Selective binding of a bioactive porphyrin-based photosensitizer to the G-quadruplex from the KRAS oncogene promoter.
G-Quadruplexes
/ drug effects
HeLa Cells
Humans
Inverted Repeat Sequences
Ligands
Light
Molecular Docking Simulation
Oligonucleotides
/ chemical synthesis
Photochemotherapy
/ methods
Photosensitizing Agents
/ chemical synthesis
Porphyrins
/ chemical synthesis
Promoter Regions, Genetic
Proto-Oncogene Mas
Proto-Oncogene Proteins p21(ras)
/ genetics
Solubility
Water
Biophysics
Chlorins
G-quadruplex
Ligands
Photodynamic activity
Singlet oxygen generation
Journal
International journal of biological macromolecules
ISSN: 1879-0003
Titre abrégé: Int J Biol Macromol
Pays: Netherlands
ID NLM: 7909578
Informations de publication
Date de publication:
15 Feb 2020
15 Feb 2020
Historique:
received:
29
08
2019
revised:
07
10
2019
accepted:
17
12
2019
pubmed:
25
12
2019
medline:
21
11
2020
entrez:
25
12
2019
Statut:
ppublish
Résumé
The G-quadruplex-forming sequence within the KRAS proto-oncogene P1 promoter is a promising target for anticancer therapy. Porphyrin derivatives are among the most rewarding G-quadruplex binders. They can also behave as photosensitizers. Three water-soluble, positively charged porphyrin-like compounds were synthesized and tested for their interaction with the KRAS G-quadruplex by circular dichroism, fluorescence, and molecular docking calculations. For a comparison of ligands binding affinity and selectivity, TMPyP4 was taken as a reference. One out of the three tested compounds proved biological activity and selectivity for G-quadruplex over duplex DNA. It also showed to discriminate between different G-quadruplex topologies, with a preference for the parallel over antiparallel conformation. Molecular docking studies suggested a preferential binding to the 3'-end of the KRAS G-quadruplex driven through π-π stacking interactions. Biological assays also revealed a good photodynamic-induced cytotoxicity on HeLa cells. The reported results show that these porphyrin-like compounds could actually give the basis for the development of G-quadruplex ligands with effective photodynamic-induced cytotoxicity on cancer cells. The possibility of obtaining photosensitizers with improved physico-chemical features and able to selectively target G-quadruplexes is a very interesting perspective to develop new therapeutic agents.
Sections du résumé
BACKGROUND
BACKGROUND
The G-quadruplex-forming sequence within the KRAS proto-oncogene P1 promoter is a promising target for anticancer therapy. Porphyrin derivatives are among the most rewarding G-quadruplex binders. They can also behave as photosensitizers.
METHODS
METHODS
Three water-soluble, positively charged porphyrin-like compounds were synthesized and tested for their interaction with the KRAS G-quadruplex by circular dichroism, fluorescence, and molecular docking calculations. For a comparison of ligands binding affinity and selectivity, TMPyP4 was taken as a reference.
RESULTS
RESULTS
One out of the three tested compounds proved biological activity and selectivity for G-quadruplex over duplex DNA. It also showed to discriminate between different G-quadruplex topologies, with a preference for the parallel over antiparallel conformation. Molecular docking studies suggested a preferential binding to the 3'-end of the KRAS G-quadruplex driven through π-π stacking interactions. Biological assays also revealed a good photodynamic-induced cytotoxicity on HeLa cells.
CONCLUSIONS
CONCLUSIONS
The reported results show that these porphyrin-like compounds could actually give the basis for the development of G-quadruplex ligands with effective photodynamic-induced cytotoxicity on cancer cells.
GENERAL SIGNIFICANCE
CONCLUSIONS
The possibility of obtaining photosensitizers with improved physico-chemical features and able to selectively target G-quadruplexes is a very interesting perspective to develop new therapeutic agents.
Identifiants
pubmed: 31870869
pii: S0141-8130(19)36977-6
doi: 10.1016/j.ijbiomac.2019.12.152
pii:
doi:
Substances chimiques
KRAS protein, human
0
Ligands
0
MAS1 protein, human
0
Oligonucleotides
0
Photosensitizing Agents
0
Porphyrins
0
Proto-Oncogene Mas
0
Water
059QF0KO0R
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
244-251Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.