Design, Synthesis, and Process Chemistry Studies of Agents Having Anti-Cancer Properties

Breast cancer is the second leading cause of cancer deaths in American women. The use of estrogen receptor modulators is the most common treatment for early stage breast cancer and for prevention of its recurrence after surgery. However, among the available agents in this class, none display an ideal therapeutic profile. Therefore, it was aimed to design and synthesize selective estrogen receptor modulators (SERMs) which can overcome problems associated with the currently available agents. Toward that end, process chemistry studies were undertaken to enhance a synthetic route to natural glyecollin I (GLY I) which is a novel SERM that has promising anti-estrogenic and anti-cancerproperties. Reaction yields across several steps were improved by optimizing reaction conditions and a few steps were improved by adopting alternative synthetic protocols. In doing so, not only were the total number of steps reduced from 15 to 13, but the overall yield was also tripled, i.e. from 3 percent to 9 percent. Molecular modeling and receptor docking studies were carried out during the design of GLY I related analogs obtained from intermediates produced during the scale-up syntheses. While performing such studies it was deduced that the active sites of the two subtypes of estrogen receptors(ERs), namely ERα and ERβ, are very similar except for two key aspects. First, the active site His residue in ERα lays slightly closer to the active site Arg and Glu as compared to the one found in ERβ. Second, the imidazole ring of the active site His residue in the two ERs is oriented quite differently in three-dimensional space. The new designed and synthesized GLY I related analogs possess pharmacophores that may be able to exploit these differences in the active sites. This, in turn, could lead to more selective estrogen receptor modulation. These analogs also possess varying degrees of flexibility while displaying their key pharmacophores important for receptor binding and selectivity.