Iron Chelator Transmetalative Approach to Inhibit Human Ribonucleotide Reductase

Kavita Gaur, Sofia C. Pérez Otero, Josué A. Benjamín-Rivera, Israel Rodríguez, Sergio A. Loza-Rosas, Alexandra M. Vázquez Salgado, Eman A. Akam, Liz Hernández-Matias, Rohit K. Sharma, Nahiara Alicea, Martin Kowaleff, Anthony V. Washington, Andrei V. Astashkin, Elisa Tomat, Arthur D. Tinoco

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Efforts directed at curtailing the bioavailability of intracellular iron could lead to the development of broad-spectrum anticancer drugs given the metal's role in cancer proliferation and metastasis. Human ribonucleotide reductase (RNR), the key enzyme responsible for synthesizing the building blocks of DNA replication and repair, depends on Fe binding at its R2 subunit to activate the catalytic R1 subunit. This work explores an intracellular iron chelator transmetalative approach to inhibit RNR using the titanium(IV) chemical transferrin mimetic (cTfm) compounds Ti(HBED) and Ti(Deferasirox)2. Whole-cell EPR studies reveal that the compounds can effectively attenuate RNR activity though seemingly causing different changes to the labile iron pool that may account for differences in their potency against cells. Studies of Ti(IV) interactions with the adenosine nucleotide family at pH 7.4 reveal strong metal binding and extensive phosphate hydrolysis, which suggest the capacity of the metal to disturb the nucleotide substrate pool of the RNR enzyme. By decreasing intracellular Fe bioavailability and altering the nucleotide substrate pool, the Ti cTfm compounds could inhibit the activity of the R1 and R2 subunits of RNR. The compounds arrest the cell cycle in the S phase, indicating suppressed DNA replication, and induce apoptotic cell death. Cotreatment cell viability studies with cisplatin and Ti(Deferasirox)2reveal a promising synergism between the compounds that is likely owed to their distinct but complementary effect on DNA replication.

Original languageEnglish (US)
Pages (from-to)865-878
Number of pages14
JournalJACS Au
Volume1
Issue number6
DOIs
StatePublished - Jun 28 2021
Externally publishedYes

Keywords

  • Titanium(IV) chemical transferrin mimetic complexes
  • intracellular iron(III) transmetalation
  • metal-based anticancer strategy
  • ribonucleotide reductase inhibition
  • titanium(IV) binding of nucleotides

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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