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The use of the di-(p-anisyl)methyl (DAM) group at N1 of 1,4-benzodiazepin-2-ones and 1,4-benzodiazepine-2,5-diones derived from enantiopure proteinogenic amino acids has allowed retentive replacement of the C3-proton through a deprotonation/trapping protocol. The DAM group is easily removed by acidic hydrolysis following the retentive substitution process, which allows the subsequent installation of diverse N1 functionality.

Glycine-derived 1H-benzo[e][1,4]diazepin-2(3H)-ones (BZDs) featuring C9- and N1-substitution has displayed enantiomerization barriers too high to be measured by [super 1]H NMR coalescence experiments. The studies have shown the highest enantiomerization barriers ever determined for a BZD.

Enantiopure amino-acid derived 1H-benzo[e][1,4]diazepin-2(3H)-ones (BZDs) have undergone highly retentive deprotonation/alkylation reactions and a new alanine-derived BZD is prepared for determining their stereochemical course. Minimization of torsional effects at the BZD ring fusion and maximization of imine and amide resonance are described that are in favor of concave-face alkylation.

Procaspase-Activating Compound 1 (PAC-1) is an orth∙hydroxy N-acyl hydrazone that enhances the enzymatic activity of procaspase-3 in vitro and induces apoptosis in cancer cells. An analogue of PAC-1, called S-PAC-1, was evaluated in a veterinary clinical trial in pet dogs with lymphoma and found to have considerable potential as an anticancer agent. With the goal of identifying more potent compounds in this promising class of experimental therapeutics, a combinatorial library based on PAC-1 was created, and the compounds were evaluated for their ability to induce death of cancer cells in culture. For library construction, 31 hydrazides were condensed in parallel with 27 aldehydes to create 837 PAC-1 analogues, with an average purity of 91%. The compounds were evaluated for their ability to induce apoptosis in cancer cells, and through this work, six compounds were discovered to be substantially more potent than PAC-1 and S-PAC-1. These six hits were further evaluated for their ability to relieve zinc-mediated inhibition of procaspase-3 in vitro. In general, the newly identified hit compounds are two- to four-fold more potent than PAC-1 and S-PAC-1 in cell culture, and thus have promise as experimental therapeutics for treatment of the many cancers that have elevated expression levels of procaspase-3. [ABSTRACT FROM AUTHOR]

Benzodiazepines are privileged scaffolds in medicinal chemistry, but enantiopure examples containing quaternary stereogenic centers are extremely rare. We demonstrate that installation of the di- (p-anisyl)methyl (DAM) group at Ni of 1 ,4-benzodiazepin-2-ones and 1 ,4-benzodiazepine-2,5-diones derived from enantiopure proteinogenic amino acids allows retentive replacement of the C3-proton via a deprotonation/trapping protocol. A wide variety of carbon and nitrogen electrophiles function well in this reaction, providing the corresponding quaternary benzodiazepines with excellent enantioselectivity. Deprotonation/trapping experiments on a pair of diastereomeric 1 ,4-benzodiazepine-2,5-diones provide evidence for a key role of conformational chirality in these enantioselective reactions. Acidic removal of the DAM group is fast and high-yielding and can be performed selectively in the presence of a N-Boc indole. Thus the synthesis of quaternary benzodiazepines with diverse N1 functionality can now be accomplished. [ABSTRACT FROM AUTHOR]

A goal of personalized medicine as applied to oncology is to identify compounds that exploit a defined molecular defect in a cancerous cell. A compound called procaspase-activating compound 1 (PAC-1) was reported that enhances the activity of procaspase-3 in vitro and induces apoptotic death in cancer cells in culture and in mouse xenograft models. Experimental evidence indicates that PAC-1 activates procaspase-3 in vitro through chelation of inhibitory zinc ions. Described herein is the synthesis and biological activity of a family of PAC-1 derivatives where key functional groups have been systematically altered. Analysis of these compounds reveals a strong correlation between the in vitro procaspase-3 activating effect and their ability to induce death in cancer cells in culture. Importantly, we also show that a fluorescently labeled version of PAC-1 co-localizes with sites of caspase-3 activity in cancer cells. The data presented herein further bolster the hypothesis that PAC-1 induces apoptosis in cancer cells through the direct activation of procaspase-3, has implications for the design and discovery of next-generation procaspase-3 activating compounds, and sheds light on the anti-apoptotic role of cellular zinc.