Preclinical data highlight AZD1390 as a potentially powerful new therapy to enhance brain tumor patient responses to radiotherapy.

Simple nucleophiles with structural similarities to known hydroboration catalysts can readily mediate the formation of BH 3 and borohydride species from pinacolborane (HBpin). Alkyne and alkene hydroboration reactions were successfully mediated by nucleophiles through BH 3 generation, with BH 3 -catalyzed hydroboration found to dominate catalysis. NMR spectroscopy and kinetic analyses showed that the nucleophiles NaO t Bu, Na[N(SiMe 3 ) 2 ], n Bu 2 Mg, and n BuLi only promoted the formation of BH 3 and were not "true" hydroboration catalysts.

The continued development of hydroboration catalysts typifies the importance of this transformation as a testbed for catalytic activity and as a fundamental reaction for organic synthesis. Catalytic hydroboration studies routinely investigated the decomposition of HBcat but in the case of HBpin, decomposition is not commonly investigated due to its perceived stability.Organoboranes catalyze the hydroboration of alkenes and alkynes; these species can be formed

Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER + breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of N-[1-(3fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f ]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.

The mechanism of R2BH-catalyzed hydroboration of alkynes by 1,3,2-dioxaborolanes has been investigated by in situ 19 F NMR spectroscopy, kinetic simulation, isotope entrainment, single-turnover labelling ( 10 B/ 2 H), and density functional theory (DFT) calculations. For the Cy2BH catalyzed hydroboration 4-fluorophenylacetylene by pinacolborane, the resting state is the anti-Markovnikov addition product ArCH=CHBCy2. Irreversible and turnover-rate limiting reaction with pinacolborane (k ~7´10 -3 M -1 s -1 ) regenerates Cy2BH and releases E-Ar-CH=CHBpin. Two irreversible events proceed in concert with turnover. The first is a Markovnikov hydroboration leading to regioisomeric E-Ar-CH(Bpin)=CH2. This is unreactive to pinacolborane at ambient temperature, resulting in catalyst inhibition every ~10 2 turnovers. The second is hydroboration of the alkenylboronate to give ArCH2CH(BCy2)Bpin, again leading to catalyst inhibition. 9-BBN behaves analogously to Cy2BH, but with higher anti-Markovnikov selectivity, a lower barrier to secondary hydroboration, and overall lower efficiency. The key process for turnover is B-H/C-B metathesis, proceeding by stereospecific transfer of the E-alkenyl group within a transient, µ-B-H-B bridged, 2-electron-3-centre bonded B-C-B intermediate.