The DNA damage response (DDR) secures the integrity of the genome of eukaryotic cells. DDR deficiencies can promote tumorigenesis but concurrently may increase dependence on alternative repair pathways. The ataxia telangiectasia and Rad3-related (ATR) kinase plays a central role in the DDR by activating essential signaling pathways of DNA damage repair. Here, we studied the effect of the novel selective ATR kinase inhibitor BAY 1895344 on tumor cell growth and viability. Potent antiproliferative activity was demonstrated in a broad spectrum of human tumor cell lines. BAY 1895344 exhibited strong monotherapy efficacy in cancer xenograft models that carry DNA damage repair deficiencies. The combination of BAY 1895344 with DNA damage-inducing chemotherapy or external beam radiotherapy (EBRT) showed synergistic antitumor activity. Combination treatment with BAY 1895344 and DDR inhibitors achieved strong synergistic antiproliferative activity in vitro, and combined inhibition of ATR and PARP signaling using olaparib demonstrated synergistic antitumor activity in vivo. Furthermore, the combination of BAY 1895344 with the novel, nonsteroidal androgen receptor antagonist darolutamide resulted in significantly improved antitumor efficacy compared with respective singleagent treatments in hormone-dependent prostate cancer, and addition of EBRT resulted in even further enhanced antitumor efficacy. Thus, the ATR inhibitor BAY 1895344 may provide new therapeutic options for the treatment of cancers with certain DDR deficiencies in monotherapy and in combination with DNA damage-inducing or DNA repair-compromising cancer therapies by improving their efficacy.
Alkaloids account for some of the most beautiful and biologically active natural products. Although they are usually classified along biosynthetic criteria, they can also be categorized according to certain structural motifs. Amongst these, the α-tertiary amine (ATA), i.e. a tetrasubstituted carbon atom surrounded by three carbons and one nitrogen, is particularly interesting. A limited number of methods have been described to access this functional group and fewer still are commonly used in synthesis. Herein, we review some approaches to asymmetrically access ATAs and provide an overview of alkaloid total syntheses where those have been employed.
Quaternary centres bearing a nitrogen substituent (α-tertiary amines and their derivatives) are found in a variety of bioactive molecules but pose a major challenge in synthesis, particularly when enantiomeric purity is required. Approaches comparable to those used for tertiary alcohols are typically hampered by the poor electrophilicity of imines, requiring powerful nucleophiles that may also act as bases. A set of powerful alternative approaches make use of the rearrangement of readily available precursors, often (but not always) with formation of a new tertiary carbon to nitrogen bond. In this Feature Article we review the scope, limitations and specificities of some of these rearrangements in order to illuminate their synthetic potential.
Organolithiums add in an umpolung fashion to the beta-carbon of N-carbamoyl enamines (N-vinyl ureas). The reaction proceeds with syn diastereospecificity and provides urea-stabilized, configurationally defined organolithiums. Facilitated by coordinating solvents (THF or DMPU), these undergo intramolecular attack on an N'-aryl group, resulting in retentive arylation of the organolithium and hence overall addition of an alkyl or aryl group to both carbon atoms of the urea-substituted alkene. Facile deprotection in hot butanol permits the rapid, multicomponent construction of heavily substituted amines.
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