New Water-Soluble Copper(II) Complexes with Morpholine-Thiosemicarbazone Hybrids: Insights into the Anticancer and Antibacterial Mode of Action

Kateryna Ohui; Eleonora Afanasenko; Felix Bacher; Rachel Lim Xue Ting; Ayesha Zafar; Núria Blanco-Cabra; Eduard Torrents; Orsolya Dömötör; Nóra V. May; Denisa Darvasiova; Éva A. Enyedy; Ana Popović-Bijelić; Jóhannes Reynisson; Peter Rapta; Maria V. Babak; Giorgia Pastorin; Vladimir B. Arion

doi:10.1021/acs.jmedchem.8b01031

New Water-Soluble Copper(II) Complexes with Morpholine-Thiosemicarbazone Hybrids: Insights into the Anticancer and Antibacterial Mode of Action

Kateryna Ohui
, Eleonora Afanasenko
, Felix Bacher
, Rachel Lim Xue Ting
, Ayesha Zafar
, Núria Blanco-Cabra
, Eduard Torrents
, Orsolya Dömötör
, Nóra V. May
, Denisa Darvasiova
, Éva A. Enyedy
, Ana Popović-Bijelić
, Jóhannes Reynisson
, Peter Rapta
, Maria V. Babak^*
, Giorgia Pastorin
, Vladimir B. Arion^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

112 Citations (Scopus)

39 Downloads (CityUHK Scholars)

Abstract

Six morpholine-(iso)thiosemicarbazone hybrids HL¹ -HL⁶ and their Cu(II) complexes with good-to-moderate solubility and stability in water were synthesized and characterized. Cu(II) complexes [Cu(L ^1-6 )Cl] (1-6) formed weak dimeric associates in the solid state, which did not remain intact in solution as evidenced by ESI-MS. The lead proligands and Cu(II) complexes displayed higher antiproliferative activity in cancer cells than triapine. In addition, complexes 2-5 were found to specifically inhibit the growth of Gram-positive bacteria Staphylococcus aureus with MIC₅₀ values at 2-5 μg/mL. Insights into the processes controlling intracellular accumulation and mechanism of action were investigated for 2 and 5, including the role of ribonucleotide reductase (RNR) inhibition, endoplasmic reticulum stress induction, and regulation of other cancer signaling pathways. Their ability to moderately inhibit R2 RNR protein in the presence of dithiothreitol is likely related to Fe chelating properties of the proligands liberated upon reduction.

Original language	English
Pages (from-to)	512-530
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	2
Online published	3 Dec 2018
DOIs	https://doi.org/10.1021/acs.jmedchem.8b01031
Publication status	Published - 24 Jan 2019
Externally published	Yes

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SDG 3 Good Health and Well-being

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10.1021/acs.jmedchem.8b01031

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Ohui, K., Afanasenko, E., Bacher, F., Ting, R. L. X., Zafar, A., Blanco-Cabra, N., Torrents, E., Dömötör, O., May, N. V., Darvasiova, D., Enyedy, É. A., Popović-Bijelić, A., Reynisson, J., Rapta, P., Babak, M. V., Pastorin, G., & Arion, V. B. (2019). New Water-Soluble Copper(II) Complexes with Morpholine-Thiosemicarbazone Hybrids: Insights into the Anticancer and Antibacterial Mode of Action. Journal of Medicinal Chemistry, 62(2), 512-530. https://doi.org/10.1021/acs.jmedchem.8b01031

@article{fb11b9f717ed43439f60542d74d67e82,

title = "New Water-Soluble Copper(II) Complexes with Morpholine-Thiosemicarbazone Hybrids: Insights into the Anticancer and Antibacterial Mode of Action",

abstract = "Six morpholine-(iso)thiosemicarbazone hybrids HL1 -HL6 and their Cu(II) complexes with good-to-moderate solubility and stability in water were synthesized and characterized. Cu(II) complexes [Cu(L 1-6 )Cl] (1-6) formed weak dimeric associates in the solid state, which did not remain intact in solution as evidenced by ESI-MS. The lead proligands and Cu(II) complexes displayed higher antiproliferative activity in cancer cells than triapine. In addition, complexes 2-5 were found to specifically inhibit the growth of Gram-positive bacteria Staphylococcus aureus with MIC50 values at 2-5 μg/mL. Insights into the processes controlling intracellular accumulation and mechanism of action were investigated for 2 and 5, including the role of ribonucleotide reductase (RNR) inhibition, endoplasmic reticulum stress induction, and regulation of other cancer signaling pathways. Their ability to moderately inhibit R2 RNR protein in the presence of dithiothreitol is likely related to Fe chelating properties of the proligands liberated upon reduction.",

