Synthesis of novel sulfonamide derivatives containing pyridin-3-ylmethyl 4-(benzoyl)piperazine-1-carbodithioate moiety as potent PKM2 activators

Pyruvate kinase M2 isoform (PKM2) plays a key role in cancer progression through both metabolic and non-metabolic functions, thus it is recognized as a potential target for cancer diagnosis and treatment. In this study, we discovered a sulfonamide-dithiocarbamate compound 8a as a novel PKM2 activator from a random screening of an in-house compound library. Then, a series of lead compound 8a analogs were designed and synthesized for screening as potent PKM2 activators. Among them, compound 8b (AC(50) = 0.136 mu M) and 8k (AC(50) = 0.056 mu M) showed higher PKM2 activation activities than positive control NZT (AC(50) = 0.228 mu M), and they (IC50 1 mu M) exhibited more significant anti-proliferative activities against human tumor cell lines than NZT (IC50 10 mu M). Especially, compound 8k inhibited the proliferation of multiple cancer cells, but showed little toxicity on normal cells. In addition, we found that compound 8k inhibit the colony formation of MCF7 cells. Western blot analysis demonstrated that 8k could reduce PKM2 nuclear localization and block the downstream signaling pathway of PKM2, resulting in suppression of tumor cell proliferation. Overall, compound 8k may be a promising candidate for further mechanistic investigation of PKM2 and cancer therapy.

Automated summary

In this study, a novel PKM2 activator, compound 8a, was discovered from a compound library screening, leading to the synthesis of analogs such as compound 8b and 8k which showed higher PKM2 activation and anti-proliferative activities. Compound 8k demonstrated potent inhibition of cancer cell proliferation with low toxicity to normal cells, and also inhibited colony formation of MCF7 cells by blocking PKM2 signaling pathway. These findings suggest that compound 8k could be a promising candidate for further exploration in PKM2-related mechanisms and cancer therapy.