The idea of boron based pro estrogens
The idea of boron-based pro-estrogens has been utilized before; in previous studies, the selective estrogen receptor modulators (SERMs) tamoxifen and endoxifen have been masked as boronate esters.13, 14, 15 Tamoxifen and endoxifen both target ERα as therapies for breast cancer. The previous work focused mostly on the cellular consequences of these boronate ester SERMs observing similar or enhanced effects to the unmodified anti-estrogens in breast cancer cells. They were able to observe the presence of the SERMs after incubation of the boronate esters with MCF7 or T47D cells, presumably due to increased levels of ROS.13, 15 In addition, they showed increased bioavailability and drug accumulation at tumor sites within mouse xenograft models.
Due to the successes of tamoxifen and endoxifen boronate esters, we set out to mask alternative estrogens. In particular, we focused on the potent and selective ERβ agonist diarylpropionitrile (DPN, Fig. 1a).16, 17 ERβ selective ligands, such as DPN, have shown significant promise in exhibiting neuroprotective effects in a number of neurological diseases.18, 19, 20, 21, 22, 23, 24 In addition, molecules that activate ERβ repress transcription of proinflammatory genes; specifically, DPN has been shown to be effective in a model of inflammation following lung injury. Due to the increased levels of ROS and pathological oxidative stress within neurodegenerative disorders and inflammatory diseases, we hypothesize that appending a boronate ester to the ERβ ligand will allow for consumption H2O2 and simultaneous release of the active ligand achieving dual results. In addition, the masking of the active phenol would allow for selective release of the estrogen in the presence of H2O2, providing site-selective modulation of ER. Herein, we report the synthesis of boronic GSK2606414 pinacol ester pro-estrogens of endogenous estrogens and the ERβ-selective agonist DPN. The boronate esters have decreased affinity for both ERα and ERβ and are converted into the active phenol in the presence of H2O2 in vitro and in cells.
Results and discussion
Conclusions In summary, we have prepared several steroidal and non-steroidal boronate esters as pro-estrogens for the estrogen receptors. They are converted rapidly and completely to the phenolic estrogens when reacted with H2O2. In addition, the presence of the boronic acid pinacol ester decreases the binding affinity for both ERα and ERβ by 3–20 fold depending on the ligand. The ERβ-selective ligand DPN was masked as three different boronate esters 6a-6c, which have similar functionality and reactivity in vitro. The integration of a ROS reactive group into a functional estrogen has implications in a variety of neurodegenerative and inflammatory diseases. The pro-estrogens 6a-6c could have dual effects in absorbing H2O2 and releasing an ERβ-selective ligand with therapeutic potential. In particular, pro-estrogen 6c, that masks both phenolic rings, exhibits increased selectivity for H2O2, and diminishes the binding affinity for the receptors most significantly. In addition, the ERβ agonist activity is masked by the boronate esters of 6c in a cellular environment; however, when H2O2 is at a pathological level, the agonist activity is restored. This work expands upon previous studies with boronate ester linked SERMs in breast cancer contexts illustrating together that the installation of a boronate ester is a promising pro-drug strategy for ER modulation. Due to the complexity of ER signaling, context specific estrogens (e.g. SERMs and subtype-selective ligands) are constantly being developed. The release of an active ER ligand in the presence of H2O2 provides an alternative approach to developing context specific estrogens or anti-estrogens.
Introduction Rupture of an intracranial aneurysm remains one of the most devastating neurosurgical vascular diseases. Although many epidemiologic factors and modifiable risk factors have been implicated in the progression of disease,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 the development of aneurysms has largely been associated with genetic predisposition.13, 14 There has been significant effort toward the investigation of genetic loci for the formation of intracranial aneurysms, and prior studies have identified a number of differentially expressed genes in aneurysm tissue.15, 16, 17