Oncogenic and telomeric G-quadruplexes: Targets for porphyrin-triphenylphosphonium conjugates.

DNA chains with sequential guanine (G) repeats can lead to the formation of G-quadruplexes (G4), which are found in functional DNA and RNA regions like telomeres and oncogene promoters. The development of molecules with adequate structural features to selectively stabilize G4 structures can counteract cell immortality, highly described for cancer cells, and also downregulate transcription events underlying cell apoptosis and/or senescence processes. We describe here, the efficiency of four highly charged porphyrins-phosphonium conjugates to act as G4 stabilizing agents.

-Dibenzoporphyrin Pyridinium Derivatives as Potential G-Quadruplex DNA Ligands.

Since the occurrence of tumours is closely associated with the telomerase function and oncogene expression, the structure of such enzymes and genes are being recognized as targets for new anticancer drugs. The efficacy of several ligands in telomerase inhibition and in the regulation of genes expression, by an effective stabilisation of G-quadruplexes (G4) DNA structures, is being considered as a promising strategy in cancer therapies. When evaluating the potential of a ligand for telomerase inhibition, the selectivity towards quadruplex versus duplex DNA is a fundamental attribute due to the large amount of double-stranded DNA in the cellular nucleus.

Reaction of Corroles with Sarcosine and Paraformaldehyde: A New Facet of Corrole Chemistry.

Details on the unexpected formation of two new (dimethylamino)methyl corrole isomers from the reaction of 5,10,15-tris(pentafluorophenyl)corrolatogallium(III) with sarcosine and paraformaldehyde are presented. Semi-empirical calculations on possible mechanism pathways seem to indicate that the new compounds are probably formed through a Mannich-type reaction. The extension of the protocol to the free-base 5,10,15-tris(pentafluorophenyl)corrole afforded an unexpected new seven-membered ring corrole derivative, confirming the peculiar behavior of corroles towards known reactions when compared to the well-behaved porphyrin counterparts.

Interfacial assembly of zinc(II) phthalocyanines on graphene oxide (GO): Stable "turn-off-on" nanoplatforms to detect G-quadruplexes (G4).

Hypothesis: The aggregation of phthalocyanines (Pcs) enfeebles their suitability as G-quadruplex (G4) ligands over time. It is hypothesized that the interfacial assembly of Pcs on graphene oxide (GO) influences intermolecular interactions, thereby affecting their physicochemical properties and inducing stabilization of Pcs in solution. Hence, the stacking of Pcs on GO could be tuned to create nanosystems with the ability to detect G4 for longer periods through a slow release of Pcs.

Diketopyrrolo[3,4-c]pyrrole derivative as a promising ligand for the stabilization of G-quadruplex DNA structures.

Telomerase, oncogenes and tumor suppressors are closely associated with tumour occurrence, therefore these structures are being recognized as targets for the development of new anticancer drugs. The efficacy of several molecules in telomerase inhibition and regulation of genes expression, by adduct formation with G-quadruplexes (G4), has been studied by biophysical and biochemical methods with promising results. We report here the synthesis and structural characterization of a small positively charged diketopyrrolo[3,4-c]pyrrole derivative, identified as DPP(PyMe), that showed very promising results as G4 stabilizing ligand.

The Interactions of HTMPyP, Analogues and Its Metal Complexes with DNA G-Quadruplexes-An Overview.

The evidence that telomerase is overexpressed in almost 90% of human cancers justifies the proposal of this enzyme as a potential target for anticancer drug design. The inhibition of telomerase by quadruplex stabilizing ligands is being considered a useful approach in anticancer drug design proposals. Several aromatic ligands, including porphyrins, were exploited for telomerase inhibition by adduct formation with G-Quadruplex (GQ).

Phthalocyanines for G-quadruplex aptamers binding.

