymerase cleavage, caspase-3 activation, and Bcl-2 cleavage. A prolonged G2M cell cycle arrest accompanied by a sustained phosphorylation of mitotic spindle checkpoint protein, BubR1, and the antiapoptotic proteins Bcl-2 and Bcl-xLpreceded apoptotic events in K562 chronic myeloid leukemia (CML) cells. Molecular docking studies in conjunction with comprehensive cell line data rule out CA-4 and β-lactam derivatives as P-glycoprotein substrates. Furthermore, both CA-4 and CA-432 induced significantly more apoptosis compared with imatinib mesylate in ex vivo samples from patients with CML, including those positive for the T315I mutation displaying resistance to imatinib mesylate and dasatinib. In summary, synthetic intrinsically stable analogs of CA-4 that display significant clinical potential as antileukemic agents have been designed and synthesized.

Published
2010
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10. The vascular targeting agent combretastatin-A4 and a novel cis-Restricted {beta}-Lactam Analogue, CA-432, induce apoptosis in human chronic myeloid leukemia cells and ex vivo patient samples including those displaying multidrug resistance.

Author

Greene, Lisa M, Nathwani, Seema M, Bright, Sandra A, Fayne, Darren, Croke, Aisling, Gagliardi, Maria, McElligott, Anthony M, O'Connor, Lisa, Carr, Miriam, Keely, Niall O, O'Boyle, Niamh M, Carroll, Peig, Sarkadi, Balazs, Conneally, Eibhlin, Lloyd, David G, Lawler, Mark, Meegan, Mary J, and Zisterer, Daniela M

Abstract

Combretastatin-A4 (CA-4) is a natural derivative of the African willow tree Combretum caffrum. CA-4 is one of the most potent antimitotic components of natural origin, but it is, however, intrinsically unstable. A novel series of CA-4 analogs incorporating a 3,4-diaryl-2-azetidinone (β-lactam) ring were designed and synthesized with the objective to prevent cis -trans isomerization and improve the intrinsic stability without altering the biological activity of CA-4. Evaluation of selected β-lactam CA-4 analogs demonstrated potent antitubulin, antiproliferative, and antimitotic effects in human leukemia cells. A lead β-lactam analog, CA-432, displayed comparable antiproliferative activities with CA-4. CA-432 induced rapid apoptosis in HL-60 acute myeloid leukemia cells, which was accompanied by depolymerization of the microtubular network, poly(ADP-ribose) polymerase cleavage, caspase-3 activation, and Bcl-2 cleavage. A prolonged G(2)M cell cycle arrest accompanied by a sustained phosphorylation of mitotic spindle checkpoint protein, BubR1, and the antiapoptotic proteins Bcl-2 and Bcl-x(L) preceded apoptotic events in K562 chronic myeloid leukemia (CML) cells. Molecular docking studies in conjunction with comprehensive cell line data rule out CA-4 and β-lactam derivatives as P-glycoprotein substrates. Furthermore, both CA-4 and CA-432 induced significantly more apoptosis compared with imatinib mesylate in ex vivo samples from patients with CML, including those positive for the T315I mutation displaying resistance to imatinib mesylate and dasatinib. In summary, synthetic intrinsically stable analogs of CA-4 that display significant clinical potential as antileukemic agents have been designed and synthesized.

Published
2010
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11. 3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells.

Author

Wang, Shu, Malebari, Azizah M., Greene, Thomas F., O'Boyle, Niamh M., Fayne, Darren, Nathwani, Seema M., Twamley, Brendan, McCabe, Thomas, Keely, Niall O., Zisterer, Daniela M., and Meegan, Mary J.

Subjects
TUBULINS, CANCER cells, BREAST cancer, CELL cycle, EPITHELIAL cells, ESSENTIAL drugs
Abstract

Microtubule-targeted drugs are essential chemotherapeutic agents for various types of cancer. A series of 3-vinyl-β-lactams (2-azetidinones) were designed, synthesized and evaluated as potential tubulin polymerization inhibitors, and for their antiproliferative effects in breast cancer cells. These compounds showed potent activity in MCF-7 breast cancer cells with an IC50 value of 8 nM for compound 7s 4-[3-Hydroxy-4-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-3-vinylazetidin-2-one) which was comparable to the activity of Combretastatin A-4. Compound 7s had minimal cytotoxicity against both non-tumorigenic HEK-293T cells and murine mammary epithelial cells. The compounds inhibited the polymerisation of tubulin in vitro with an 8.7-fold reduction in tubulin polymerization at 10 μM for compound 7s and were shown to interact at the colchicine-binding site on tubulin, resulting in significant G2/M phase cell cycle arrest. Immunofluorescence staining of MCF-7 cells confirmed that β-lactam 7s is targeting tubulin and resulted in mitotic catastrophe. A docking simulation indicated potential binding conformations for the 3-vinyl-β-lactam 7s in the colchicine domain of tubulin. These compounds are promising candidates for development as antiproiferative microtubule-disrupting agents. [ABSTRACT FROM AUTHOR]

Published
2019
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13. Design, Synthesis and Biochemical Evaluation of Novel Selective Estrogen Receptor Ligand Conjugates Incorporating an Endoxifen-Combretastatin Hybrid Scaffold

Author

Bassem Yassin, Mary J. Meegan, David Lloyd, Gloria Ana, Niall O. Keely, Miriam Carr, Daniela M. Zisterer, Keely, Niall O, Carr, Miriam, Yassin, Bassem, Ana, Gloria, Lloyd, David G, Zisterer, Daniela, and Meegan, Mary J

Subjects
conjugates, 0301 basic medicine, Medicine (miscellaneous), Estrogen receptor, Pharmacology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, estrogen receptor ligands, selective estrogen receptor modulators, tumour targeting, tamoxifen, endoxifen, hormone-dependent breast cancer, medicine, Pharmacology & Pharmacy, Cytotoxicity, lcsh:QH301-705.5, Combretastatin, Chemistry, Ligand (biochemistry), 030104 developmental biology, lcsh:Biology (General), Biochemistry, Cell culture, Selective estrogen receptor modulator, 030220 oncology & carcinogenesis, Tamoxifen, Conjugate, medicine.drug
Abstract

Nuclear-receptors are often overexpressed in tumours and can thereby be used as targets when designing novel selective chemotherapeutic agents. To date, many conjugates incorporating an estrogen receptor (ER) ligand have been synthesised in order to direct chemical agents to tissue sites containing ERs. A series of ER ligand conjugates were synthesised incorporating an antagonistic ER ligand scaffold based on endoxifen, covalently-bound via an amide linkage to a variety of combretastatin-based analogues, which may act as antimitotic agents. These novel endoxifen-combretastatin hybrid scaffold analogues were biochemically evaluated in order to determine their antiproliferative and cytotoxicity effects in both the ER-positive MCF-7 and the ER-negative MDA-MB-231 human breast cancer cell lines. ER competitive binding assays were carried out to assess the binding affinity of the lead conjugate 28 towards both the ER alpha and ER beta isoforms. In results from the NCI 60-cell line screen, the lead conjugate 28 displayed potent and highly selective antiproliferative activity towards the MCF-7 human cancer cell line (IC50 = 5 nM). In the ER-binding assays, the lead conjugate 28 demonstrated potent ER competitive binding in ER alpha (IC50 value: 0.9 nM) and ER beta (IC50 value: 4.7 nM). Preliminary biochemical results also demonstrate that the lead conjugate 28 may exhibit pure antagonism. This series makes an important addition to the class of ER antagonists and may have potential applications in anticancer therapy. Refereed/Peer-reviewed

Published
2016
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