A series of 2-(thioalkyl)pentanedioic acids were synthesized and evaluated as inhibitors of glutamate carboxypeptidase II (GCP II, EC 3.4.17.21). The inhibitory potency of these thiol-based compounds against GCP II was found to be dependent on the number of methylene units between the thiol group and pentanedioic acid. A comparison of the SAR of the thiol-based inhibitors to that of the phosphonate-based inhibitors provides insight into the role of each of the two zinc-binding groups in GCP II inhibition. The most potent thiol-based inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (IC(50) = 90 nM), was found to be orally bioavailable in rats and exhibited efficacy in an animal model of neuropathic pain following oral administration.

A series of functionalized and optically active major-groove polybinaphthyls and minor-groove polybinaphthyls have been synthesized by using the Suzuki coupling reaction and have been spectroscopically characterized. The application of these chiral polymers in the asymmetric addition of diethylzinc to aldehydes has been studied. A minor-groove polybinaphthyl is found to be an excellent catalyst for the asymmetric reaction of diethylzinc with a number of aldehydes. The molecular weight and the molecular weight distribution of the polymer have little effects on the catalytic process. The chiral polymer can be easily recovered and reused without loss of catalytic activity as well as enantioselectivity. These rigid and sterically regular chiral polybinaphthyls represent a new generation of enantioselective polymeric catalysts. The reaction of the polybinaphthyls as well as certain monomeric binaphthyl molecules with diethylzinc has been investigated which has provided further information on the novel polymeric catalysts.

Tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA-cross-linking pyrrolobenzodiazepine compounds as the payload. Despite promising early clinical results with this class of ADCs, doses achievable have been low due to systemic toxicity. Here we describe the development of a new class of potent DNA-interacting agents wherein changing the mechanism of action from a cross-linker to a DNA alkylator improves the tolerability of the ADC. ADCs containing the DNA alkylator displayed similar in vitro potency, but improved bystander killing and in vivo efficacy, compared to those of the cross-linker. Thus, the improved in vivo tolerability and anti-tumor activity achieved in rodent models with ADCs of the novel DNA alkylator could provide an efficacious, yet safer option for cancer treatment.on May 9, 2018.

No abstract