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 language | English |
|---|---|
| Article number | e202200368 |
| Journal | ChemMedChem |
| Volume | 18 |
| Issue number | 3 |
| DOIs | |
| State | Published - Feb 1 2023 |
Bibliographical note
Publisher Copyright:© 2022 Wiley-VCH GmbH.
Funding
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. 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.
| Funders | Funder number |
|---|---|
| National Institutes of Health (NIH) | R01CA243529, S10 OD28690-01 |
| National Childhood Cancer Registry – National Cancer Institute | |
| University of Kentucky Markey Comprehensive Cancer Center | P30CA177558 |
UN SDGs
This output contributes to the following UN Sustainable Development Goals (SDGs)
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SDG 3 Good Health and Well-being
Keywords
- DNA cross linking
- Mithramycin
- Ovarian cancer
- Platinum complexes
- Platinum resistance
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Pharmacology
- Drug Discovery
- General Pharmacology, Toxicology and Pharmaceutics
- Organic Chemistry
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