The G-quadruplex (G4)-forming sequence within the AS1411 derivatives with alternative nucleobases and backbones can improve the chemical and biological properties of AS1411. Zn(II) phthalocyanine (ZnPc) derivatives have potential as high-affinity G4 ligands because they have similar size and shape to the G-quartets. The interactions of four Zn(II) phthalocyanines with the G4 AS1411 aptamer and its derivatives were determined by biophysical techniques, molecular docking and gel electrophoresis.

Hybrids Based on Graphene Oxide and Porphyrin as Tools for Detection and Stabilization of DNA G-Quadruplexes.

Telomerase inhibition has been an important strategy in cancer therapies, but for which effective drugs are still required. Here, noncovalent hybrid nanoplatforms containing the tetracationic 5,10,15,20-tetrakis(1-methyl-pyridinium-4-yl)porphyrin (TMPyP) and graphene oxide (GO) were prepared for promoting telomerase inhibition through the selective detection and stabilization of DNA guanine-quadruplex (G-Q) structures. Upon binding TMPyP to the GO sheets, the typical absorption bands of porphyrin have been red-shifted and the fluorescence emission was quenched.

Multicharged Phthalocyanines as Selective Ligands for G-Quadruplex DNA Structures.

The stabilization of G-Quadruplex DNA structures by ligands is a promising strategy for telomerase inhibition in cancer therapy since this enzyme is responsible for the unlimited proliferation of cancer cells. To assess the potential of a compound as a telomerase inhibitor, selectivity for quadruplex over duplex DNA is a fundamental attribute, as the drug must be able to recognize quadruplex DNA in the presence of a large amount of duplex DNA, in the cellular nucleus. By using different spectroscopic techniques, such as ultraviolet-visible, fluorescence and circular dichroism, this work evaluates the potential of a series of multicharged phthalocyanines, bearing four or eight positive charges, as G-Quadruplex stabilizing ligands.

Imidazole and imidazolium porphyrins: gas-phase chemistry of multicharged ions.

Electrospray ionization mass spectrometry/mass spectrometry in the positive ion mode was used to investigate the gas-phase chemistry of multicharged ions from solutions of porphyrins with 1,3-dimethylimidazolium-2-yl (DMIM) and 1-methylimidazol-2-yl (MIm) meso-substituents. The studied compounds include two free bases and 12 complexes with transition metals (Cu(II), Zn(II), Mn(III), and Fe(III)). The observed multicharged ions are either preformed or formed during the electrospraying process by reduction or protonation and comprise closed-shell and hypervalent mono-radical and bi-radical ions.

Nonclassic metallointercalators with dipyridophenazine: DNA interaction studies and leishmanicidal activity.

Complexes [Cu(CH3COO)(dppz)2]CH3COO (1) and [Zn(dppz)2](BF4)2 (2) with the intercalator dipyridophenazine (dppz) were prepared to obtain metallointercalators with increased geometrical flexibility compared to octahedral ones. Biophysical results (thermal denaturation, circular dichroism, rheometry, atomic force microscopy) indicate a strong interaction with DNA by intercalation and the existence of a positive cooperative effect with groove binding being preferred at low concentration of complexes. Induced circular dichroism (ICD) studies with DNA show that compounds 1 and 2 have a preferred orientation when binding to DNA.

Differentiation of aminomethyl corrole isomers by mass spectrometry.

Two new isomeric aminomethyl corrole derivatives of [5,10,15-tris(pentafluorophenyl)corrolato]gallium(III) were synthesized with pyridine (py) molecules as axial ligands. When investigated by electrospray ionization mass spectrometry, in the positive and the negative ion modes, these compounds showed an unusual gas-phase behavior that could be used for their differentiation. In the positive ion mode, the differentiation was achieved through the formation of diagnostic fragment ions formed from [M-py + H](+) precursors, by (CH(3) )(2) NH and HF losses.

Charge and substituent effects on the stability of porphyrin/G-quadruplex adducts.

