C-terminal Binding Proteins (CtBP) 1 and 2 are oncogenic transcriptional co-regulators overexpressed in many cancer types, with their expression level correlating to worse prognostic outcomes and aggressive tumor features. CtBP negatively regulates the expression of many tumor suppressor genes, while coactivating genes that promote proliferation, epithelial-mesenchymal transition, and cancer stem cell self-renewal activity. In light of this evidence, the development of novel inhibitors that mitigate CtBP function may provide clinically actionable therapeutic tools. This review article focuses on the progress made in understanding CtBP structure, role in tumor progression, and discovery and development of CtBP inhibitors that target CtBP's dehydrogenase activity and other functions, with a focus on the theory and rationale behind the designs of current inhibitors. We provide insight into the future development and use of rational combination therapy that may further augment the efficacy of CtBP inhibitors, specifically addressing metastasis and cancer stem cell populations within tumors.

Nitrogen-containing compounds are the most common structural architectures in drug candidates, natural and biological products, and small-molecule therapeutics. Within the body of work of transition-metal-catalyzed direct C−H amination reactions, palladium remains in the forefront and has been established as one of the most useful transition metals for C−N bond formation. The fundamental organometallic reactivity of palladium in its 0, I, II, III, and IV oxidation states make it special and useful in challenging carbon−heteroatom bond-formation reactions. Palladium undergoes facile formation of chelation-assisted palladacycle and palladiumnitrenoid intermediates that open an avenue for new bond formation. It has been utilized in various new synthetic approaches toward both intermolecular and intramolecular C−N bond formation reactions that employ nitrogen sources ranging from free, unprotected amines to electrophilic nitrogen sources. Palladium's compatibility with various functional groups and oxidants as well as the mild reaction conditions (temperature and air atmosphere) used with this metal have attracted many scientists to the area and will continue to advance new mechanistic insights and opportunities to explore palladium catalysis for C−N bond synthesis. Here, we summarize the progress of Pd-catalyzed C−N bond advances involving both the reaction development and mechanisms in numerous synthetically useful intra-and intermolecular C−H catalytic aminations.

N-Chelation-directed C-H activation reactions that utilize the Pd(II)/Pd(IV) catalytic cycle have been previously reported. To date, these reactions employ only homogeneous palladium catalysts. The first use of a solid-supported Pd(II) catalyst [Pd(II) nanoparticles on multiwalled carbon nanotubes, Pd(II)/MWCNT] to carry out N-chelation-directed C-H to C-O, C-Cl, and C-Br transformations is reported. The results presented demonstrate that the solid-supported Pd(II)/MWCNT catalyst can effectively catalyze C-H activation reactions using the Pd(II)/Pd(IV) catalytic cycle.

Oncogenic transcriptional coregulators C-terminal Binding Protein (CtBP) 1 and 2 possess regulatory D-isomer specific 2-hydroxyacid dehydrogenase (D2-HDH) domains that provide an attractive target for small molecule intervention. Findings that the CtBP substrate 4-methylthio 2-oxobutyric acid (MTOB) can interfere with CtBP oncogenic activity in cell culture and in mice confirm that such inhibitors could have therapeutic benefit. Recent crystal structures of CtBP 1 and 2 revealed that MTOB binds in an active site containing a dominant tryptophan and a hydrophilic cavity, neither of which are present in other D2-HDH family members. Here we demonstrate the effectiveness of exploiting these active site features for design of high affinity inhibitors. Crystal structures of two such compounds, phenylpyruvate (PPy) and 2-hydroxyimino-3-phenylpropanoic acid (HIPP), show binding with favorable ring stacking against the CtBP active site tryptophan and alternate modes of stabilizing the carboxylic acid moiety. Moreover, ITC experiments show that HIPP binds to CtBP with an affinity greater than 1000-fold over that of MTOB and enzymatic assays confirm that HIPP substantially inhibits CtBP catalysis. These results, thus, provide an important step, and additional insights, for the development of highly selective antineoplastic CtBP inhibitors.

Simocyclinone D8 (SD8) exhibits antibiotic activity against gram-positive bacteria but not against gramnegative bacteria. The molecular basis of the cytotoxicity of SD8 is not fully understood, although SD8 has been shown to inhibit the supercoiling activity of Escherichia coli gyrase. To understand the mechanism of SD8, we have employed biochemical assays to directly measure the sensitivities of E. coli and Staphylococcus aureus type II topoisomerases to SD8 and microarray analysis to monitor the cellular responses to SD8 treatment. SD8 is a potent inhibitor of either E. coli or S. aureus gyrase. In contrast, SD8 exhibits only a moderate inhibitory effect on S. aureus topoisomerase IV, and E. coli topoisomerase IV is virtually insensitive to SD8. The antimicrobial effect of SD8 against E. coli has become evident in the absence of the AcrB multidrug efflux pump. As expected, SD8 treatment exhibits the signature responses to the loss of supercoiling activity in E. coli: upregulation of gyrase genes and downregulation of the topoisomerase I gene. Unlike quinolone treatment, however, SD8 treatment does not induce the SOS response. These results suggest that DNA gyrase is the target of SD8 in both gram-positive and gram-negative bacteria and that the lack of the antibacterial effect against gram-negative bacteria is due, in part, to the activity of the AcrB efflux pump.