Cytotoxicity of metal 8-quinolinethiolates

Abstract

High cytotoxicity has been established for the 8-quinolinethiolates of copper, cadmium, indium, antimony, bismuth, ruthenium, rhodium, palladium, osmium, iridium, and platinum on HT-1080 (human fibrosarcoma), MG-22A (mouse hepatoma), and B-16 (mouse melanoma) tumor cells. The greatest activity against HT-1080 was possessed by the iridium complex, and against MG-22A by the osmium complex. All the investigated metal 8-quinolinethiolates were highly toxic in relation to NIH 3T3 normal mouse embryo fibroblasts.Keywords: 8-quinolinethiolates of metals, cytotoxicity.We showed recently that 8-quinolineselenolates of metals possess high cytotoxicity on tumor cells HT-1080 (human fibrosarcoma), MG-22A (mouse hepatoma), Neuro 2A (mouse neuroblastoma), and especially on B-16 mouse melanoma [1,2]. However all these compounds, displaying high activity to tumor cells, are also toxic in relation to normal mouse embryo fibroblasta NIH 3T3 [2].On the other hand, many organic derivatives of metals containing a metal-sulfur bond also possess antitumor activity, such as copper [3], gold [4], gallium [5], germanium [6], tin [7], rhodium [8], and palladium [9]. Consequently we decided to determine the cytotoxicity of 8-quinolinethiolates of metals in order to assess the effect of the nature of the ligand on the cytotoxicity of complexes and to compare the activity and toxicity of compounds analogous in structure containing a metal-sulfur and metal-selenium bond. N S N N S S n M n+ 1a-k 2 1 a M = Cu, b M = Cd, c M = In, d M = Sb, e M = Bi, f M = Ru, g M = Rh, h M = Pd, i M = Os, j M = Ir, k M = Pt; 1 a,b,h,k n = 2, c-g, i, j n = 3For this purpose we have synthesized a series of complexes of 8-quinolinethiol with metals 1a-k (Table 1) by the interaction of sodium 8-quinolinethiolate with metal salts and have studied their cytotoxicity (Table 2) on three lines of tumor cells HT-1080, MG-22-A, and B-16. Action was also tested on normal mouse embryo fibroblasts NIH 3T3, which also served to determine the toxicity of compounds (alternative method of determining LD 50 ). The toxicity of the corresponding di(8-quinolinyl) disulfide was determined separately. __________________________________________________________________________________________

Cytotoxic di(8-quinolyl) disulfides

“…Cytotoxicity of compounds 1-28. in vitro relative to monolayers of HT-1080 tumor cells (human fibrosarcoma), MG-22A (mouse hepatoma), and NIH-3T3 normal cells (embryonic mouse fibroblasts) were measured in 96 well plastic plates using the dyes CV, MTT, and NR according to methods [28,29] certified by us earlier [1, [30][31][32]. The concentrations of compounds causing the death of 50% of the cells (LC 50 , µg/ml) are given in Tables 1-3.…”

Synthesis and cytotoxicity of metal 4-methyl-8-quinolinethiolates

“…The highest activity to HT-1080 was shown by the iridium complex and to the MG-22A by the osmium complex. However, all of the metal 8-quinolinethiolates studied proved highly toxic towards normal NIH 3T3 mouse embryonic fibroblasts [5].…”

“…We have shown that the 8-quinolinethiolates of copper, cadmium, indium, antimony, bismuth, ruthenium, rhodium, palladium, osmium, iridium, and platinum show high cytotoxicity towards HT-1080 (human fibrosarcoma), MG-22A (mouse hepatoma), and B-16 (mouse melanoma) cells [5]. The highest activity to HT-1080 was shown by the iridium complex and to the MG-22A by the osmium complex.…”

“…The introduction of substituents in the quinoline ring allowed us to decrease the toxicity and increase the selectivity of di(8-quinolyl) disulfides [6] and also to decrease the toxicity of the analogous metal 8-quinolineselenolates through introduction of a 4-methyl group into the quinoline ring [7]. We have therefore synthesized a series of metal 4-methyl-8-quinolinethiolates 1a-g (Table 1) with the aim of decreasing the toxicity of the highly active complexes and studied their cytotoxicity on two tumour cell lines HT-1080 and MG-22A as well as on normal NIH 3T3 fibroblasts which served as a toxicity measure of the compounds (alternative method of determining LD 50 [8]).…”

“…We have therefore synthesized a series of metal 4-methyl-8-quinolinethiolates 1a-g (Table 1) with the aim of decreasing the toxicity of the highly active complexes and studied their cytotoxicity on two tumour cell lines HT-1080 and MG-22A as well as on normal NIH 3T3 fibroblasts which served as a toxicity measure of the compounds (alternative method of determining LD 50 [8]). The introduction of a methyl group into position 4 of the quinoline ring decreases the toxicity of the metal 4-methyl-8-quinolinethiolates by more than one order when compared with that of the complexes with unsubstituted ligand [5]. This most significantly affects the toxicity of the iridium 1f (LC 50 85 µg/ml), rhodium 1c (LC 50 78 µg/ml), and palladium 1d (LC 50 40 µg/ml) complexes.…”