Rucaparib (RUC) is a potent poly (ADP-ribose) polymerase inhibitor for the treatment of advanced ovarian cancer and recurrent epithelial ovarian cancer. It is marketed in the form of its camsylate salt with a solubility of 1.4 nmol L−1 and absolute oral bioavailability of 36–37%. To expand the solid-state scope of RUC, three salts with fumaric acid (RUC/FA, 2 : 1), adipic acid (RUC/AA, 1 : 1) and pimelic acid (RUC/PA, 1 : 1) were synthesized and characterized. The crystal structure and infrared spectroscopy analyses demonstrate that proton transfer occurs between the RUC and FA/AA/PA molecules, confirming the formation of salts. In comparison with the commercial camsylate salt of RUC, RUC/AA and RUC/PA exhibit significantly enhanced solubility without sacrificing hygroscopicity and physical stability. Therefore, RUC/AA and RUC/PA may have the potential for developing improved formulations of RUC.
Revealing drug–protein interaction is highly important to select a drug candidate with improved drug-like properties in the early stages of drug discovery. This highlights the urgent need to develop assays that enable the analysis of drug–protein interaction with high speed. Herein, this purpose was realized by the development of an affinity chromatographic method with a two-fold higher speed than typical assays like frontal analysis and zonal elution. The method involved synthesis of a stationary phase by immobilizing poly(ADP-ribose) polymerase-1 (PARP1) onto macroporous silica gel through a one-step bioorthogonal reaction, characterization of mutual displacement interaction of two canonical drugs to the immobilized PARP1, determination of the interaction between three (iniparib, rucaparib, and olaparib) drugs and the protein, and validation of these parameters by typical frontal analysis. The numbers of binding sites on the column were (2.85 ± 0.05) × 10–7, (1.89 ± 0.71) × 10–6, and (1.49 ± 0.06) × 10–7 M for iniparib, rucaparib, and olaparib, respectively. On these sites, the association constants of the three drugs to the protein were (9.85 ± 0.56) × 104, (2.85 ± 0.34) × 104, and (1.07 ± 0.35) × 105 M–1. The determined parameters presented a good agreement with the calculation by typical frontal analyses, which indicated that the current continuous competitive frontal analysis method was reliable for determining drug–protein interaction. Application of the methods was achieved by screening tubeimosides I and II as the bioactive compounds against breast cancer in Bolbostemma paniculatum. Their mechanism may be the interference of DNA repair via down-regulating PARP1 and meiotic recombination 11 expressions, thus leading to oncogene mutations and death of cancer cells. The method was high speed since it allowed simultaneous determination of binding parameters between two drugs and a protein with a smaller number of experiments to be performed. Such a feature made the method an attractive alternative for high-speed analysis of drug–protein interaction or the other bindings in a binary system.
危险品化学品经营许可证（带存储）