Development of Half-Sandwich Ru, Os, Rh, and Ir Complexes Bearing the Pyridine-2-ylmethanimine Bidentate Ligand Derived from 7-Chloroquinazolin-4(3H)-one with Enhanced Antiproliferative Activity

Łomzik, Michał; Błauż, Andrzej; Tchoń, Daniel; Makal, Anna; Rychlik, Błażej; Plażuk, Damian

doi:10.1021/acsomega.3c10482

Title: Development of Half-Sandwich Ru, Os, Rh, and Ir Complexes Bearing the Pyridine-2-ylmethanimine Bidentate Ligand Derived from 7-Chloroquinazolin-4(3H)-one with Enhanced Antiproliferative Activity

Journal Article · 13 April 2024 · ACS Omega

DOI: https://doi.org/10.1021/acsomega.3c10482 · OSTI ID:2470804

^[1]; Błauż, Andrzej ^[1];

^[2]; Makal, Anna ^[3];

^[1];

^[1]

University of Lodz (Poland)
University of Warsaw (Poland); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
University of Warsaw (Poland)

Kinesin spindle protein (KSP) inhibitors are one of the most promising anticancer agents developed in recent years. Herein, we report the synthesis of ispinesib-core pyridine derivative conjugates, which are potent KSP inhibitors, with half-sandwich complexes of ruthenium, osmium, rhodium, and iridium. Conjugation of 7-chloroquinazolin-4(3H)-one with the pyridine-2-ylmethylimine group and the organometallic moiety resulted in up to a 36-fold increased cytotoxicity with IC₅₀ values in the micromolar and nanomolar range also toward drug-resistant cells. All studied conjugates increased the percentage of cells in the G₂/M phase, simultaneously decreasing the number of cells in the G₁/G₀ phase, suggesting mitotic arrest. Additionally, ruthenium derivatives were able to generate reactive oxygen species (ROS); however, no significant influence of the organometallic moiety on KSP inhibition was observed, which suggests that conjugation of a KSP inhibitor with the organometallic moiety modulates its mechanism of action.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: National Science Centre Poland (NCN); USDOE

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2470804

Journal Information:: ACS Omega, Journal Name: ACS Omega Journal Issue: 16 Vol. 9; ISSN 2470-1343

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Title: Development of Half-Sandwich Ru, Os, Rh, and Ir Complexes Bearing the Pyridine-2-ylmethanimine Bidentate Ligand Derived from 7-Chloroquinazolin-4(3H)-one with Enhanced Antiproliferative Activity

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