Insight into the toxic effects of cis-dichloridoplatinum(II) complexes containing 7-azaindole halogeno derivatives in tumor cells

Abstract

The cisplatin analogues cis-[PtCl2(3ClHaza)2] (1) and cis-[PtCl2(3IHaza)2] (2) (3ClHaza and 3IHaza are 3-chloro-7-azaindole and 3-iodo-7-azaindole, respectively) are quite toxic to ovarian tumor cells, with moderately better IC50 values than for cisplatin in the cisplatin-sensitive cell line A2780. We investigated potential factors which might be involved in the mechanism underlying the cytotoxic effects of 1 and 2 and compared these factors with those involved in the mechanism underlying the effects of conventional cisplatin. Our data indicate that the higher cytotoxicity of 1 and 2 originates mainly from their efficient cellular accumulation, different effects at the level of cell cycle regulation, and reduced propensity for DNA adduct repair. Studies of their reactivity toward cellular components reveal efficient binding to DNA, which is typically required for an active platinum drug. Further results suggest that 1 and 2 are capable of circumventing resistance to cisplatin induced by alterations in cellular accumulation and DNA repair. Hence, the latter two factors appear to be responsible for differences in the toxicity of 1 or 2, and cisplatin in tumor cells. The results of this work reinforce the idea that direct analogues of conventional cisplatin-containing halogeno-substituted 7-azaindoles offer much promise for the design of novel therapeutic agents.

Platinum(II) Iodido Complexes of 7-Azaindoles with Significant Antiproliferative Effects: An Old Story Revisited with Unexpected Outcomes

“…Treatment by complexes 6 and 8 led to the cell cycle perturbations different from recently reported cis - and trans -platinum(II) diiodido complexes [10] as well as from mixed-ligand platinum(II) dichlorido complexes containing 7-azaindole-based N -donor ligand [6], whose application resulted in higher S cell cycle phase populations. Only the low portion of populations (1.2–4.3%) corresponding to apoptotic and necrotic cells were identified in the sub-G1 region after 24 h exposure to complexes 6 and 8 (Fig 4), which is considerably different than recently reported for dichlorido analogues (sub-G1 populations of ca 30%) of the herein studied platinum(II) diiodido complexes [43]. Cisplatin , on the other hand, showed a typical increase of the S cell cycle phase populations in both the cancer cell lines [6,10,42,43], resulting in higher S and lower G0/G1 populations than observed for complexes 6 and 8 (and control cells) on both MCF-7 and A2780 cancer cells (Fig 4).…”

“…Only the low portion of populations (1.2–4.3%) corresponding to apoptotic and necrotic cells were identified in the sub-G1 region after 24 h exposure to complexes 6 and 8 (Fig 4), which is considerably different than recently reported for dichlorido analogues (sub-G1 populations of ca 30%) of the herein studied platinum(II) diiodido complexes [43]. Cisplatin , on the other hand, showed a typical increase of the S cell cycle phase populations in both the cancer cell lines [6,10,42,43], resulting in higher S and lower G0/G1 populations than observed for complexes 6 and 8 (and control cells) on both MCF-7 and A2780 cancer cells (Fig 4). Taken together, application of complexes 6 and 8 led to the cell cycle perturbations indirectly indicating different mechanism of action from cisplatin .…”

In Vitro Antitumor Active Gold(I) Triphenylphosphane Complexes Containing 7-Azaindoles

“…Consequently, the G 0 /G 1 population decreased for 1 and 5 as compared with the control cells, while the number of cells in the S cell cycle phase was comparable for 1 and 5 , and the non-treated control cells. Different modification of the A2780 cell cycle, induced by the studied gold(I) complexes (i.e., G 2 -arrest) and cisplatin (i.e., S-arrest), is indicative for different mechanism of anticancer action of 1 and 5 , as compared with conventional cisplatin [47]. The mentioned G 2 -arrest observed at the A2780 cells treated by the complexes 1 and 5 is different from the cell cycle modification provoked by different gold(I) complexes including auranofin .…”

Reinvestigation of the crystal structure, vibrational spectroscopic studies and DFT calculations of 5-bromo-7-azaindole with dual N–H⋅⋅⋅N hydrogen bonds in dimers

“…13, the hydrogen atoms were located using the rigid model with the fixed C-H bond lengths (0.95 Å) and the identical values of the H n -C-N and H n -C-C angles (n=2, 3,4,6). In our study, the coordinates and isotropic displacement parameters of all hydrogen atoms were refined freely.…”

“…These compounds have revealed the antiproliferative [1], anticancer [2][3][4][5] and anti-inflammatory [6] activities. They also act as protein kinase inhibitors in the treatment of kinase induced diseases [7,8].…”