Design, Synthesis and Antiproliferative Evaluation of Novel Disulfides Containing 1,3,4-Thiadiazole Moiety

Shuai Zhang, Xiao-jia Liu, Rui Tang, Hai-xin Wang, Hai-ying Liu, Yu-ming Liu, Bao-quan Chen
2017 Chemical and pharmaceutical bulletin  
A series of novel disulfides containing 1,3,4-thiadiazole moiety were designed, synthesized, and the structures of all products were identified by spectral data (IR, NMR, and high resolution (HR)-MS). Their in vitro antiproliferative activities were evaluated using 2-(2-methoxy-4-nitro-phenyl)-3-(4-nitro-phenyl)-5-(2,4-disulfopheyl)-2H-tetrazolium monosodium salt (CCK-8) assay against human cancer cell lines, A549 (human lung cancer cell), HeLa (human cervical cancer cell), SMMC-7721 (human
more » ... r cancer cell) and normal cell lines L929. The bioassay results indicated that most of the tested compounds 6a-k, 7a-k and 8a-k exhibited antiproliferation with different degrees, and some compounds showed better effects than positive control 5-fluorouracil (5-FU) against various cancer cell lines. Among these compounds, compound 6e exhibited the most potent inhibitory activity against A549 cells with IC 50 value of 3.62 µM. Compounds 6i, 7a, 7g, 8a and 8b showed significantly antiproliferative activities against HeLa cells with IC 50 values of 3.88, 3.76, 3.59, 3.38 and 3.12 µM, respectively. Compounds 6a, 7a and 8a owned high antiproliferative activities against SMMC-7721 cells with IC 50 values of 2.54, 2.69 and 2.31 µM, respectively. Furthermore, all of the tested compounds showed weak cytotoxic effect against the normal cell lines L929. Based on the preliminary results, the substituent groups are vital for improving the potency and selectivity of this class of compounds. Results and Discussion Chemistry As depicted in Chart 1, thirty three disulfides containing 1,3,4-thiadiazole moiety were synthesized and reported for the first time. The preparation of S-alkyl-thioisothiourea hydrochloride 2 was carried out by reported literature method. 38) The preparation of 2-chloro-N-(substituted-phenyl)acetamide 4 was carried out by reported literature method. 39) The reaction of commercially available 2,5-dimercapto-1,3,4thiadiazole with compound 4 in the presence of NaOH in water and ethanol at room temperature yielded the desired intermediates 5a-k in 70-81% yields. Finally, the target compounds 6a-k, 7a-k and 8a-k were successfully obtained by the reaction of intermediates 5a-k and compound 2 in the presence of NaHCO 3 in methanol and water at room temperature. All of the novel synthesized compounds 6a-k, 7a-k and 8a-k were purified by silica gel column chromatography and their structures were characterized by IR, 1 H-NMR, 13 C-NMR and high resolution-electrospray ionization (HR-ESI)-MS.
doi:10.1248/cpb.c17-00485 pmid:28966280 fatcat:g6nsf7efxrebdn7bx33mel34da