G-Quadruplex Recognition by Quinacridines: a SAR, NMR, and Biological Study (original) (raw)
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Indian Journal of Pharmaceutical Sciences, 2018
Chemotherapy is often the treatment of choice for many types of cancer and the search for new chemotherapeutic agents still plays a major role in the fight against cancer. A reasonable approach in this area deals with use of compounds interacting with DNA and/or inhibiting enzymes critical for cell survival and replication. Amsacrine is one such compound, a well-known antiproliferative agent used to treat some types of cancers including acute adult leukaemia [1]. The poisoning of topo II activity inhibits the relegation process and causes lethal double-strand breaks in DNA, leading to cell cycle arrest and apoptosis. The intercalative property was referred to the planar aromatic system of the acridine moiety [2]. In the same context, acridines have gained strong ground for various biological activities like antimicrobial [3] , antioxidant [4] , anticancer [5-8] , antimalarial [9] , antiinflammatory [10] , analgesic [11] , antileishmanial [12] , antinociceptive [13] , acetylcholinesterase inhibitory [14] and antiherpes [15]. Amsacrine is the best known compound of 9-anilinoacridines series. It was one of the first DNA-intercalating agents to be considered as a topoisomerase II inhibitor. The intercalation process is the strongest type of reversible binding to the double helical DNA in compounds with sufficiently large coplanar aromatic chromophore. Several detailed SAR studies of acridine-based DNA-intercalating agents suggest that the mode of binding is important and the chromophore intercalate with the DNA base
HETEROCYCLES, 2007
thiazepino [2,3-h]quinolinecarboxylic acid 3 is prepared by PPA-catalyzed thermal lactamization of the respective 8-amino-7-[(2-carboxyethyl)thio]-1,4-dihydroquinoline-3-carboxylic acid 9. The latter synthon is obtained by reduction of the 8-nitro-1,4-dihydroquinoline precursor 8 which, in turn, is made accessible via interaction of 3-mercaptopropionic acid with 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-1,4dihydroquinoline-3-carboxylic acid 7 in the presence of triethylamine. A benzo-homolog of 3, namely tetrahydroquino[7,8-b]benzothiazepine-3-carboxylic acid 6, is analogously prepared via the raction of 2-mercaptobenzoic acid with 7, followed by reduction of the resulting 7-[(2-carboxyphenyl)thio]-8-nitro product 10 into the corresponding 8-amino derivative 11, and subsequent lactamization. The structures assigned to 3, 6 and 8-11 are based on microanalytical and spectral (IR, MS, NMR) data. Molecules 2007, 12 1559
Bioconjugate Chemistry, 2007
Oligodeoxyribonucleotides of sequence d( 5′ TGGGAG 3′ ) carrying bulky aromatic groups at the 5′ end were found to exhibit potent anti-HIV activity [Hotoda, H., et al. (1998) J. Med. Chem. 41, 3655-3663 and references therein]. Structure-activity relationship investigations indicated that G-quadruplex formation, as well as the presence of large aromatic substituents at the 5′-end, were both essential for their antiviral activity. In this work, we synthesized some representative examples of the anti-HIV active Hotoda's 6-mers and analyzed the resulting G-quadruplexes by CD, DSC, and molecular modeling studies, in comparison with the unmodified oligonucleotide. In the case of the sequence carrying the 3,4-dibenzyloxybenzyl (DBB) group, identified as the best candidate for further drug optimization, we developed an alternative protocol to synthesize the 5′-DBB-thymidine phosphoramidite building block in higher yields. The thermodynamic and kinetic parameters for the association/dissociation processes of the 5′-conjugated quadruplexes, determined with respect to the unmodified one, were discussed in light of the molecular modeling studies. The aromatic groups at the 5′ position of d( 5′ TGGGAG 3′ ) dramatically enhance both the equilibrium and the rate of formation of the quadruplex complexes. The overall stability of the investigated quadruplexes was found to correlate with the reported IC 50 values, thus furnishing quantitative evidence for the hypothesis that the G-quadruplex structures are the ultimate active species, effectively responsible for the biological activity.
