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Antiproliferative Properties and G-Quadruplex-Binding of Symmetrical Naphtho[1,2-b:8,7-b']dithiophene Derivatives.

ABSTRACT: Background: G-quadruplex (G4) forming sequences are recurrent in telomeres and promoter regions of several protooncogenes. In normal cells, the transient arrangements of DNA in G-tetrads may regulate replication, transcription, and translation processes. Tumors are characterized by uncontrolled cell growth and tissue invasiveness and some of them are possibly mediated by gene expression involving G-quadruplexes. The stabilization of G-quadruplex sequences with small molecules is considered a promising strategy in anticancer targeted therapy. Methods: Molecular virtual screening allowed us identifying novel symmetric bifunctionalized naphtho[1,2-b:8,7-b']dithiophene ligands as interesting candidates targeting h-Telo and c-MYC G-quadruplexes. A set of unexplored naphtho-dithiophene derivatives has been synthesized and biologically tested through in vitro antiproliferative assays and spectroscopic experiments in solution. Results: The analysis of biological and spectroscopic data highlighted noteworthy cytotoxic effects on HeLa cancer cell line (GI₅₀ in the low μM range), but weak interactions with G-quadruplex c-MYC promoter. Conclusions: The new series of naphtho[1,2-b:8,7-b']dithiophene derivatives, bearing the pharmacophoric assumptions necessary to stabilize G-quadruplexes, have been designed and successfully synthesized. The interesting antiproliferative results supported by computer aided rational approaches suggest that these studies are a significant starting point for a lead optimization process and the isolation of a more efficacious set of G-quadruplexes stabilizers.

SUBMITTER: Lauria A

PROVIDER: S-EPMC8303715 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Three symmetrical bis-aryl-α,β-unsaturated ketone derivatives, 2,6-di((E)-benzylidene)-cyclohexan-1-one (DBC), 2,6-bis((E)-4-chlorobenzylidene)cyclohexan-1-one (BCC), and (1E,1'E,4E,4'E)-5,5'-(1,4-phenylene)bis(2-methyl-1-phenylpenta-1,4-dien-3-one) (PBMP), have been prepared using the aldol condensation approach toward ketones having two enolizable sites. The structures of DBC, BCC, and PBMP have been resolved via spectrometric methods. Moreover, the crystal structure of PBMP is determined by the single-crystal X-ray diffraction (SC-XRD) technique, which revealed that the PBMP molecular assembly is stabilized by the intermolecular C-H···O bonding and C-O···π and weak T-shaped offset π···π stacking interactions. The Hirshfeld surface analysis (HSA) of the PBMP crystal structure was performed as well, and the results were compared with the results of DBC and BCC. The density functional theory (DFT) study results revealed that the longer conjugated molecule of PBMP has smaller but still quite significant HOMO-LUMO gaps compared to the smaller molecules of BCC and DBC. The natural population analysis (NPA) and natural bonding orbital (NBO) analysis were performed. Accordingly, the hydrogen bonding and dipole-dipole interactions stabilize the crystal structures of these compounds. Additionally, the NBO analysis showed numerous high-energy stabilizing interactions for the PBMP compound due to the presence of numerous delocalized and relatively easily polarizable π-electrons, thus implying its significant thermodynamic stability. According to the global reactivity parameter (GRP) analysis, the compounds BCC and DBC are relatively stable in redox processes and have high thermodynamic stability and relatively lower reactivity in general. The molecular electrostatic potential (MEP) analysis results imply potential formation of the intermolecular hydrogen bonding and dispersion interactions, which stabilizes the crystal structures of these compounds.

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Antiproliferative Properties and G-Quadruplex-Binding of Symmetrical Naphtho[1,2-b:8,7-b']dithiophene Derivatives.

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