Interaction of Pyrrolobenzodiazepine (PBD) Ligands with Parallel Intermolecular G-Quadruplex Complex Using Spectroscopy and ESI-MS

Gajjela, Raju; Srinivas, R.; Reddy, Vangala Santhosh; Idris, Mohammed M.; Kamal, Ähmed; Nagesh, Narayana

doi:10.1371/journal.pone.0035920

Cited by 17 publications

(17 citation statements)

References 61 publications

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“…Similar interactions were observed for metalla-rectangles 5 and 7 after addition to CT DNA at 1:0.5 and 1:1 stoichiometries. This behavior suggests a stabilization of CT DNA [25]. When metalla-rectangle 8 was added to CT DNA, the positive CD band showed a higher hyperchromicity with an increase of the metalla-rectangle concentrations, indicating an excellent stabilization of CT DNA by metalla-rectangle 8, see Figure 7.…”

Section: Studiesmentioning

confidence: 83%

Exploiting Natural Products to Build Metalla-Assemblies: The Anticancer Activity of Embelin-Derived Rh(III) and Ir(III) Metalla-Rectangles

et al. 2014

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Abstract:Six new pentamethylcyclopentadienyl Rh(III) and Ir(III) metalla-rectangles ([3](CF 3 SO 3 ) 4 -[8](CF 3 SO 3 ) 4 ) have been prepared by a self-assembly strategy using the embelin-derived metalla-clips (η 5 -C 5 Me 5 ) 2 M 2 (μ 4 -C 6 HRO 4 -κO)Cl 2 (M = Rh, 1; M = Ir, 2; R = (CH 2 ) 10 CH 3 ) and the linear ditopic ligands, pyrazine, 4,4'-bipyridine and 1,2-bis (4-pyridyl)ethylene. These new metalla-rectangles have been obtained in high yield and isolated as their triflate salts. The complexes have been fully characterized by standard spectroscopic techniques and the antiproliferative activity of these tetranuclear complexes was evaluated in vitro on cancerous (DU-145, A-549, HeLa) and noncancerous (HEK-293) cell lines. The biological study has showed a better activity for the rhodium derivatives over the iridium analogs and for all complexes a very good selectivity for cancerous over noncancerous cells. The presence of lipophilic side chains coupled with the positive charge of the tetranuclear complexes suggested a cytotoxic activity involving the mitochondrial machinery, as demonstrated by multiple biological experiments.

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Section: Studiesmentioning

confidence: 83%

Exploiting Natural Products to Build Metalla-Assemblies: The Anticancer Activity of Embelin-Derived Rh(III) and Ir(III) Metalla-Rectangles

et al. 2014

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“…Nitrogen-containing ligands like TMPyP4, BRACO-19, Telomestatin etc., were found to be efficient in stabilizing quadruplex DNA and controlling tumor cell proliferation [23]–[27]. We have earlier reported the interaction and stabilization of quadruplex DNA by several nitrogen-containing ligands [28]–[31].…”

Section: Introductionmentioning

confidence: 99%

Phenyl 1,2,3-Triazole-Thymidine Ligands Stabilize G-Quadruplex DNA, Inhibit DNA Synthesis and Potentially Reduce Tumor Cell Proliferation over 3′-Azido Deoxythymidine

et al. 2013

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Triazoles are known for their non-toxicity, higher stability and therapeutic activity. Few nucleoside (L1, L2 and L3) and non-nucleoside 1,2,3-triazoles (L4–L14) were synthesised using click chemistry and they were screened for tumor cell cytotoxicity and proliferation. Among these triazole ligands studied, nucleoside ligands exhibited higher potential than non-nucleoside ligands. The nucleoside triazole analogues, 3′-Phenyl-1,2,3- triazole-thymidine (L2) and 3′-4-Chlorophenyl-1,2,3-triazole-thymidine (L3), demonstrated higher cytotoxicity in tumor cells than in normal cells. The IC50 value for L3 was lowest (50 µM) among the ligands studied. L3 terminated cell cycle at S, G2/M phases and enhanced sub-G1 populations, manifesting induction of apoptosis in tumor cells. Confocal studies indicated that nucleoside triazole ligands (L2/L3) cause higher DNA fragmentation than other ligands. Preclinical experiments with tumor-induced mice showed greater reduction in tumor size with L3. In vitro DNA synthesis reaction with L3 exhibited higher DNA synthesis inhibition with quadruplex forming DNA (QF DNA) than non quadruplex forming DNA (NQF DNA). Tm of quadruplex DNA increased in the presence of L3, indicating its ability to enhance stability of quadruplex DNA at elevated temperature and the results indicate that it had higher affinity towards quadruplex DNA than the other forms of DNA (like dsDNA and ssDNA). From western blot experiment, it was noticed that telomerase expression levels in the tissues of tumor-induced mice were found to be reduced on L3 treatment. Microcalorimetry results emphasise that two nucleoside triazole ligands (L2/L3) interact with quadruplex DNA with significantly higher affinity (Kd≈10−7 M). Interestingly the addition of an electronegative moiety to the phenyl group of L2 enhanced its anti-proliferative activity. Though IC50 values are not significantly low with L3, the studies on series of synthetic 1,2,3-triazole ligands are useful for improving and building potential pro-apoptotic ligands.

