In vivo Structure‐Activity Relationship of Dihydromethysticin in Reducing Nicotine‐Derived Nitrosamine Ketone (NNK)‐Induced Lung DNA Damage against Lung Carcinogenesis in A/J Mice. (4th March 2022) - Hati, Santanu
Abstract: Lung cancer is the leading cause of cancer‐related deaths and chemoprevention should be developed. We recently identified dihydromethysticin (DHM) as a promising candidate to prevent NNK‐induced lung tumorigenesis. To probe its mechanisms and facilitate its future translation, we investigated the structure‐activity relationship of DHM on NNK‐induced DNA damage in A/J mice. Twenty DHM analogs were designed and synthesized. Their activity in reducing NNK‐induced DNA damage in the target lung tissues was evaluated. The unnatural enantiomer of DHM was identified to be more potent than the natural enantiomer. The methylenedioxy functional moiety did not tolerate modifications while the other functional groups (the lactone ring and the ethyl linker) accommodated various modifications. Importantly, analogs of high structural similarity to DHM with distinct efficacy in reducing NNK‐induced DNA damage have been identified. They will serve as chemical probes to elucidate the mechanisms of DHM in blocking NNK‐induced lung carcinogenesis. Abstract : Where there's smoke … : The structure‐activity relationship of dihydromethysticin (DHM) on nicotine‐derived nitrosamine ketone (NNK)‐induced DNA damage in A/J mice was investigated, which not only identified more potent analogs but also developed in vivo chemical probes for future mechanistic characterization of DHM in preventing lung carcinogenesis.