Pd-catalyzed cross-coupling reactions that form C–N bonds have become useful methods to synthesize anilines and aniline derivatives, an important class of compounds throughout chemical research. A key factor in the widespread adoption of these methods has been the continued development of reliable and versatile catalysts that function under operationally simple, user-friendly conditions. This review provides an overview of Pd-catalyzed N-arylation reactions found in both basic and applied chemical research from 2008 to the present. Selected examples of C–N cross-coupling reactions between nine classes of nitrogen-based coupling partners and (pseudo)aryl halides are described for the synthesis of heterocycles, medicinally relevant compounds, natural products, organic materials, and catalysts.

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

The use of drug-like macrocycles is emerging as an exciting area of medicinal chemistry, with several recent examples highlighting the favorable changes in biological and physicochemical properties that macrocyclization can afford. Natural product macrocycles and their synthetic derivatives have long been clinically useful and attention is now being focused on the wider use of macrocyclic scaffolds in medicinal chemistry in the search for new drugs for increasingly challenging targets. With the increasing awareness of concepts of drug-likeness and the dangers of 'molecular obesity', functionalized macrocyclic scaffolds could provide a way to generate ligand-efficient molecules with enhanced properties. In this review we will separately discuss the effects of macrocyclization upon potency, selectivity and physicochemical properties, concentrating on recent case histories in oncology drug discovery. Additionally, we will highlight selected advances in the synthesis of macrocycles and provide an outlook on the future use of macrocyclic scaffolds in medicinal chemistry.

https://www.future-science.com/doi/pdf/10.4155/fmc.12.93

Macrocycles in new drug discovery

https://www.cell.com/cell-chemical-biology/pdf/S1074-5521(10)00198-5.pdf

Probing the Probes: Fitness Factors For Small Molecule Tools

Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d) we describe Astex’s approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.

Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design.

Targeted inhibition of the molecular chaperone Hsp90 results in the simultaneous blockade of multiple oncogenic signaling pathways and has, thus, emerged as an attractive strategy for the development of novel cancer therapeutics. Ganetespib (formerly known as STA-9090) is a unique resorcinolic triazolone inhibitor of Hsp90 that is currently in clinical trials for a number of human cancers. In the present study, we showed that ganetespib exhibits potent in vitro cytotoxicity in a range of solid and hematologic tumor cell lines, including those that express mutated kinases that confer resistance to small-molecule tyrosine kinase inhibitors. Ganetespib treatment rapidly induced the degradation of known Hsp90 client proteins, displayed superior potency to the ansamycin inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), and exhibited sustained activity even with short exposure times. In vivo, ganetespib showed potent antitumor efficacy in solid and hematologic xenograft models of oncogene addiction, as evidenced by significant growth inhibition and/or regressions. Notably, evaluation of the microregional activity of ganetespib in tumor xenografts showed that ganetespib was efficiently distributed throughout tumor tissue, including hypoxic regions >150 μm from the microvasculature, to inhibit proliferation and induce apoptosis. Importantly, ganetespib showed no evidence of cardiac or liver toxicity. Taken together, this preclinical activity profile indicates that ganetespib may have broad application for a variety of human malignancies, and with select mechanistic and safety advantages over other first- and second-generation Hsp90 inhibitors.

https://mct.aacrjournals.org/content/molcanther/11/2/475.full.pdf

Ganetespib, a Unique Triazolone-Containing Hsp90 Inhibitor, Exhibits Potent Antitumor Activity and a Superior Safety Profile for Cancer Therapy

A novel class of heat shock protein 90 (Hsp90) inhibitors was developed from an unbiased screen to identify protein targets for a diverse compound library These indol-4-one and indazol-4-one derived 2-aminobenzamides showed strong binding affinity to Hsp90, and optimized analogues exhibited nanomolar antiproliferative activity across multiple cancer cell lines Heat shock protein 70 (Hsp70) induction and specific client protein degradation in cells on treatment with the inhibitors supported Hsp90 inhibition as the mechanism of action Computational chemistry and X-ray crystallographic analysis of selected member compounds clearly defined the protein-inhibitor interaction and assisted the design of analogues 4-[6,6-Dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzamide (SNX-2112, 9) was identified as highly selective and potent (IC(50) Her2 = 11 nM, HT-29 = 3 nM); its prodrug amino-acetic acid 4-[2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-phenylamino]-cyclohexyl ester methanesulfonate (SNX-5422, 10) was orally bioavailable and efficacious in a broad range of xenograft tumor models (eg 67% growth delay in a HT-29 model) and is now in multiple phase I clinical trials

Discovery of novel 2-aminobenzamide inhibitors of heat shock protein 90 as potent, selective and orally active antitumor agents.

5548 The molecular chaperone Hsp90 plays a central role in maintaining the functional competency of a number of signaling transducers involved in cell growth, survival and oncogenesis. For this reason Hsp90 has become an exciting therapeutic target for the treatment of cancer. Derivatives of the natural product geldanamycin, 17-AAG and 17-DMAG, inhibit Hsp90 by competing with ATP binding and are currently under clinical investigation. We present here the discovery and characterization of SNX-5542 as a novel, water soluble, orally active small molecule inhibitor of Hsp90 that is structurally unrelated to any of the current published Hsp90 inhibitors. In vitro and in vivo evidence, presented herein, demonstrate that SNX-5542 acts as a highly selective Hsp90 inhibitor with activity and efficacy equivalent to or better than published Hsp90 inhibitors. These data include: 1) competitive displacement of ATP from Hsp90, 2) Hsp90 client degradation that is time dependent in cells treated with compound, 3) compound dependent upregulation of Hsp70 and 4) broad, potent antiproliferative response in human cancer cells treated with SNX-5542. SNX-5542 exhibits low nanomolar potency in each of the in vitro cellular assays tested. The in vivo efficacy of orally dosed SNX-5542 was demonstrated in human xenograft models of colon and breast cancer. Additionally, pharmacodynamic evidence of Hsp90 inhibition was characterized in tumor tissue samples from these experiments. Initial preclinical toxicity studies are favorable indicating that SNX-5542 has the potential to be clinically beneficial in the treatment of a wide range of cancers. SNX-5542 also represents a new tool for addressing Hsp90 biology and physiology.

Bert Pronk

Papers

Discovery of novel 2-aminobenzamide inhibitors of heat shock protein 90 as potent, selective and orally active antitumor agents.

A novel, orally active, small molecule Hsp90 inhibitor.