Design, synthesis and evaluation of fluorescent dihydropyridine–dihydropyrimidinone hybrids as inducers of cell-cycle arrest in a prostate cancer cell line <i>via</i> Aurora kinase interactions
Fluorescent dihydropyridine-dihydropyrimidinone (DHP-DHPM) hybrids were easily synthesized through the combination of Hantzsch and Biginelli multicomponent reactions followed by a copper-catalyzed azide-alkyne cycloaddition reaction (CuAAC, click chemistry) protocol. Nine hybrids showed promising antitumor activity for the PC3 prostate cancer cell line, notably compounds 9d and 9g. Both hybrids exhibited high selectivity for tumor cells, with significant selectivity indices (SI), particularly 9g (SI >68.8). Selectivity was qualitatively observed by the internalization of the fluorescent hybrids through high-resolution confocal laser scanning microscopy (CLSM). <i>In silico</i> investigations and western blotting analysis showed a selective inhibition of the isoform C of Aurora kinase by hybrid 9d. A mechanism of action including cell cycle arrest at the G<sub>0</sub>/G<sub>1</sub> phase, inhibition of cell migration and invasion, and modulation of key signaling pathways such as MAPK, AKT, and mTOR are discussed.
Authors
- Vanessa Pereira de Souza (ORCID: https://orcid.org/0000-0003-3143-6926)
- Ronaldo A. Pilli (ORCID: https://orcid.org/0000-0002-5919-7763)
- Dennis Russowsky (ORCID: https://orcid.org/0000-0001-5968-9760)
- Alexandra Maria Ramos Bezerra (ORCID: https://orcid.org/0000-0002-7972-5535)
- Rui Manuel Reis (ORCID: https://orcid.org/0000-0002-9639-7940)
- Luciane Sussuchi da Silva (ORCID: https://orcid.org/0000-0002-7470-4655)
- Renato José da Silva Oliveira (ORCID: https://orcid.org/0000-0001-6500-4190)
- Eric Allison Philot (ORCID: https://orcid.org/0000-0002-0642-4467)
- Simone Queiroz Pantaleão (ORCID: https://orcid.org/0000-0002-5183-7906)
- Carolyne B. Braga (ORCID: https://orcid.org/0000-0003-1800-386X)
- Izabela Natália Faria Gomes (ORCID: https://orcid.org/0000-0003-0551-138X)
- Cíntia Regina Niederauer Ramos (ORCID: https://orcid.org/0000-0003-3402-2948)
- Samuel José Santos (ORCID: https://orcid.org/0000-0003-2412-5791)
Institutions
- Universidade Federal do Rio Grande do Sul (BR)
- Universidade Estadual de Campinas (UNICAMP) (BR)
- Centro Universitário da Fundação Educacional de Barretos (BR)
- Hospital de Câncer de Barretos (BR)
- Instituto Barretos de Tecnologia (BR)
- Universidade Federal do ABC (BR)
- Ministry of Agriculture, Livestock, and Food Supply (BR)
- University of Minho (PT)
Publication Details
- Journal
- RSC Medicinal Chemistry
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1039/d5md00635j
- Citations
- 1
- Primary Topic
- Microtubule and mitosis dynamics
- Type
- article
- Field-Weighted Citation Impact
- 1.15