A Synthesis of Novel Sulfur-Linked Fused Thienotriazolopyrimidine Derivatives

Interleukin-6 (IL-6) binds to its receptor (IL-6R, a ligandbinding 80 kDa glycoprotein chain) and induces the homodimerization of a signal transducing glycoprotein 130 (gp130), leading to the activation of the Janus kinase (Jak)/signal transducer and signal activator of transcription-3 (STAT3). STAT3 is also frequently over-expressed or persistently activated in most tumors and cancer, and activated STAT3 was found to suppress tumor-immune surveillance. Therefore, the blockade of STAT3 activation pathway stimulated by IL-6 could be an attractive therapeutic target for discovery of new drugs and is currently under intense investigation. In the other hand, thienotriazolopyrimidines have recently attracted much interest because of their pharmacological and therapeutic properties including anticancer, anti-inflammatory, urea transport protein (UT-B) inhibitor, Shiga toxin trafficking inhibitor 1, and xanthine oxidase inhibitor 2, as shown in Figure 1. Furthermore, sulfur-linked triazoles (3thio-1,2,4-triazoles) have been reported to possess a wide range of biological activities such as antifungal agent, diacylglycerol acyltransferase 1 (DGAT1) inhibitor 3, carbonic anhydrase inhibition, somatostatin sst2/sst5 agonists, and dopamine D3 receptor antagonist 4. 5 We have synthesized over the years thienopyrimidine and thienotriazolopyrimidine derivatives of promising biological activity. From a programme to discover novel inhibitors using thienopyrimidine derivatives, some of sulfur-linked thienotriazolopyrimidine compounds were recently found to possess potent IL-6/STAT3 inhibition. This result encouraged us to prepare new sulfur-linked tetracyclic thienotriazolopyrimidines in attempt to improve the IL-6/STAT3 inhibitory activity.