Novel platinum(II) and platinum(IV) antitumor agents that exhibit potent cytotoxicity and selectivity

Aleen Khoury; E. Elias; S. Mehanna; W. Shebaby; Krishant M. Deo; N. Mansour; C. Khalil; K. Sayyed; J.A. Sakoff; J. Gilbert; C.F. Daher; Christopher P. Gordon; R.I. Taleb; Janice R. Aldrich-Wright

doi:10.1021/acs.jmedchem.2c01310

Novel platinum(II) and platinum(IV) antitumor agents that exhibit potent cytotoxicity and selectivity

Aleen Khoury, E. Elias, S. Mehanna, W. Shebaby, Krishant M. Deo, N. Mansour, C. Khalil, K. Sayyed, J.A. Sakoff, J. Gilbert, C.F. Daher, Christopher P. Gordon, R.I. Taleb, Janice R. Aldrich-Wright

Western Sydney University

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

Abstract

A novel platinum(II) complex 47OMESS(II) and its platinum(IV) derivative 47OMESS(IV) were synthesized and characterized. Cytotoxicity studies against mesenchymal cells (MCs) and lung (A549), breast (MDA-MB-231), and melanoma (A375) cancer cells demonstrated 7-20-fold superior activity for both complexes relative to cisplatin. Remarkably, 47OMESS(IV) demonstrated 17-22-fold greater selectivity toward the cancerous cells compared to the non-cancerous MCs. Western blot analysis on A549 cells showed the involvement of the intrinsic apoptotic pathway. Cellular fractionation and uptake experiments in A549 cells using ICP-mass spectrometry (MS) indicated that 47OMESS(II) and 47OMESS(IV) cross the cellular membrane predominantly via active transport mechanisms. The significant improvement in selectivity that is exhibited by 47OMESS(IV) is reported for the first time for this class of complexes.

Original language	English
Pages (from-to)	16481-16493
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	65
Issue number	24
DOIs	https://doi.org/10.1021/acs.jmedchem.2c01310
Publication status	Published - 2022

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Khoury, A., Elias, E., Mehanna, S., Shebaby, W., Deo, K. M., Mansour, N., Khalil, C., Sayyed, K., Sakoff, J. A., Gilbert, J., Daher, C. F., Gordon, C. P., Taleb, R. I., & Aldrich-Wright, J. R. (2022). Novel platinum(II) and platinum(IV) antitumor agents that exhibit potent cytotoxicity and selectivity. Journal of Medicinal Chemistry, 65(24), 16481-16493. https://doi.org/10.1021/acs.jmedchem.2c01310

@article{72d5c136186d4634bfcee6faa34ac273,

title = "Novel platinum(II) and platinum(IV) antitumor agents that exhibit potent cytotoxicity and selectivity",

abstract = "A novel platinum(II) complex 47OMESS(II) and its platinum(IV) derivative 47OMESS(IV) were synthesized and characterized. Cytotoxicity studies against mesenchymal cells (MCs) and lung (A549), breast (MDA-MB-231), and melanoma (A375) cancer cells demonstrated 7-20-fold superior activity for both complexes relative to cisplatin. Remarkably, 47OMESS(IV) demonstrated 17-22-fold greater selectivity toward the cancerous cells compared to the non-cancerous MCs. Western blot analysis on A549 cells showed the involvement of the intrinsic apoptotic pathway. Cellular fractionation and uptake experiments in A549 cells using ICP-mass spectrometry (MS) indicated that 47OMESS(II) and 47OMESS(IV) cross the cellular membrane predominantly via active transport mechanisms. The significant improvement in selectivity that is exhibited by 47OMESS(IV) is reported for the first time for this class of complexes.",

author = "Aleen Khoury and E. Elias and S. Mehanna and W. Shebaby and Deo, {Krishant M.} and N. Mansour and C. Khalil and K. Sayyed and J.A. Sakoff and J. Gilbert and C.F. Daher and Gordon, {Christopher P.} and R.I. Taleb and Aldrich-Wright, {Janice R.}",

year = "2022",

doi = "10.1021/acs.jmedchem.2c01310",

language = "English",

volume = "65",

pages = "16481--16493",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "24",

}

Khoury, A, Elias, E, Mehanna, S, Shebaby, W, Deo, KM, Mansour, N, Khalil, C, Sayyed, K, Sakoff, JA, Gilbert, J, Daher, CF, Gordon, CP, Taleb, RI & Aldrich-Wright, JR 2022, 'Novel platinum(II) and platinum(IV) antitumor agents that exhibit potent cytotoxicity and selectivity', Journal of Medicinal Chemistry, vol. 65, no. 24, pp. 16481-16493. https://doi.org/10.1021/acs.jmedchem.2c01310

TY - JOUR

T1 - Novel platinum(II) and platinum(IV) antitumor agents that exhibit potent cytotoxicity and selectivity

AU - Khoury, Aleen

AU - Elias, E.

AU - Mehanna, S.

AU - Shebaby, W.

AU - Deo, Krishant M.

AU - Mansour, N.

AU - Khalil, C.

AU - Sayyed, K.

AU - Sakoff, J.A.

AU - Gilbert, J.

AU - Daher, C.F.

AU - Gordon, Christopher P.

AU - Taleb, R.I.

AU - Aldrich-Wright, Janice R.

PY - 2022

Y1 - 2022

N2 - A novel platinum(II) complex 47OMESS(II) and its platinum(IV) derivative 47OMESS(IV) were synthesized and characterized. Cytotoxicity studies against mesenchymal cells (MCs) and lung (A549), breast (MDA-MB-231), and melanoma (A375) cancer cells demonstrated 7-20-fold superior activity for both complexes relative to cisplatin. Remarkably, 47OMESS(IV) demonstrated 17-22-fold greater selectivity toward the cancerous cells compared to the non-cancerous MCs. Western blot analysis on A549 cells showed the involvement of the intrinsic apoptotic pathway. Cellular fractionation and uptake experiments in A549 cells using ICP-mass spectrometry (MS) indicated that 47OMESS(II) and 47OMESS(IV) cross the cellular membrane predominantly via active transport mechanisms. The significant improvement in selectivity that is exhibited by 47OMESS(IV) is reported for the first time for this class of complexes.

AB - A novel platinum(II) complex 47OMESS(II) and its platinum(IV) derivative 47OMESS(IV) were synthesized and characterized. Cytotoxicity studies against mesenchymal cells (MCs) and lung (A549), breast (MDA-MB-231), and melanoma (A375) cancer cells demonstrated 7-20-fold superior activity for both complexes relative to cisplatin. Remarkably, 47OMESS(IV) demonstrated 17-22-fold greater selectivity toward the cancerous cells compared to the non-cancerous MCs. Western blot analysis on A549 cells showed the involvement of the intrinsic apoptotic pathway. Cellular fractionation and uptake experiments in A549 cells using ICP-mass spectrometry (MS) indicated that 47OMESS(II) and 47OMESS(IV) cross the cellular membrane predominantly via active transport mechanisms. The significant improvement in selectivity that is exhibited by 47OMESS(IV) is reported for the first time for this class of complexes.

UR - https://hdl.handle.net/1959.7/uws:74781

U2 - 10.1021/acs.jmedchem.2c01310

DO - 10.1021/acs.jmedchem.2c01310

M3 - Article

SN - 0022-2623

VL - 65

SP - 16481

EP - 16493

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 24

ER -

Novel platinum(II) and platinum(IV) antitumor agents that exhibit potent cytotoxicity and selectivity

Abstract

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