author = "Kateryna Ohui and Eleonora Afanasenko and Felix Bacher and Ting, \{Rachel Lim Xue\} and Ayesha Zafar and N{\'u}ria Blanco-Cabra and Eduard Torrents and Orsolya D{\"o}m{\"o}t{\"o}r and May, \{N{\'o}ra V.\} and Denisa Darvasiova and Enyedy, \{{\'E}va A.\} and Ana Popovi{\'c}-Bijeli{\'c} and J{\'o}hannes Reynisson and Peter Rapta and Babak, \{Maria V.\} and Giorgia Pastorin and Arion, \{Vladimir B.\}",

year = "2019",

month = jan,

day = "24",

doi = "10.1021/acs.jmedchem.8b01031",

language = "English",

volume = "62",

pages = "512--530",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

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}

Ohui, K, Afanasenko, E, Bacher, F, Ting, RLX, Zafar, A, Blanco-Cabra, N, Torrents, E, Dömötör, O, May, NV, Darvasiova, D, Enyedy, ÉA, Popović-Bijelić, A, Reynisson, J, Rapta, P, Babak, MV, Pastorin, G & Arion, VB 2019, 'New Water-Soluble Copper(II) Complexes with Morpholine-Thiosemicarbazone Hybrids: Insights into the Anticancer and Antibacterial Mode of Action', Journal of Medicinal Chemistry, vol. 62, no. 2, pp. 512-530. https://doi.org/10.1021/acs.jmedchem.8b01031

New Water-Soluble Copper(II) Complexes with Morpholine-Thiosemicarbazone Hybrids: Insights into the Anticancer and Antibacterial Mode of Action. / Ohui, Kateryna; Afanasenko, Eleonora; Bacher, Felix et al.
In: Journal of Medicinal Chemistry, Vol. 62, No. 2, 24.01.2019, p. 512-530.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

TY - JOUR

T1 - New Water-Soluble Copper(II) Complexes with Morpholine-Thiosemicarbazone Hybrids

T2 - Insights into the Anticancer and Antibacterial Mode of Action

AU - Ohui, Kateryna

AU - Afanasenko, Eleonora

AU - Bacher, Felix

AU - Ting, Rachel Lim Xue

AU - Zafar, Ayesha

AU - Blanco-Cabra, Núria

AU - Torrents, Eduard

AU - Dömötör, Orsolya

AU - May, Nóra V.

AU - Darvasiova, Denisa

AU - Enyedy, Éva A.

AU - Popović-Bijelić, Ana

AU - Reynisson, Jóhannes

AU - Rapta, Peter

AU - Babak, Maria V.

AU - Pastorin, Giorgia

AU - Arion, Vladimir B.

PY - 2019/1/24

Y1 - 2019/1/24

N2 - Six morpholine-(iso)thiosemicarbazone hybrids HL1 -HL6 and their Cu(II) complexes with good-to-moderate solubility and stability in water were synthesized and characterized. Cu(II) complexes [Cu(L 1-6 )Cl] (1-6) formed weak dimeric associates in the solid state, which did not remain intact in solution as evidenced by ESI-MS. The lead proligands and Cu(II) complexes displayed higher antiproliferative activity in cancer cells than triapine. In addition, complexes 2-5 were found to specifically inhibit the growth of Gram-positive bacteria Staphylococcus aureus with MIC50 values at 2-5 μg/mL. Insights into the processes controlling intracellular accumulation and mechanism of action were investigated for 2 and 5, including the role of ribonucleotide reductase (RNR) inhibition, endoplasmic reticulum stress induction, and regulation of other cancer signaling pathways. Their ability to moderately inhibit R2 RNR protein in the presence of dithiothreitol is likely related to Fe chelating properties of the proligands liberated upon reduction.

AB - Six morpholine-(iso)thiosemicarbazone hybrids HL1 -HL6 and their Cu(II) complexes with good-to-moderate solubility and stability in water were synthesized and characterized. Cu(II) complexes [Cu(L 1-6 )Cl] (1-6) formed weak dimeric associates in the solid state, which did not remain intact in solution as evidenced by ESI-MS. The lead proligands and Cu(II) complexes displayed higher antiproliferative activity in cancer cells than triapine. In addition, complexes 2-5 were found to specifically inhibit the growth of Gram-positive bacteria Staphylococcus aureus with MIC50 values at 2-5 μg/mL. Insights into the processes controlling intracellular accumulation and mechanism of action were investigated for 2 and 5, including the role of ribonucleotide reductase (RNR) inhibition, endoplasmic reticulum stress induction, and regulation of other cancer signaling pathways. Their ability to moderately inhibit R2 RNR protein in the presence of dithiothreitol is likely related to Fe chelating properties of the proligands liberated upon reduction.

UR - https://www.scopus.com/pages/publications/85058881195

UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-85058881195&origin=recordpage

U2 - 10.1021/acs.jmedchem.8b01031

DO - 10.1021/acs.jmedchem.8b01031

M3 - RGC 21 - Publication in refereed journal

C2 - 30507173

SN - 0022-2623

VL - 62

SP - 512

EP - 530

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 2

ER -

New Water-Soluble Copper(II) Complexes with Morpholine-Thiosemicarbazone Hybrids: Insights into the Anticancer and Antibacterial Mode of Action

Abstract

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