The adduct ions of two tetramolecular G-quadruplexes formed from the d(TGGGGT) and d(TTGGGGGT) single strands with a group of cationic porphyrins, with different charges and substituents, and one neutral porphyrin, were investigated by ESI-MS and ESI-MS/MS in the negative ion mode. Formation of [Q + nNH(4)(+)+P(p+)-(z + n + p)H(+)](z-) adduct ions (where Q = quadruplex, n = number of quartets minus 1, P = porphyrin and p(+) = 0,1,2,3,4) indicates that the porphyrins are bound outside the quadruplexes providing an additional stabilization to those structures. The fragmentation pathways of the [Q + nNH(4)(+)+P(p+)-(z + n + p)H(+)](z-) adduct ions depend on the number of positive charges (p(+)) of the porphyrins and on the overall complex charge (z(-)), but do not show a significant dependence on the type of the substituent groups in the porphyrins.

Gas-phase fragmentation of protonated C60-pyrimidine derivatives.

Electrospray ionization mass spectrometry/mass spectrometry (ESI/MS/MS) and multiple stage mass spectrometry (MSn, n > 2) were used in the positive ion mode, with two different types of mass spectrometers, a quadrupole time-of-flight and an ion trap, to characterize two sets of different types of C60-aminopyrimidine exohedral derivatives. In one set, the pyrimidine moiety bears an amino acid methyl ester residue, and in the other the pyrimidine ring is part of a nucleoside-type moiety, the latter existing as two separated diastereoisomers.We have found that retro-cycloaddition processes occur for the closed shell protonated species formed by electrospraying C60 derivatives synthesized by Diels-Alder reactions, whereas for the C60 derivatives synthesized via 1,3-dipolar cycloadditions, these processes did not occur.

Reduction and adduct formation from electrosprayed solutions of porphyrin salts.

The solutions of four meso-tetrakis(N-alkylpyridinium-4-yl)porphyrin salts and of the p-toluenesulfonate salt of meso-tetrakis(4-trimethylammoniumphenyl)porphyrin, in methanol, were studied by electrospray mass spectrometry, in order to investigate the influence of the type of counter ion, the length of the substituent N-alkyl groups of the four (N-alkylpyridinium-4-yl)porphyrins and the presence of an aromatic (alkylpyridinium) or aliphatic (trimethylammonium) nitrogen, in ion formation. In our experimental conditions, adducts with the counter ions were formed only for the meso-tetrakis(4-trimethylammoniumphenyl)porphyrin and were not observed for the other porphyrins, even when the counter ion was the same. In contrast, formation of reduced species, such as the [M(4+) + e(-)]3+, [M(4+) + 2e(-)]2+, [M(4+) + 4e(-) + 2H(+)]2+, and [M(4+) + 5e(-) + 2H(+)]+ ions was observed only for the (N-alkylpyridinium-4-yl)porphyrins and the appearance of these species is apparently solvent related and may occur via counter ion/solvent adducts.

Reduction of cationic free-base meso-tris-N-methylpyridinium-4-yl porphyrins in positive mode electrospray ionization mass spectrometry.

Reductions involving more than one electron with formation of the M+ and [M+2H]+ ions were observed for electrosprayed meso-tris(N-methylpyridinium-4-yl)porphyrin iodides, MI3. These reductions were studied by using different solvents and flow rates. Formation of the [M+2H]+ ions occurred only for protic solvents and to a larger extent at lower flow rates.

Interactions of cationic porphyrins with double-stranded oligodeoxynucleotides: a study by electrospray ionisation mass spectrometry.

Electrospray ionisation mass spectrometry (ESI-MS), electrospray ionisation tandem mass spectrometry (ESI-MS/MS) and Ultraviolet-visible (UV-vis) spectroscopy were used to investigate the non-covalent interactions between small oligonucleotide duplexes with the GC motif and a group of cationic meso(N-methylpyridynium-4-yl)porphyrins (four free bases with one to four positive charges, and the zinc complex of the tetracationic free base). The results obtained point to outside binding of the porphyrins, with the binding strength increasing with the number of positive charges. Fragmentations involving losses from both chains were observed for the porphyrins with N-methylpyridinium-4-yl groups in opposite meso positions.