UBC Theses and Dissertations

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UBC Theses and Dissertations

Synthesis of autophagy inhibiting virantmycin analogs Zhang, Lingzhi


(–)-Virantmycin (1.12), first isolated from Streptomyces nitrosporeus in 1981, was found to be a potent inhibitor of autophagy with an IC₅₀ of 0.5 μM against rapamycin-induced autophagy in MCF-7 cells. Recent studies showed that autophagy inhibition considerably reduced the growth of pancreatic ductal adenocarcinoma (PDAC) in mouse models. Therefore, virantmycin’s sub- μM potency as an early stage autophagy inhibitor makes it an interesting “lead compound” for the development of a treatment for PDAC. Previous attempts failed to make the benzoic acid from aryl iodide, using Kogen’s method. The current method for synthetic access to virantmycin analogs employs microwave irradiation to generate aryl nitriles, such as 2.144, for further installation of the carboxyl group at the aryl ring. Analogs 2.108 and 2.152 show the most potent autophagy inhibiting activity among the synthetic analogues prepared to date. The construction of simplified pharmacophore analogs 2.108 and 2.152 allows for scalable synthesis to provide quantities for animal testing.

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