Mutations in estrogen receptor alpha (ER) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Since a significant proportion of therapy-resistant breast cancer metastases continue to be dependent on ER signaling, there remains a critical need to develop the next generation of ER antagonists that can overcome aberrant ER activity. Through our drug discovery efforts, we identified H3B-5942 which covalently inactivates both wild-type and mutant ER by targeting Cys530 and enforcing a unique antagonist conformation. H3B-5942 belongs to a class of ER antagonist referred to as Selective Estrogen Receptor Covalent Antagonists (SERCAs).In vitro comparisons of H3B-5942 with standard of care (SoC) 10, 2018; DOI: 10.1158/2159-8290.CD-17-1229 3Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on July SignificanceNearly 30% of endocrine-therapy resistant breast cancer metastases harbor constitutively activating mutations in ER. Selective Estrogen Receptor Covalent Antagonist (SERCA) H3B-5942 engages C530 of both ER WT and ER MUT, promotes a unique antagonist conformation, and demonstrates improved in vitro and in vivo activity over standard of care (SoC) agents.Importantly, single agent efficacy can be further enhanced by combining with CDK4/6 or mTOR inhibitors.

The synthesis and investigation of the catalytic properties of Au nanoparticles (AuNPs) is an area of intense research. Despite much effort being made to this field, attaining both high catalytic activity and selectivity at the same time remains elusive. Herein a new mild reductive thiolate‐deprotection strategy is reported to prepare nanoporous silica‐supported ultrasmall AuNP catalysts that show very efficient catalytic activity and high selectivity for oxidation reactions.

A mesoporous silica-supported iron(III) catalyst was successfully synthesized by tethering ethylenediamine ligands onto the mesopore channel walls of mesoporous silica and then using the diamine groups to support Fe(III) ions. The resulting material is shown to be an efficient catalyst for the ring-opening of various epoxides by a series of alcohols as well as water under mild reaction conditions giving good-to-high yields of the corresponding ring-opened products. Among the alcohols tested with styrene oxide substrate giving 2-alkoxy-2-phenylethanol products, MeOH was the most reactive. It gave the highest percent conversion and yield (∼100%) within a relatively short reaction time of 6 h, whereas the longer alkyl alcohols gave a relatively lower yield of 93 to ∼100% with longer reaction times of 9−56 h. When the alkyl groups of the linear alkyl alcohols were longer, the rates of the catalytic reaction were slower. For instance, EtOH gave ∼100% yield in 9 h, but n-PrOH produced 93% product in 45 h. Substituted alkyl alcohols produced only 9−62% product in even longer reaction times of 72−144 h, with the more substituted alcohols giving the slower reaction rates. The catalyst was also shown to ring-open other epoxides, such as chloropropylene oxide and 2-methyl-1,2-epoxypropane. The chloropropylene oxide was found to react much more slowly than the 2-methyl-1,2-epoxypropane, whereas the 2-methyl-1,2-epoxypropane underwent catalytic reaction slightly more slowly than styrene oxide in the presence of the catalyst under the same reaction conditions. The catalyst was shown to be reusable multiple times without leaching of the Fe(III) ions.

Advancement in cancer therapy requires a better understanding of the detailed mechanisms that induce death in cancer cells. Besides apoptosis, themode of other types of cell death has been increasingly recognized in response to therapy. Paraptosis is a non-apoptotic alternative form of programmed cell death, morphologically) distinct from apoptosis and autophagy. In the present study, Withaferin-A (WA) induced hyperpolarization of mitochondrial membrane potential and formation of many cytoplasmic vesicles. This was due to progressive swelling and fusion of mitochondria and dilation of endoplasmic reticulum (ER), forming large vacuolar structures that eventually filled the cytoplasm in human breast cancer cell-lines MCF-7 and MDA-MB-231. The level of indigenous paraptosis inhibitor, Alix/AIP-1 (Actin Interacting Protein-1) was down-regulated by WA treatment. Additionally, prevention of WA-induced cell death and vacuolation on co-treatment with protein-synthesis inhibitor indicated requirement of de-novo protein synthesis. Co-treatment with apoptosis inhibitor resulted in significant augmentation of WA-induced death in MCF-7 cells, while partial inhibition in MDA-MB-231 cells; implyingthat apoptosis was not solely responsible for the process.WA-mediated cytoplasmic vacuolationcould not be prevented by autophagy inhibitor wortmanninas well, claiming this process to be a non-autophagic one. Early induction of ROS (Reactive Oxygen Species)by WA in both the cell-lines was observed. ROS inhibitorabrogated the effect of WA on: cell-death, expression of proliferation-associated factor andER-stress related proteins,splicing of XBP-1 (X Box Binding Protein-1) mRNA and formation of paraptotic vacuoles.All these results conclusively indicate thatWA induces deathin bothMCF-7 and MDA-MB-231 cell lines byROS-mediated paraptosis.

The development of a highly enantioselective catalytic oxa-Pictet-Spengler reaction has proven a great challenge for chemical synthesis. We now report the first example of such a process, which was realized by utilizing a nitrated confined imidodiphosphoric acid catalyst. Our approach provides substituted isochroman derivatives from both aliphatic and aromatic aldehydes with high yields and excellent enantioselectivities. DFT calculations provide insight into the reaction mechanism.

Photoredox catalysis enables unique and broadly applicable chemical reactions but controlling their selectivity has proven to be difficult. The pursuit of enantioselectivity is a particularly daunting challenge, arguably due to the high energy of the activated radical (ion) intermediates, and previous approaches have invariably required pairing of the photoredox catalytic cycle with an additional activation mode for asymmetric induction. A potential solution for photoredox reactions proceeding via radical ions would be catalytic pairing with enantiopure counterions. However, while attempts toward this approach have been described, high selectivity has not yet been accomplished. Here we report a potentially general solution to radical cation-based asymmetric photoredox catalysis. We describe organic salts, featuring confined IDPi counteranions that catalyze highly enantioselective [2+2]-cross cycloadditions of styrenes.

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We report on the synthesis and catalytic properties of a class of hybrid organic-inorganic mesoporous bifunctional heterogeneous catalysts for efficient catalysis of two-step tandem reactions in one pot. With a solvent-assisted grafting method, two different catalytic groups, that is, an organoamine and a palladium-organodiamine complex, were immobilized onto high-surface-area mesoporous silica sequentially, by using their corresponding organosilanes in 2-propanol or toluene as the solvent in the first step and toluene as the solvent in the second step. Both MCM-41 and SBA-15 mesoporous silicas were used as support materials for the two catalytic groups, and the effect of different sequential grafting of the two organosilanes in 2-propanol or toluene on the structures and the catalytic properties of the resulting bifunctional catalysts were investigated. By using the resulting amine/Pd IIdiamine bifunctional mesoporous material as catalyst, the occurrence of two very important C-C bond forming reactions,