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“…The three PBD dimers, SJG-136 ( 6 ), DRG-16 ( 7 ) and ELB-21 ( 8 ) have structural similarity to the PBD dimer (PBD2, 10 ) evaluated by Raju and co-workers [53] (see Figure 2 ). …”

Section: Introductionmentioning

confidence: 64%

“… Anthramycin methyl ether ( 1 ), the PBD-C8-ester ( 2 ) and the PBD-C8-morpholine ( 3 ) do not possess any π-systems in their C8-side chains, whereas the PBD C8-conjugates 4 and 5 both have C8-substituents consisting of aromatic rings. The three PBD dimers, SJG-136 ( 6 ), DRG-16 ( 7 ) and ELB-21 ( 8 ) have structural similarity to the PBD dimer (PBD2, 10 ) evaluated by Raju and co-workers [53] (see Figure 2 ). …”

Section: Introductionmentioning

confidence: 64%

“…To investigate this further, the isolated MPB-Py-Py fragment ( 12 , Figure 3 ) that comprises the C8-substituent of 5 was evaluated and found to have a Δ T m value of up to 2.9°C at a 50∶1 ligand/DNA molar ratio. In the case of the PBD1 ( 9 ) and PBD2 ( 10 ) molecules studied by Raju and co-workers [53], it is likely that a similar phenomenon was taking place during their experiments, with the relatively bulky C8-substituents binding to the quadruplex DNA rather than the PBD components. In our study, the relative lack of interaction of the eight PBD molecules with the different quadruplex sequences was further confirmed by CD spectroscopy which failed to show any notable change in the characteristic signals after the addition of up to 10 molar equivalents of ligands.…”

Section: Introductionmentioning

confidence: 81%

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Pyrrolobenzodiazepines (PBDs) Do Not Bind to DNA G-Quadruplexes

et al. 2014

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The pyrrolo[2,1-c][1,4] benzodiazepines (PBDs) are a family of sequence-selective, minor-groove binding DNA-interactive agents that covalently attach to guanine residues. A recent publication in this journal (Raju et al, PloS One, 2012, 7, 4, e35920) reported that two PBD molecules were observed to bind with high affinity to the telomeric quadruplex of Tetrahymena glaucoma based on Electrospray Ionisation Mass Spectrometry (ESI-MS), Circular Dichroism, UV-Visible and Fluorescence spectroscopy data. This was a surprising result given the close 3-dimensional shape match between the structure of all PBD molecules and the minor groove of duplex DNA, and the completely different 3-dimensional structure of quadruplex DNA. Therefore, we evaluated the interaction of eight PBD molecules of diverse structure with a range of parallel, antiparallel and mixed DNA quadruplexes using DNA Thermal Denaturation, Circular Dichroism and Molecular Dynamics Simulations. Those PBD molecules without large C8-substitutents had an insignificant affinity for the eight quadruplex types, although those with large π-system-containing C8-substituents (as with the compounds evaluated by Raju and co-workers) were found to interact to some extent. Our molecular dynamics simulations support the likelihood that molecules of this type, including those examined by Raju and co-workers, interact with quadruplex DNA through their C8-substituents rather than the PBD moiety itself. It is important for the literature to be clear on this matter, as the mechanism of action of these agents will be under close scrutiny in the near future due to the growing number of PBD-based agents entering the clinic as both single-agents and as components of antibody-drug conjugates (ADCs).

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Interaction of Pyrrolobenzodiazepine (PBD) Ligands with Parallel Intermolecular G-Quadruplex Complex Using Spectroscopy and ESI-MS

Cited by 17 publications

References 61 publications

Exploiting Natural Products to Build Metalla-Assemblies: The Anticancer Activity of Embelin-Derived Rh(III) and Ir(III) Metalla-Rectangles

Exploiting Natural Products to Build Metalla-Assemblies: The Anticancer Activity of Embelin-Derived Rh(III) and Ir(III) Metalla-Rectangles

Phenyl 1,2,3-Triazole-Thymidine Ligands Stabilize G-Quadruplex DNA, Inhibit DNA Synthesis and Potentially Reduce Tumor Cell Proliferation over 3′-Azido Deoxythymidine

Pyrrolobenzodiazepines (PBDs) Do Not Bind to DNA G-Quadruplexes

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