Synthesis and electronic properties of ester substituted 1,4-dicyanodibenzodioxins and evaluation of anti-proliferative activity of all isomeric 1,2-, 2,3- and 1,4-dicyanodibenzodioxins against HeLa cell line
“…3) of the different compounds and TPP plots with the DPBF plot, first by normalizing with respect to DPBF and then again normalizing with respect to the slope of the TPP line. Therefore, our earlier observation of high in vitro ROS levels for incubated HeLa cells, [5] could be related to the cellular DNA-targeting by our cytotoxic dibenzodoxins, rendering the normal cellular processes inoperative and subsequently producing oxidative stress on the cell. Therefore, in order to understand the observed bioactivity of our molecules, it will be crucial to further study their DNA-binding mechanisms.Fig.…”
Section: Resultsmentioning
confidence: 99%
“…We have previously shown that HeLa cells incubated with our dibenzodioxins (compound 2 from Fig. 1 among others) suffered from oxidative stress condition [ 5 ]. When hypoxic tumor cells undergo drug induced life cycle changes, the levels of intracellular reactive oxygen species (ROS) increases.…”
Section: Resultsmentioning
confidence: 99%
“…When hypoxic tumor cells undergo drug induced life cycle changes, the levels of intracellular reactive oxygen species (ROS) increases. Beyond a certain threshold, ROS could activate programmed cell death pathways such as apoptosis [ 5 ]. Singlet oxygen ( 1 O 2 ), a form of ROS with very short half-life is also known to be very cytotoxic [ 18 ] and can be utilized in promoting tumor cell death by causing damage to cellular substructures, particularly the nuclear material.…”
Section: Resultsmentioning
confidence: 99%
“…Singlet oxygen ( 1 O 2 ), a form of ROS with very short half-life is also known to be very cytotoxic [ 18 ] and can be utilized in promoting tumor cell death by causing damage to cellular substructures, particularly the nuclear material. Based upon our previous observation of high level of ROS induction by dibenzodioxins (compound 2 ) in vitro , [ 5 ] we were thus interested in evaluating whether and to what extent ROS could be produced by our dibenzodioxins and phenazines ( Fig. 1 ) in solution.…”
Section: Resultsmentioning
confidence: 99%
“…We previously synthesised push-pull dibenzodioxin molecules ( Fig. 1 ), and they exhibited promising in vitro cytotoxicity against HeLa tumor cell line and no cytotoxicity against normal HEK 293 and HaCaT cell lines [ 5 , 6 ]. The IC 50 values of all derivatives against HeLa cell line were in low micromolar ranges and these values are similar as compared with earlier reported dibenzodioxins [ 7 ].…”
Push-pull dibenzodioxins and phenazines having ‘anthracene-like’ planar structures and good charge transfer character had been previously synthesised in our laboratory. The dibenzodioxins had earlier proven their anti-proliferative nature against HeLa tumor cell lines. Since phenazines are structural analogues of the former, these molecules were evaluated in course of the current study for their cytotoxic action against HeLa cell lines and they exhibited strong anti-tumor activity. This behavior could be related to their good DNA binding property. The DNA binding modes of molecules
1
–
4
(Fig. 1) were evaluated using various experimental techniques and they interacted with DNA in a non-covalently by both intercalative as well as groove binding mechanisms. Molecule
1
follows predominantly intercalative binding mode whereas molecules
2
and
3
have nearly equal and opposite preferences for both groove binding and intercalative modes. For molecule
4
, groove binding is preferred mode of binding to DNA. A rationale for such differential binding behaviour is provided based on the subtle structural differences in our synthesised dibenzodioxins and phenazines. Elucidation of the mode of a molecule-DNA-binding event is relevant for understanding the mechanism of action of these molecules and will help promote further research into designing better DNA targeting small molecules.
