Practical and Scalable Manufacturing Process for the Key Intermediate of Poly(ADP-Ribose) Polymerase Inhibitor Olaparib.

Olaparib (Lynparza) is a potent, highly selective inhibitor of poly(ADP-ribose)polymerase enzymes, approved by the U.S. FDA and EMA for the treatment of ovarian cancer. Herein, we report a practical, economical, and scalable process for the synthesis of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid, a key intermediate for olaparib. The low-cost industrial byproduct phthalhydrazide was used as the starting material to construct the phthalazinone moiety, which allowed access to the key intermediate by the Negishi coupling reaction. Optimization of each step has enabled the development of an environmentally benign and robust process with effective control of impurities.

Guanosine Borate Hydrogel and Self-Assembled Nanostructures Capable of Enantioselective Aldol Reaction in Water.

A guanosine-based hydrogel formed by the self-assembly of guanosine and 4-((l-prolinamide)methyl)phenylboronic acid was constructed. The G quartets were selectively stabilized by K+ ions to form a self-supporting transparent hydrogel. These guanosine-derived assemblies were used to catalyze the aldol reaction in water without any additives, affording desirable conversion and enantioselectivity of the product. The controlled assays of small-molecule components indicated that the stable assemblies were the definite species that achieved high enantioselective catalysis. The current catalytic system can be readily recovered by simple extraction and still acquired good performance of the reaction after four cycles.

Double-strand cleavage of DNA by a polyamide-phenazine-di-N-oxide conjugate.

Phenazine and its derivatives have been widely applied as nucleic acid cleavage agents due to active oxygen activating the C-H bond of the substrate. However, diffusion of oxygen radicals limits their potential applications in the DNA-targeted metal-free drug. Introduction of groove binder moiety such as polyamide enhanced the regional stability of radical molecules and reduced cytotoxicity of the drugs. In this work, we described the design and synthesis of a polyamide-modified phenazine-di-N-oxide as a DNA double-strand cleavage agent. The gel assays showed the hybrid conjugates can effectively break DNA double strands in a non-random manner under physiological conditions. The probable binding mode to DNA was investigated by sufficient spectral experiments, revealing weak interaction between hybrid ligand and nucleic acid molecules. The results of our study have implications on the design of groove-binding hybrid molecules as new artificial nucleases and may provide a strategy for developing efficient and safe DNA cleavage reagents.