Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization.

The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models.

Pd-catalyzed sequential C-C bond formation and cleavage: evidence for an unexpected generation of arylpalladium(II) species.

A Pd(II)-catalyzed reaction engaging alkenyl ß-keto esters is reported that leads to the formation of 1-naphthols and an unexpected generation of arylpalladium(II) species. Interception of the in situ generated arylpalladium(II) species in a Mizoroki-Heck reaction, together with additional mechanistic studies, provided strong evidence in support of the first aromatization-driven ß-carbon elimination process. A single Pd catalyst served to promote a series of both C-C bond forming and cleavage events in an unprecedented manner.

Cyclization reaction for the synthesis of polysubstituted naphthalenes in the presence of Au(I) precatalysts.

Au(I)-catalyzed cyclization of alkenyl carbonyl compounds leading to a variety of substituted naphthalenes has been developed. This process exploits a dual function of the Au(I) catalyst: (1) the oxophilic nature of the Au(I) catalyst, counterintuitive to the π-acidic reactivities generally associated with Au catalysts, and (2) olefin isomerization supported by the outcome of isotope scrambling experiments. It cannot be completely excluded that TfOH is a true operative catalyst in this protocol. In view of the practicality, the unnecessity of isomerically pure starting material in this reaction is particularly attractive and valuable.

Asymmetric synthesis of tetrahydroquinolin-3-ols via CoCl2-catalyzed reductive cyclization of nitro cyclic sulfites with NaBH4.

A new method for the construction of chiral 3-substituted tetrahydroquinoline derivatives based on asymmetric dihydroxylation and CoCl(2)-catalyzed reductive cyclization of nitro cyclic sulfites with NaBH(4) has been described with high optical purities. This method has been successfully applied in the formal synthesis of PNU 95666E and anachelin H chromophore.

Pyrophosphate selective fluorescent chemosensors based on coumarin-DPA-Cu(II) complexes.

Two new coumarin derivatives displayed highly selective "Off-On" fluorescence changes with pyrophosphate between various anions including ATP, ADP, AMP and inorganic phosphate in 100% aqueous solution.