“…3) of the different compounds and TPP plots with the DPBF plot, first by normalizing with respect to DPBF and then again normalizing with respect to the slope of the TPP line. Therefore, our earlier observation of high in vitro ROS levels for incubated HeLa cells, [5] could be related to the cellular DNA-targeting by our cytotoxic dibenzodoxins, rendering the normal cellular processes inoperative and subsequently producing oxidative stress on the cell. Therefore, in order to understand the observed bioactivity of our molecules, it will be crucial to further study their DNA-binding mechanisms.Fig.…”
Section: Resultsmentioning
confidence: 99%
“…We have previously shown that HeLa cells incubated with our dibenzodioxins (compound 2 from Fig. 1 among others) suffered from oxidative stress condition [ 5 ]. When hypoxic tumor cells undergo drug induced life cycle changes, the levels of intracellular reactive oxygen species (ROS) increases.…”
Section: Resultsmentioning
confidence: 99%
“…When hypoxic tumor cells undergo drug induced life cycle changes, the levels of intracellular reactive oxygen species (ROS) increases. Beyond a certain threshold, ROS could activate programmed cell death pathways such as apoptosis [ 5 ]. Singlet oxygen ( 1 O 2 ), a form of ROS with very short half-life is also known to be very cytotoxic [ 18 ] and can be utilized in promoting tumor cell death by causing damage to cellular substructures, particularly the nuclear material.…”
Section: Resultsmentioning
confidence: 99%
“…Singlet oxygen ( 1 O 2 ), a form of ROS with very short half-life is also known to be very cytotoxic [ 18 ] and can be utilized in promoting tumor cell death by causing damage to cellular substructures, particularly the nuclear material. Based upon our previous observation of high level of ROS induction by dibenzodioxins (compound 2 ) in vitro , [ 5 ] we were thus interested in evaluating whether and to what extent ROS could be produced by our dibenzodioxins and phenazines ( Fig. 1 ) in solution.…”
Section: Resultsmentioning
confidence: 99%
“…We previously synthesised push-pull dibenzodioxin molecules ( Fig. 1 ), and they exhibited promising in vitro cytotoxicity against HeLa tumor cell line and no cytotoxicity against normal HEK 293 and HaCaT cell lines [ 5 , 6 ]. The IC 50 values of all derivatives against HeLa cell line were in low micromolar ranges and these values are similar as compared with earlier reported dibenzodioxins [ 7 ].…”
Push-pull dibenzodioxins and phenazines having ‘anthracene-like’ planar structures and good charge transfer character had been previously synthesised in our laboratory. The dibenzodioxins had earlier proven their anti-proliferative nature against HeLa tumor cell lines. Since phenazines are structural analogues of the former, these molecules were evaluated in course of the current study for their cytotoxic action against HeLa cell lines and they exhibited strong anti-tumor activity. This behavior could be related to their good DNA binding property. The DNA binding modes of molecules
1
–
4
(Fig. 1) were evaluated using various experimental techniques and they interacted with DNA in a non-covalently by both intercalative as well as groove binding mechanisms. Molecule
1
follows predominantly intercalative binding mode whereas molecules
2
and
3
have nearly equal and opposite preferences for both groove binding and intercalative modes. For molecule
4
, groove binding is preferred mode of binding to DNA. A rationale for such differential binding behaviour is provided based on the subtle structural differences in our synthesised dibenzodioxins and phenazines. Elucidation of the mode of a molecule-DNA-binding event is relevant for understanding the mechanism of action of these molecules and will help promote further research into designing better DNA targeting small molecules.
Push‐pull dibenzodioxins with electron withdrawing and donating groups were prepared in good yields through a short and simple synthesis. Strong green emission above 500 nm occurs in those derivatives where there is maximum charge transfer to the most electron deficit terephthalonitrile ring, from proximal cyclic amino donor groups. Theoretical calculations support experimental findings through evaluation of excited state properties. In molecules with a nitro group, the excited state localizes electron density exclusively onto it and twisted nitro geometry was also found. In effect, electronic charge cannot relocate into the molecular plane, rendering them non‐fluorescent. Also, studies on the fluorescent derivatives show that best emission would occur when the donor moiety contains a saturated cyclic amino ring and the amines are 2°. Overall, our study establishes structure‐property guidelines and limits on dibenzodioxin functionalization towards preparing fluorescent derivatives of the same.
A series of dibenzodioxins containing electron push-pull groups were synthesized using simple methods and their spectroscopic and redox behavior was studied. Electrochemical experiments were performed to measure the redox potentials of the substituted dibenzodioxins. The role of individual molecular subunits in tweaking the redox potential values was delineated by comparing them with the electrochemical properties of analogous heteroacenes. In many cases, our redox potentials were found to be comparably low with that of many wellknown heteroacenes.
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