Synthesis and Cytotoxicity of Silicon Containing Pyridine and Quinoline Sulfides

Silicon containing pyridine and quinoline sulfides have been prepared using phase transfer catalytic system thiol/alkyl halide / solid KOH/18-crown-6 / toluene. The target S-ethers were isolated in yields up to 81%. The cytotoxicity of the synthesized compounds was studied. Among pyridine sulfides S-[3-(1-methyl- 1-silacyclohexyl)propyl] derivatives 5e and 6e exhibit the highest cytotoxicity. Aliphatic silicon derivatives were considerably less active. 8-[(Trimethylsilylmethyl)thio]quinoline (8a) exhibits the highest activity among quinoline sulfides.


INTRODUCTION
Pyridine and quinoline sulfides and related compounds exhibit a wide range of biological activity/1/o Among these activities antitumor and cytotoxic activities of pyridine /2-8/ and quinoline /9-12/ sulfides were described.
The known methods for the preparation of sulfides are based on reaction of hetaryl thiols with alkyl or aryl halides in the presence of K2CO3 Me2Co/13/, NaOMe DMF/14/or Nail MezSO4 /15/ systems.
We have found that 3-(hataryltio)-l-propynyl(trimethyl)silanes exhibit high cytotoxicity /17/. In the present work the novel N-beterocyclic sulfides with trialkylsily and silacyclic substituents have been synthesized as potential antitumor agents.
Vol. 9, Nos. /-2, 2002 Synthesis and Ctotoxicity of Silicon Containing Pyridine and Quinoline Sulfides MATERIALS AND METHODS Chemistry H NMR spectra were recorded on a Varian 200 Mercury instrument using CDCIa as a solvent and hexamethyldisiloxane (HMDSO) as an internal standard (0.055 ppm). Mass spectra were registered on a GC-MS HP 6890 (70 eV). GC analysis was performed on a Chrom-5 instrument equipped with flame-ionization detector using glass column packed with 5% OV-101 / Chromosorb W-HP (80-100 mesh) (1.2 rn x 3 mm).
The mixture was refluxed with stirring to achieve the disappearance of the substrates, filtered over the thin silica gel layer and concentrated under reduced pressure. The residue was purified by column chromatography on silicagel (eluent benzene ethyl acetate in different mixtures) to give products [5][6][7][8]. The results are shown in Tables 3. In vitro cycotoxicity assay Monolayer cell lines were cultivated for 72 h in DMEM standard medium without an indicator and antibiotics. After the ampoule was defrozen not more than four passages were performed. The control cells and cells with tested substances in the range of 2-5 104 cell/mL concentration (depending on line nature) were placed on separate 96 wells plates. Solutions containing test compounds were diluted and added in wells to give the final concentrations of 50, 25, 12.5, and 6.25 tg/mL. Control cells were treated in the same manner only in the absence of test compounds. Plates were cultivated for 72 h. The quantity of survived cells was determined using crystal violet (CV) or 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolinium bromide (MTT) coloration that was assayed by multiscan spectrophotometer. The quantity of alive cells on the control plate was taken in calculations as 100%/20,21/. The concentration ofNO was determined according to/20/.

Thiol
The experimental evaluations of cytotoxic properties are presented in Table 4. A preliminary analysis of the structure-activity relationship for the cytotoxic action clearly indicates the strong influence of the silylalkyl substituent structure. tzd/nttnds Lttke,ics el al. Pyridine and quinoline sulfides bearing dimethylheptylsilyl group at the sulfur atom (5c, 6c, and 7c) have a slight eytotoxic effect (> 15.5 g/mL). The substitution of dimethylheptylsilyl group by trimethylsilyl (Sb, 6b, and 7b) or silahexyl group (Se, 6e, and 7e) results in considerable increase of the eytotoxic activity. It must be noted that the activity of studied compounds depends on the tumor type. In general, all silicon containing sulfides (5)(6)(7)(8) show the expressed selectivity on mouse hepatoma MG 22A cell line. However, 8-trimethylsilylmethylmereaptoquinoline 8a exhibits a greater toxicity on HT 1080 cells (2.5 tg/mL) contrary to MG 22A (3.5 tg/mL). Comparison of the tumor growth inhibition for derivatives 5-7b and 5 7 c shows a higher eytotoxie activity of the trimethylsilylpropyl group containing sulfides with respect to dimethylheptylsilylpropyl substituted sulfides. Among pyridine derivatives 4-[3-(l-methyl-1silacyclohexyl)propyl]pyridine sulfide 6e exhibits the highest eytotoxicity on MG 22A (<1 g/mL). The most active in the series of quinoline sulfides is 8-[(trimethylsilylmethyl)thio]quinoline 8a (2.5 tg/mL on human fibrosarcoma HT-1080 cell line). Studied pyridine and quinoline derivatives have a medium NOinduction ability, 2-(3'-dimethylheptylsilylpropyl)pyridine sulfide 5c being the most active (650% on MG-22A test).