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, Jürgen Rohr

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbere202200368
JournalChemMedChem
Volume18
Issue number3
DOIs
StatePublished - Feb 1 2023

Bibliographical note

Funding Information:
This work was supported by US National Institute of Health grants R01CA243529 (to J.R., O.V.T.), and the National Cancer Institute at the National Institutes of Health, including support for the Biostatistics and Bioinformatics Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558, to J.M.K), as well as and seed funding by the UK College of Pharmacy. We thank the PharmNMR and MS center in the College of Pharmacy for NMR support. NMR data reported in this publication were partly recorded on a Bruker AVANCE NEO 600 MHz high‐performance digital NMR spectrometer supported by NIH S10 OD28690‐01.

Funding Information:
This work was supported by US National Institute of Health grants R01CA243529 (to J.R., O.V.T.), and the National Cancer Institute at the National Institutes of Health, including support for the Biostatistics and Bioinformatics Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558, to J.M.K), as well as and seed funding by the UK College of Pharmacy. We thank the PharmNMR and MS center in the College of Pharmacy for NMR support. NMR data reported in this publication were partly recorded on a Bruker AVANCE NEO 600 MHz high-performance digital NMR spectrometer supported by NIH S10 OD28690-01.

Publisher Copyright:
© 2022 Wiley-VCH GmbH.

Keywords

  • DNA cross linking
  • Mithramycin
  • Ovarian cancer
  • Platinum complexes
  • Platinum resistance

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics (all)
  • Organic Chemistry

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