Mithplatins: Mithramycin SA-Pt(II) Complex Conjugates for the Treatment of Platinum-Resistant Ovarian Cancers

Suhas S. Bhosale; Abhisek Mandal; Caixia Hou; J. Robert McCorkle; David Schweer; Kristen S. Hill; Vivekanandan Subramanian; Jill M. Kolesar; Oleg V. Tsodikov; Jurgen Rohr

doi:10.1002/cmdc.202200368

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Mithplatins: Mithramycin SA-Pt(II) Complex Conjugates for the Treatment of Platinum-Resistant Ovarian Cancers

Journal article

Peer reviewed

Mithplatins: Mithramycin SA-Pt(II) Complex Conjugates for the Treatment of Platinum-Resistant Ovarian Cancers

Suhas S. Bhosale, Abhisek Mandal, Caixia Hou, J. Robert McCorkle, David Schweer, Kristen S. Hill, Vivekanandan Subramanian, Jill M. Kolesar, Oleg V. Tsodikov and Jurgen Rohr

ChemMedChem, Vol.18(3), e202200368

02/01/2023

DOI: 10.1002/cmdc.202200368

PMCID: PMC9899322

PMID: 36342449

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https://www.ncbi.nlm.nih.gov/pmc/articles/9899322View

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Abstract

DNA coordinating platinum (Pt) containing compounds cisplatin and carboplatin have been used for the treatment of ovarian cancer therapy for four decades. However, recurrent Pt-resistant cancers are a major cause of mortality. To combat Pt-resistant ovarian cancers, we designed and synthesized a conjugate of an anticancer drug mithramycin with a reactive Pt(II) bearing moiety, which we termed mithplatin. The conjugates displayed both the Mg2+-dependent noncovalent DNA binding characteristic of mithramycin and the covalent crosslinking to DNA of the Pt. The conjugate was three times as potent as cisplatin against ovarian cancer cells. The DNA lesions caused by the conjugate led to the generation of DNA double-strand breaks, as also observed with cisplatin. Nevertheless, the conjugate was highly active against both Pt-sensitive and Pt-resistant ovarian cancer cells. This study paves the way to developing mithplatins to combat Pt-resistant ovarian cancers.

Chemistry, Medicinal

Life Sciences & Biomedicine

Pharmacology & Pharmacy

Science & Technology

Details

Title: Subtitle: Mithplatins: Mithramycin SA-Pt(II) Complex Conjugates for the Treatment of Platinum-Resistant Ovarian Cancers
Creators: Suhas S. Bhosale - University of Kentucky
Abhisek Mandal - University of Kentucky
Caixia Hou - University of Kentucky
J. Robert McCorkle - University of Kentucky
David Schweer - Coll Med, Div Gynecol Oncol, 760 S Rose St, Lexington, KY 40536 USA
Kristen S. Hill - Markey Cancer Center
Vivekanandan Subramanian - University of Kentucky
Jill M. Kolesar - University of Kentucky
Oleg V. Tsodikov - University of Kentucky
Jurgen Rohr - University of Kentucky
Resource Type: Journal article
Publication Details: ChemMedChem, Vol.18(3), e202200368
DOI: 10.1002/cmdc.202200368
PMID: 36342449
PMCID: PMC9899322
NLM abbreviation: ChemMedChem
ISSN: 1860-7179
eISSN: 1860-7187
Publisher: Wiley
Number of pages: 11
Grant note: seed funding by the UK College of Pharmacy P30CA177558 / National Cancer Institute at the National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01CA243529 / US National Institute of Health grants; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA S10 OD28690-01 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
Language: English
Date published: 02/01/2023
Academic Unit: Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics
Record Identifier: 9984696554502771

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