Tuning the Cytotoxicity of Bis-Phosphino-Amines Ruthenium(II) Para-Cymene Complexes for Clinical Development in Breast Cancer

Despite some limitations such as long-term side effects or the potential presence of intrinsic or acquired resistance, platinum compounds are key therapeutic components for the treatment of several solid tumors. To overcome these limitations, maintaining the same efficacy, organometallic ruthenium(II) compounds have been proposed as a viable alternative to platinum agents as they have a more favorable toxicity profile and represent an ideal template for both, high-throughput and rational drug design. To support the preclinical development of bis-phoshino-amine ruthenium compounds in the treatment of breast cancer, we carried out chemical modifications in the structure of these derivatives with the aim of designing less toxic and more efficient therapeutic agents. We report new bis-phoshino-amine ligands and the synthesis of their ruthenium counterparts. The novel ligands and compounds were fully characterized, water stability analyzed, and their in vitro cytotoxicity against a panel of tumor cell lines representative of different breast cancer subtypes was evaluated. The mechanism of action of the lead compound of the series was explored. In vivo toxicity was also assessed. The results obtained in this article might pave the way for the clinical development of these compounds in breast cancer therapy.
We gratefully acknowledge the financial support from the Ministerio de Ciencia e Innovación y Agencia Estatal de la Investigación, Spain (Grant Nos. PID2020-117788RB-I00, PID2020-113661GB-I00, CTQ2017-84131-R and RED2018-102387-T Programa Redes Consolider), and Instituto de Salud Carlos III grant number PI16/01121. Alberto Ocaña’s lab is supported by the Instituto de Salud Carlos III (ISCIII, PI19/00808); CRIS Cancer Foundation, ACEPAIN, and Diputación de Albacete.