Cytotoxic Imidazolyl-Mesalazine Ester-Based Ru(II) Complexes Reduce Expression of Stemness Genes and Induce Differentiation of Oral Squamous Cell Carcinoma

The aggressiveness and recurrence of cancer is linked to cancer stem cells (CSCs), but drugs targeting CSCs may not succeed in the clinic due to the lack of a distinct CSC subpopulation. Clinical Pt­(II) drugs can increase stemness. We screened 15 RuII or IrIII complexes with mesal­azine or 3-amino­...

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Published in:Journal of medicinal chemistry 2023-10, Vol.66 (20), p.14061-14079
Main Authors: Kumari, Pragya, Ghosh, Subhashis, Acharya, Sourav, Mitra, Paromita, Roy, Souryadip, Ghosh, Shilpendu, Maji, Moumita, Singh, Sandeep, Mukherjee, Arindam
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container_end_page 14079
container_issue 20
container_start_page 14061
container_title Journal of medicinal chemistry
container_volume 66
creator Kumari, Pragya
Ghosh, Subhashis
Acharya, Sourav
Mitra, Paromita
Roy, Souryadip
Ghosh, Shilpendu
Maji, Moumita
Singh, Sandeep
Mukherjee, Arindam
description The aggressiveness and recurrence of cancer is linked to cancer stem cells (CSCs), but drugs targeting CSCs may not succeed in the clinic due to the lack of a distinct CSC subpopulation. Clinical Pt­(II) drugs can increase stemness. We screened 15 RuII or IrIII complexes with mesal­azine or 3-amino­benzoate Schiff bases of the general formulas [Ru­(p-cym)­L]+, [Ru­(p-cym)­L], and [Ir­(Cp*)­L]+ (L = L1–L9) and found three complexes (2, 12, and 13) that are active against oral squamous cell carcinoma (OSCC) CSCs. There is a putative oncogenic role of transcription factors (viz. NOTCH1, SOX2, c-MYC) to enhance the stemness. Our work shows that imidazolyl-mesal­azine ester-based RuII complexes inhibit growth of CSC-enriched OSCC 3D spheroids at low micromolar doses (2 μM). Complexes 2, 12, and 13 reduce stemness gene expression and induce differentiation markers (Involucrin, CK10) in OSCC 3D cultures. The imidazolyl-mesal­azine ester-based RuII complex 13 shows the strongest effect. Downregulating c-MYC suggests that RuII complexes may target c-MYC-driven cancers.
doi_str_mv 10.1021/acs.jmedchem.3c01092
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title Cytotoxic Imidazolyl-Mesalazine Ester-Based Ru(II) Complexes Reduce Expression of Stemness Genes and Induce Differentiation of Oral Squamous Cell Carcinoma
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