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

Abstract

It has been shown that the introduction of a methyl group at position 4 of the quinoline ring in metal 8-quinolinethiolates brings about a significant increase in the selectivity of their cytotoxic activity. It was found that rhodium 4-methyl-8-quinolinethiolate is 46 times less toxic than the unsubstituted 8-quinolinethiolate but with comparable toxicity towards MG-22A tumor cells (LC 50 2 µg/ml).Many organic derivatives of copper [1], ruthenium [2], rhodium [3], and palladium [4] containing a metal to sulfur bond shown antitumor activity. 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. However, all of the metal 8-quinolinethiolates studied proved highly toxic towards normal NIH 3T3 mouse embryonic fibroblasts [5].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]). N Me S n M n+ 1 a M = Cu, b M = Ru, c M = Rh, d M = Pd, e M = Os, f M = Ir, g M = Pt; a,d,g n = 2, b, c, e, f n = 3

Synthesis and cytotoxicity of methyl-and methoxy-substituted metal 8-quinolinethiolates

“…This is most markedly seen in the toxicity of the iridium complex 2c with a methyl group at position 5 (LC 50 220 µg/ml, LD 50 1785 mg/kg). The toxicity of the iridium and rhodium complexes with a methyl group at position 4 (LC 50 85 and 78 µg/ml respectively) are also an order less than toxicity of the complexes with the unsubstituted ligand [23]. The 5-methyl derivatives of iridium and osmium proved to be the least toxic while the 4-isomer was the least toxic of the rhodium derivatives.…”

“…However, all of these compounds showing high activity towards tumor cells are also toxic to normal NIH 3T3 mouse embryonic fibroblasts [22]. The toxicity of the highly active rhodium and iridium 8-quinolinethiolates can be markedly decreased by the introduction into their molecules of a methyl group at the 4 position of the quinoline ring [23]. It was also found that substituents in different positions of the quinoline ring can increase the selectivity of action of di(8-quinolyl) disulfides [26].…”

“…We have shown that not only ruthenium, rhodium, and osmium but also iridium complexes [22,23] with an 8-quinolinethiol [22,23] or 8-quinolineselenol [24,25] ligand show high cytotoxicity to HT-1080 human fibrosarcoma and MG-22A mouse hepatoma tumor cells. However, all of these compounds showing high activity towards tumor cells are also toxic to normal NIH 3T3 mouse embryonic fibroblasts [22].…”

Synthesis and cytotoxicity of methyl-substituted 8-quinolineselenolates of ruthenium, rhodium, osmium, and iridium

“…Several rhodium complexes have revealed a greater toxicity towards A549 lung carcinoma and T47D mammary gland cells than their ruthenium analogs [22] and this points to the promise of novel antitumor agents amongst rhodium compounds [23][24][25][26]. A series of osmium complexes has also shown comparable cytotoxicity towards various tumor cells [22,[27][28][29][30][31] We have found that iridium complexes [32][33][34][35] as well as those of ruthenium, rhodium, and osmium show a high cytotoxicity towards human fibrosarcoma HT-1080 and mouse hepatoma MG-22A cells with the use of 8-quinolinethiol [32][33][34] or 8-quinolineselenol [35] as ligand. Certain polypyridyl complexes of iridium actively inhibit the growth of human MCF-7 (mammary gland cancer) and HT-29 (large intestine cancer) tumor cells [36].…”

“…The toxicity of the complexes can be varied by the introduction of a substituent into the quinoline ring [35,51] but, as in the case of analogous 8-quinolinethiolates [32][33][34], the selectivity of the substituent is low.…”