Synthesis of Rapamycin Derivatives Containing the Triazole Moiety Used as Potential mTOR‐Targeted Anticancer Agents

Abstract

Rapamycin, a potent antifungal antibiotic, was approved as immunosuppressant, and lately its derivatives have been developed into mTOR targeting anticancer drugs. Structure modification was performed at the C-42 position of rapamycin, and a novel series of rapamycin triazole hybrids (4a-d, 5a-e, 8a-e, and 9a-e) was facilely synthesized via Huisgen's reaction. The anticancer activity of these compounds was evaluated against the Caski, H1299, MGC-803, and H460 human cancer cell lines. Some of the derivatives (8a-e, 9a-e) appeared to have stronger activity than that of rapamycin; however, 4a-d and 5a-e failed to show potential anticancer activity. Compound 9e with a (2,4-dichlorophenylamino)methyl moiety on the triazole ring was the most active anticancer compound, which showed IC50 values of 6.05 (Caski), 7.89 (H1299), 25.88 (MGC-803), and 8.60 μM (H460). In addition, research on the mechanism showed that 9e was able to cause cell morphological changes and to induce apoptosis in the Caski cell line. Most importantly, 9e can decrease the phosphorylation of mTOR and of its downstream key proteins, S6 and P70S6K1, indicating that 9e can effectively inhibit the mTOR signaling pathway. Thus, it may have the potential to become a new mTOR inhibitor against various cancers.

Synthesis and anticancer activity of novel rapamycin C‐28 containing triazole moiety compounds

“…Interestingly, it is worth to mention that the introduction of aryl‐amino‐methyl group on triazole ring, such as 7a , 7c , and 7d , also led to an obvious raise in anticancer activity while hydroxyl‐alkyl ( 7e and 7f ) caused anticancer potency to be lowered significantly. More interestingly, we had reported the synthesis and antitumor activities of C‐43 triazole‐based rapamycin derivatives, in which the side chain of compound 4a , 4b , 5e were almost the same with 6c , 6f , 7a , respectively, but the anticancer activities of 4a , 4b , 5e were much weaker, indicating that the anticancer activities of the rapalogs modified on C‐28 position were stronger than that of the rapalogs modified on C‐43 position.…”

“…The anticancer activities of the compounds were evaluated against A549, PC‐3, CASKI, 769‐P, ECA‐109 cancer cell lines by sulforhodamine B (SRB, Sigma) assay in vitro , as described previously …”

“…In our previous work, rapamycin was chemically modified in the position C‐43 and a number of new rapalogs with antitumor activities were obtained. Among these new rapalogs, rapamycin triazole derivative 9e and thiazole derivative 9b etc. exhibited stronger antitumor activities compared with rapamycin .…”

“…exhibited stronger antitumor activities compared with rapamycin . To obtain more potent rapalogs and further explore their structure–activity relationship, we tried to modify the structure of rapalogs we had reported before by migrating side chain moiety from the C‐43 position to C‐28 position as showed in Figure . It may open a new structural space if we can develop more potent rapalogs modified at C‐28 position.…”

Click Chemistry in Natural Product Modification

“…Due to the complex structure of rapamycin, CuAAC appears to be the best strategy for the generation of novel rapamycin derivatives. For example, C42 rapamycin-triazole N4 (IC 50 = 6.05–25.88 μ M) could exert more potent inhibitory against H1299, MGC-803, H460, and Caski cancer cells than that of rapamycin (IC 50 = 18.74–35.13 μ M) ( Xie et al, 2016 ). Mechanism studies indicated that N4 could cause the change of cell morphological, and induce apoptosis of the tested Caski cells.…”