Cytotoxic di(8-quinolyl) disulfides

Abstract

It has been shown that the nature of the substituent and its position in the quinoline ring markedly affects the antitumor activity and toxicity of di (8-quinolyl) disulfides. The greatest cytotoxicity in the series of methyl derivatives was shown by the 7-, 6-, and 3-isomers towards HT-1080 (human fibrosarcoma) and MG-22A (mouse hepatoma) tumor cells while the 2-methyl derivatives generally have no effect on these cells. High cytotoxicity was also shown (LC 50 <1 µg/ml) by other 7-substituted compounds (Cl, PhO, PhS) but they also appear to be highly toxic towards normal NIH 3Y3 mouse embryonic fibroblasts. A similar trend was observed in the series of 5-substituted compounds (NH 2 , Cl, OMe, NO 2 ) which were highly active towards tumor cells but were toxic to normal cells. The best selectivity was found for the 6-substituted quinolines, the 6-methoxy derivative at low concentration brought about the death of tumor cells but appeared much less toxic towards normal fibroblasts (LC 50 100 µg/ml with a corresponding LD 50 of 874 mg/kg ).We have previously shown that di(8-quinolyl) disulfide 1 has high cytotoxicity (LC 50 0.3-0.4 µg/ml) towards HT-1080 tumor cells (human fibrosarcoma) and MG-22A (mouse hepatoma) [1]. However, while this disulfide is highly active towards tumor cells it is toxic towards normal NIH 3T3 mouse embryonic fibroblasts (LC 50 0.7 µg/ml) [1].With the aim of decreasing the toxicity and increasing the selectivity we have prepared a series of disulfides containing one (2-25) or two (26-28) electron donor or electron acceptor substituents both in the pyridine and in the benzene part of the quinoline ring and we have studied the effect of the nature and position of the substituent on their cytotoxicity (LC 50 ) in two lines of tumor cells (HT-1080 and MG-22A) as well as to normal NIH 3T3 fibroblasts which served as a measure of the toxicity of the compound (alternative method of determining LD 50 see [2]). N S S N R R 1-28 1 R = H, 2 R = 2-Me, 3 R = 3-Me, 4 R = 4-Me, 5 R = 5-Me, 6 R = 6-Me, 7 R = 7-Me, 8 R = 2-Ph, 9 R = 4-Ph, 10 R = 5-Ph, 11 R = 6-Ph, 12 R = 4-Cl, 13 R = 5-Cl, 14 R = 7-Cl, 15 R = 2-MeO, 16 R = 5-MeO, 17 R = 6-MeO, 18 R = 4-PhO, 19 R = 5-PhO, 20 R = 7-PhO, 21 R = 5-PhS, 22 R = 7-PhS, 23 R = 5-SO 3 H, 24 R = 5-NO 2 , 25 R = 5-NH 2 , 26 R = 2,4-Me 2 , 27 R = 2,7-Me 2 , 28 R = 5,7-Cl 2

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

“…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].…”

“…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]. Hence with the aim of decreasing the toxicity and increasing the selectivity of action of cytotoxic 8-quinolinethiolate complexes we have prepared a series of 3-methyl-(1), 5-methyl-(2), 2-methoxy-(3), and 6-methoxy-8-quinolinethiolates (4) of rhodium (a), osmium (b), and iridium (c) and also the 6-methoxy-8-quinolinethiolates (4) of copper (d), cadmium (e), indium (f), antimony (g), bismuth (h), ruthenium (i), and Table 2 show the introduction of a methyl group into the quinoline ring of the rhodium, osmium, and iridium complexes decrease their toxicity when compared to their unsubstituted quinoline ligands [22].…”

“…Considering that in the series the derivatives of di(8-quinolyl) disulfides, having a substituent at position 2 of the quinoline ring are assigned as a group of low toxicity compounds and the 2-methoxy derivative shows quite good selectivity [26] we have examined a series of 2-methoxy-8-quinolinethiolate derivatives of rhodium (3a), osmium (3b), and iridium (3c). All of the complexes proved low toxicity (LD 50 ~ 3300 mg/kg) but at the same time were also inactive or showed little cytotoxicity towards HT-1080 tumor cells (LC 50 of the osmium complex 3b 30 µg/ml).…”

“…Amongst the methoxy derivatives of the di(8-quinolyl) disulfide the 6-isomer also showed good antitumor activity and selectivity [26]. The rhodium (4a), osmium (4b), iridium (4c), and ruthenium (4i) complexes with 6-methoxy-8-quinolinethiol also revealed high cytotoxicity towards the HT-1080 (LC 50 > 1 µg/ml) and MG-22A (LC 50 1-2 µg/ml) tumor cells but they were all highly toxic to normal cells.…”

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

“…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]).…”