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Exploring the Anti-Cancer Mechanism of Novel 3,4′-Substituted Diaryl Guanidinium Derivatives
- Source :
- Pharmaceuticals, Vol 13, Iss 12, p 485 (2020)
- Publication Year :
- 2020
- Publisher :
- MDPI AG, 2020.
-
Abstract
- We previously identified a guanidinium-based lead compound that inhibited BRAF through a hypothetic type-III allosteric mechanism. Considering the pharmacophore identified in this lead compound (i.e., “lipophilic group”, “di-substituted guanidine”, “phenylguanidine polar end”), several modifications were investigated to improve its cytotoxicity in different cancer cell lines. Thus, several lipophilic groups were explored, the di-substituted guanidine was replaced by a secondary amine and the phenyl ring in the polar end was substituted by a pyridine. In a structure-based design approach, four representative derivatives were docked into an in-house model of an active triphosphate-containing BRAF protein, and the interactions established were analysed. Based on these computational studies, a variety of derivatives was synthesized, and their predicted drug-like properties calculated. Next, the effect on cell viability of these compounds was assessed in cell line models of promyelocytic leukaemia and breast, cervical and colorectal carcinomas. The potential of a selection of these compounds as apoptotic agents was assessed by screening in the promyelocytic leukaemia cell line HL-60. The toxicity against non-tumorigenic epithelial MCF10A cells was also investigated. These studies allowed for several structure-activity relationships to be derived. Investigations on the mechanism of action of representative compounds suggest a divergent effect on inhibition of the MAPK/ERK signalling pathway.
Details
- Language :
- English
- ISSN :
- 14248247
- Volume :
- 13
- Issue :
- 12
- Database :
- Directory of Open Access Journals
- Journal :
- Pharmaceuticals
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.901b9fe61d644a439840a7484ae0cc01
- Document Type :
- article
- Full Text :
- https://doi.org/10.3390/ph13120485