A WEE1 Inhibitor Analog of AZD1775 Maintains Synergy with Cisplatin and Demonstrates Reduced Single-Agent Cytotoxicity in Medulloblastoma Cells was written by Matheson, Christopher J.;Venkataraman, Sujatha;Amani, Vladimir;Harris, Peter S.;Backos, Donald S.;Donson, Andrew M.;Wempe, Michael F.;Foreman, Nicholas K.;Vibhakar, Rajeev;Reigan, Philip. And the article was included in ACS Chemical Biology in 2016.Safety of N-(tert-Butoxycarbonylamino)phthalimide This article mentions the following:
The current treatment for medulloblastoma includes surgical resection, radiation, and cytotoxic chemotherapy. Although this approach has improved survival rates, the high doses of chemotherapy required for clin. efficacy often result in lasting neurocognitive defects and other adverse events. Therefore, the development of chemosensitizing agents that allow dose reductions of cytotoxic agents, limiting their adverse effects but maintaining their clin. efficacy, would be an attractive approach to treat medulloblastoma. We previously identified WEE1 kinase as a new mol. target for medulloblastoma from an integrated genomic anal. of gene expression and a kinome-wide siRNA screen of medulloblastoma cells and tissue. In addition, we demonstrated that WEE1 prevents DNA damage-induced cell death by cisplatin and that the WEE1 inhibitor AZD1775 displays synergistic activity with cisplatin. AZD1775 was developed as a WEE1 inhibitor from an initial hit from a high-throughput screen. However, given the lack of structure-activity data for AZD1775, we developed a small series of analogs to determine the requirements for WEE1 inhibition and further examine the effects of WEE1 inhibition in medulloblastoma. Interestingly, the compounds that inhibited WEE1 in the same nanomolar range as AZD1775 had significantly reduced single-agent cytotoxicity compared with AZD1775 and displayed synergistic activity with cisplatin in medulloblastoma cells. The potent cytotoxicity of AZD1775, unrelated to WEE1 inhibition, may result in dose-limiting toxicities and exacerbate adverse effects; therefore, WEE1 inhibitors that demonstrate low cytotoxicity could be dosed at higher concentrations to chemosensitize the tumor and potentiate the effect of DNA-damaging agents such as cisplatin. In the experiment, the researchers used many compounds, for example, N-(tert-Butoxycarbonylamino)phthalimide (cas: 34387-89-8Safety of N-(tert-Butoxycarbonylamino)phthalimide).
N-(tert-Butoxycarbonylamino)phthalimide (cas: 34387-89-8) belongs to indole derivatives. The indole subunit is an almost ubiquitous component of biologically active natural products, and its study has been the focus of research for decades. More than 200 indole derivatives have already been marketed as drugs or are under advanced stages of clinical trials.Safety of N-(tert-Butoxycarbonylamino)phthalimide
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Indole alkaloid derivatives as building blocks of natural products from Bacillus thuringiensis and Bacillus velezensis and their antibacterial and antifungal activity study,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles