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

Abstract

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 GI = 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 EC = 21 nM), possess selective affinity to the cdc-2-like kinase CLK4 (K = 350 nM), and be phenotypically related to paclitaxel by an unbiased panel assessment.

From an ent-Estrane, through a nat-Androstane, to the Total Synthesis of the Marine-Derived Δ8,9-Pregnene (+)-03219A

“…While semisynthesis (natural product derivatization) continues to play a significant if not central role in the modern steroid pharmaceutical industry, , interest in realizing efficient, flexible, and wholly synthetic means to such targets has served as continual inspiration for the development of synthetic organic chemistry as a discipline . Unfortunately, de novo approaches to the asymmetric construction of functionalized steroidal systems are often unwieldy and limited with respect to molecular flexibility in terms of skeletal substitution and stereochemistry. , Because of the pharmaceutically privileged nature and rich biological profile of molecules in this broad class, we have become interested in establishing fundamentally unique means to achieve their assembly. , …”