A new route to bicyclo[1.1.1]pentan-1-amine from 1-azido-3-iodobicyclo[1.1.1]pentane.

From a medicinal chemistry perspective, bicyclo[1.1.1]pentan-1-amine (1) has served as a unique and important moiety. Synthetically, however, this compound has received little attention, and only one scalable route to this amine has been demonstrated. Reduction of an easily available and potentially versatile intermediate, 1-azido-3-iodobicyclo[1.1.1]pentane (2), can offer both a flexible and scalable alternative to this target. Herein, we describe our scrutiny of this reportedly elusive transformation and report our ensuing success with this endeavor.

In silico design of small molecules.

Computational methods now play an integral role in modern drug discovery, and include the design and management of small molecule libraries, initial hit identification through virtual screening, optimization of the affinity and selectivity of hits, and improving the physicochemical properties of the lead compounds. In this chapter, we survey the most important data sources for the discovery of new molecular entities, and discuss the key considerations and guidelines for virtual chemical library design.

CLEVER: A general design tool for combinatorial libraries.

CLEVER is a computational tool designed to support the creation, manipulation, enumeration, and visualization of combinatorial libraries. The system also provides a summary of the diversity, coverage, and distribution of selected compound collections. When deployed in conjunction with large-scale virtual screening campaigns, CLEVER can offer insights into what chemical compounds to synthesize, and, more importantly, what not to synthesize. In this chapter, we describe how CLEVER is used and offer advice in interpreting the results.

Structural insights into the design of small molecule inhibitors that selectively antagonize Mcl-1.

The screening of a small focused library of rhodanine derivatives as inhibitors of Bcl-2 proteins led to the discovery of two structurally related compounds with different binding profiles against the Bcl-XL and the Mcl-1 proteins. Subsequent NMR studies with mutant proteins and in silico docking studies provide a possible rationale for the observed specificity.

CLEVER: pipeline for designing in silico chemical libraries.

Advances in virtual screening have created new channels for expediting the process of discovering novel drugs. Of particular relevance and interest are in silico techniques that enable the enumeration of combinatorial chemical libraries, generation of 3D coordinates and assessment of their propensity for drug-likeness. In a bid to provide an integrated pipeline that encompasses the common components functional for designing, managing and analyzing combinatorial chemical libraries, we describe a platform-independent, standalone Java application entitled CLEVER (Chemical Library Editing, Visualizing and Enumerating Resource). CLEVER supports chemical library creation and manipulation, combinatorial chemical library enumeration using user-specified chemical components, chemical format conversion and visualization, as well as chemical compounds analysis and filtration with respect to drug-likeness, lead-likeness and fragment-likeness based on the physicochemical properties computed from the derived molecules. Also provided is an integrated property-based graphing component that visually depicts the diversity, coverage and distribution of selected compound collections. When deployed in conjunction with large-scale virtual screening campaigns, CLEVER can offer insights into what chemical compounds to synthesize, and more importantly, what not to synthesize. The software is available at http://datam.i2r.a-star.edu.sg/clever/.

Structure-activity relationship studies of phenanthridine-based Bcl-XL inhibitors.

Despite their structural similarities, the natural products chelerythrine ( 5) and sanguinarine ( 6) target different binding sites on the pro-survival Bcl-X L protein. This paper details the synthesis of phenanthridine-based analogues of the natural products that were used to probe this difference in binding profiles. The inhibitory constants for these compounds were then measured in a fluorescence polarization assay against Bcl-X L and the tagged Bak-BH3 peptide. The results led to structure-activity relationship studies, which identified the structural motifs required for binding-site specificity as well as inhibitory activity. We also identified synthetic analogues of the natural products that display similar binding modes but with more potent IC 50 values.

Structure-activity delineation of quinones related to the biologically active Calothrixin B.

Quinones such as Calothrixins A and B display a range of biological properties. As part of our ongoing studies to elucidate the mechanism of action of the Calothrixins, several related quinones were synthesized and tested for biological activity. The results of the structure-activity relationship (SAR) studies are reported here.

Synthesis, electrochemistry, and bioactivity of the cyanobacterial calothrixins and related quinones.

The calothrixins are quinone-based natural products isolated from Calothrix cyanobacteria which show potent antiproliferative properties against several cancer cell lines. Preliminary mechanistic studies suggest that the biological mode of action of the calothrixins may be linked to their ability to undergo redox cycling. In this study we compare the bioactivities of the calothrixins with those of structurally related quinones in order to identify the structural features in the calothrixins essential for biological activity. In particular, the reduction potentials of the calothrixins and some related quinones were measured electrochemically. Our studies indicate that while there is no direct correlation between the reduction potentials and biological activities of the studied compounds, in all cases quinones with EC(50) values <1.6 microM undergo reduction to their respective semiquinones readily, with their E(1/2) values being more positive than -0.5 V versus the standard hydrogen electrode (SHE).

Friedel-Crafts acylation and metalation strategies in the synthesis of calothrixins A and B.

The total syntheses of calothrixins A and B starting from readily available indole and the acid chloride 4 are described.

A novel redox mechanism for the glutathione-dependent reversible uptake of a fungal toxin in cells.

The fungal metabolite gliotoxin is characterized by an internal disulfide bridge and can exist in either disulfide or dithiol forms. Gliotoxin and other members of the epipolythiodioxopiperazine class of toxins have immunosuppressive properties and have been implicated in human and animal mycotoxicoses. The bridged disulfide moiety is thought to be generally essential for biological activity. Here we show that only the natural (oxidized) form of gliotoxin is actively concentrated in a cell line in a glutathione-dependent manner. Intracellular levels of the toxin can be up to 1500-fold greater than the applied concentration, and toxin in the cells exists almost exclusively in the reduced form. A simple model of toxin entry followed by reduction to the cell-impermeant dithiol explains active uptake, cell density dependence of EC50 values and predicts a value for the maximum concentration of toxin at limiting cell density in agreement with the experiment. Oxidation of the intracellular toxin results in rapid efflux from the cell that also occurs when glutathione levels fall following induction of apoptotic cell death by the toxin. This mechanism allows for minimal production of the toxin while enabling maximal intracellular concentration and thus maximal efficacy of killing in a competitor organism initially present at low cell density. The toxin effluxes from the apoptotic cell exclusively in the oxidized form and can further enter and kill neighboring cells, thus acting in a pseudocatalytic way.