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. 2021 Jul 16;26(14):4309.
doi: 10.3390/molecules26144309.

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

Antonino Lauria  1 , Gabriele La Monica  1 , Alessio Terenzi  1 , Giuseppe Mannino  2 , Riccardo Bonsignore  3 , Alessia Bono  1 , Anna Maria Almerico  1 , Giampaolo Barone  1 , Carla Gentile  1 , Annamaria Martorana  1
Affiliations

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

Antonino Lauria et al. Molecules. .

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.

Keywords: G-Quadruplex; antiproliferative effect; c-MYC; h-Telo; molecular docking; planar heterocyclic scaffold; synthesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
G-quadruplex stabilizers compounds and novel naphtho[1,2-b:8,7-b’]dithiophene ligands 1.
Figure 2
Figure 2
Structures of designed napthodithiophene compounds 2–6 as G4s stabilizers.
Figure 3
Figure 3
Molecular Docking Study of 2 in complex with h-Telo (PDB id: 3CE5) and c-MYC (PDB id: 5W77) G4 sequences; (a) side and top views obtained for the best pose of 2 in complex with the h-Telo G4 sequence, (b) side and top views obtained for the best pose of 2 in complex with the c-MYC G4 sequence.
Figure 4
Figure 4
Molecular Docking Study of 4b in complex with h-Telo (PDB id: 3CE5) and c-MYC (PDB id: 5W77) G4 sequences; (a) side and top views obtained for the best pose of 4b in complex with the h-Telo G4 sequence; (b) shows the side and the top views obtained for the best pose of 4b in complex with the c-MYC G4 sequence.
Scheme 1
Scheme 1
Synthesis of ethyl ester 3,8-diamino-naphtho[1,2-b:8,7-b’]dithiophene-2,9-carboxilate 2. Reagents and conditions: (i) NCS, CH3CN, −15 °C, N2, (yield 86%); (ii) pyridine, Tf2O, 0 °C, (yield 75%); (iii) Zn(CN)2, Pd(PPh3)4, DMF, N2, (yield 69%); (iv) N(Et)3, DMSO, rt, (yield 73%).
Scheme 2
Scheme 2
Synthesis of the Naphtho-DiThiophene 3. Reagents and conditions: (i) 10% NaOH, EtOH, reflux, (yield 50%).
Scheme 3
Scheme 3
Synthesis of 3,8-diamino-N-benzyl-naphtho[1,2-b:8,7-b’]dithiophene-2,9-dicarboxamides (4a,b). Reagents and conditions: (i) HBTU, N(Et)3, AcOEt, (yields: 4a = 43%; 4b = 36%).
Scheme 4
Scheme 4
Synthesis ethyl 3,8-(benzoylamino)-naphtho[1,2-b:8,7-b’]dithiophene-2,9-dicarboxylates 5a–c. Reagents and conditions: (i) pyridine, rt for 12h, (yields: 5a = 24%; 5b = 30%; 5c = 23%).
Scheme 5
Scheme 5
Synthesis 3,8-(benzoylamino)-naphtho[1,2-b:8,7-b’]dithiophene-2,9-dicarboxylic acid 6a,b. Reagents and conditions: (i) pyridine, rt for 12h, (yields for both 6a,b = 20%).
Figure 5
Figure 5
Antiproliferative activity exerted by the naphtho[1,2-b:8,7-b’]dithiophenes: (A) compound 2; (B) derivative 4b; (C) compound 5a; (D) compound 3 (black line) and compound 4a (red line) against HeLa cell line. In each panel, the antiproliferative activity is reported as GI50 value.
Figure 6
Figure 6
(a) UV-Vis spectra of 2 (black continuous line) in the presence of increasing amounts of c-MYC G4 collected in 100 mM KCl and 50 mM Tris-HCl buffer (pH = 7.4). (b) Circular dichroism spectra of (a) c-MYC G4 in presence of increasing amounts of 2 in 100 mM KCl and 50 mM Tris-HCl buffer (pH = 7.4). (c) Representative FRET DNA melting spectra of fluorolabelled c-MYC G4 alone (black curve) and in the presence of 5 equivalents of 2 (red trace) in 10mM potassium cacodylate buffer.
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