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Synthesis and Discovery of Estra-1,3,5(10),6,8-pentaene-2,16α-diol

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journal contribution
posted on 14.09.2018 by HtooTint Wai, Kang Du, Jason Anesini, Wan Shin Kim, Alan Eastman, Glenn C. Micalizio
A metallacycle-centered approach to the assembly of partially aromatic synthetic steroids was investigated as a means to prepare a boutique collection of unique steroidal agents. The synthesis and discovery of estra-1,3,5(10),6,8-pentaene-2,16α-diol (VII) is described, along with structure–activity relationships related to its cytotoxic properties. Overall, VII was found to have a GI50 = 0.2 μg/mL (∼800 nM) in MDA-MB-231 human breast cancer cells, be an efficacious estrogen receptor agonist with potency for ERβ > ERα (ERβ EC50 = 21 nM), possess selective affinity to the cdc-2-like kinase CLK4 (Kd = 350 nM), and be phenotypically related to paclitaxel by an unbiased panel assessment.