Molecules (Basel, Switzerland), 2018
In this paper, the selective interactions of synthetic derivatives of two natural compounds, berberine and palmatine, with DNA G-quadruplex structures were reported. In particular, the previous works on this subject concerning berberine were further presented and discussed, whereas the results concerning palmatine are presented here for the first time. In detail, these palmatine derivatives were developed by inserting seven different small peptide basic chains, giving several new compounds that have never been reported before. The preliminary studies of the interactions of these compounds with various G-quadruplex-forming sequences were carried out by means of various structural and biochemical techniques, which showed that the presence of suitable side chains is very useful for improving the interaction of the ligands with G-quadruplex structures. Thus, these new palmatine derivatives might act as potential anticancer drugs.
A Fragment-Based Approach for the Development of G-Quadruplex Ligands: Role of the Amidoxime Moiety
Molecules (Basel, Switzerland), 2018
G-quadruplex (G4) nucleic acid structures have been reported to be involved in several human pathologies, including cancer, neurodegenerative disorders and infectious diseases; however, G4 targeting compounds still need implementation in terms of drug-like properties and selectivity in order to reach the clinical use. So far, G4 ligands have been mainly identified through high-throughput screening methods or design of molecules with pre-set features. Here, we describe the development of new heterocyclic ligands through a fragment-based drug discovery (FBDD) approach. The ligands were designed against the major G4 present in the long terminal repeat (LTR) promoter region of the human immunodeficiency virus-1 (HIV-1), the stabilization of which has been shown to suppress viral gene expression and replication. Our method is based on the generation of molecular fragment small libraries, screened against the target to further elaborate them into lead compounds. We screened 150 small mole...
Molecules, 2004
Synthesis of novel 5-methylidene-1,2,3,5-tetrahydro[2,1-b]-quinazoline derivatives 2-4 with potential biological activities mediated by α-adrenergic and/or imidazoline receptors was performed by reacting 2-chloro-4,5-dihydroimidazole (1) with the corresponding 2-aminoacetophenones. Compound 2, which incorporates an enamine moiety, underwent a 1,3-dipolar cycloaddition reaction with the appropriate nitrones 5-9 to give 1,2,3,5-tetrahydro-imidazo[2,1-b]quinazolin-5,5 '-spiro-2 ' ,3 '-diphenylisoxazolidines 10-14. Reactions of the title compounds 2 and 4 with dimethyl acetylenedicarboxylate (DMAD) afforded dimethyl 2-(2,3-dihydroimidazo[2,1-b]quinazolin-5(1H)-ylidenemethyl)but-2-enedioates 15, 16. Imidazo[2,1-b]quinazoline 2 was further treated with acetyl chloride, benzoyl chloride and mesyl chloride to give the 1-substituted derivatives 17, 18 and 19, respectively. The structures of all new compounds obtained were confirmed by elemental analysis and spectral data (IR, 1 Hand 13 C-NMR) as well as X-ray crystallographic analysis of 3 and 18.
ChemistrySelect, 2024
The reaction of 2-amino-4,6-dimethylpyridine with 4-cyanobenzaldehyde, salicylaldehyde or 2-hydroxy-1-naphthaldehyde furnished the corresponding N-aryl-(2-pyridyl)aldimines in very good yields. The synthetised Schiff bases were characterized by FT-IR, 1 H, 13 C, DEPT-135 and [ 1 H, 13 C]-HSQC NMR spectroscopy, HRMS and elemental analyses. Additionally, the structure of 2-((E)-(4,6-dimethylpyridin-2-ylimino)methyl)phenol was unambiguously determined by single crystal X-ray diffraction analysis. Hirshfeld analysis of molecular packing was performed. The most common intermolecular interaction is the hydrogenhydrogen (56.8 %) contacts while the most significant interactions are the O…H (6.5 %) and C…C (4.2 %) contacts. DFT calculated geometric parameters and NMR chemical shifts are well correlated with the experimental data. This compound has a net dipole moment of 2.4261 Debye. The MCF-7 growth was suppressed by N-aryl-(2-pyridyl)aldimines more than that for T47D cell line. The IC 50 values of 4-((E)-(4,6-dimethylpyridin-2ylimino)methyl)benzonitrile against MCF-7 and T47D cell lines were the lowest and it is considered the most promising candidate as anticancer agent. Furthermore, this study conducted a molecular docking of benzonitrile-based Schiff base onto DNA duplex to explore a potential molecular mechanism for the robust anticancer activities of this Schiff base adduct. The molecular docking results indicate that benzonitrile-based Schiff base exhibits characteristics of a potential DNA minor groove binder.