Robert A. Volkmann

Drug effects viewed from a signal transduction network perspective.

Understanding how drugs affect cellular network structures and how resulting signals are translated into drug effects holds the key to the discovery of medicines. Herein we examine this cause-effect relationship by determining protein network structures associated with the generation of specific in vivo drug-effect patterns. Medicines having similar in vivo pharmacology have been identified by a comparison of drug-effect profiles of 1320 medicines. Protein network positions reached by these medicines were ascertained by examining the coinvestigation frequency of these medicines and 1179 protein network constituents in millions of scientific investigations. Interestingly, medicine associations obtained by comparing by drug-effect profiles mirror those obtained by comparing drug-protein coinvestigation frequency profiles, demonstrating that these drug-protein reachability profiles are relevant to in vivo pharmacology. By using protein associations obtained in these investigations and independent, curated protein interaction information, drug-mediated protein network topology models can be constructed. These protein network topology models reveal that drugs having similar pharmacology profiles reach similar discrete positions in cellular protein network systems and provide a network view of medicine cause-effect relationships.

The total synthesis of argiotoxins 636, 659 and 673

Practical syntheses of three polyamine spider toxins isolated from the venom of Argiope aurantia are described.

Nucleophilic Addition to Imines and Imine Derivatives

Synthetic and biological interest in highly functionalized acyclic and cyclic amines has contributed to the wealth of experimental methodology developed for the addition of carbanions to the carbon–nitrogen double bond of imines/imine derivatives (azomethines). While a variety of practical methods exist for the enantio- and stereo-selective syntheses of substituted alcohols from aldehyde and ketone precursors, related imine additions have inherent structural limitations. Nonetheless imines, by virtue of nitrogen substitution, add a synthetic dimension not available to ketones. In addition, improved procedures for the preparation and activation of imines/imine derivatives have increased the scope of the imine addition reaction.

1. Boron trifluoride activaed 3-thiazolines. An efficient preparation of functionalized thiazolidines.

Abstract Boron trifluoride activated 2,2,5-trialkyl-3-thiazolines react with a wide range of organometallic reagents to generate substituted thiazolidines.

Synthesis of neurotoxic nephila spider venoms: NSTX-3 and JSTX-3

Abstract Efficient and practical synthetic routes to the polyamine spider venom principles, NSTX-3 and JSTX-3 are described.

Analysis of system structure-function relationships.

Preclinical pharmacology studies conducted with experimental medicines currently focus on assessments of drug effects attributed to a drugs putative mechanism of action. The high failure rate of medicines in clinical trials, however, underscores that the information gathered from these studies is insufficient for forecasting drug effect profiles actually observed in patients. Improving drug effect predictions and increasing success rates of new medicines in clinical trials are some of the key challenges currently faced by the pharmaceutical industry. Addressing these challenges requires development of new methods for capturing and comparing “system‐wide” structure–effect information for medicines at the cellular and organism levels. The current investigation describes a strategy for moving in this direction by using six different descriptor sets for examining the relationship between molecular structure and broad effect information of 1064 medicines at the cellular and the organism level. To compare broad drug effect information between different medicines, information spectra for each of the 1064 medicines were created, and the similarity between information spectra was determined through hierarchical clustering. The structure–effect relationships ascertained through these comparisons indicate that information spectra similarity obtained through preclinical ligand binding experiments using a model proteome provide useful estimates for the broad drug effect profiles of these 1064 medicines in organisms. This premise is illustrated using the ligand binding profiles of selected medicines in the dataset as biomarkers for forecasting system‐wide effect observations of medicines that were not included in the incipient 1064‐medicine analysis.

Synthetic and mechanistic studies involving the condensation of penicillin grignards and boron trifluoride activated oxime ethers

Abstract High stereocontrol is observed in the BF3 mediated condensation of anions derived from mono and dibromopenicillanic ester sulfones and oxime ethers.

A new class of selective and potent inhibitors of neuronal nitric oxide synthase.

The synthesis and SAR of a series of 6-(4-(substituted)phenyl)-2-aminopyridines as inhibitors of nitric oxide synthase are described. Compound 3a from this series shows potent and selective inhibition of the human nNOS isoform, with pharmacokinetics sufficient to provide in vivo inhibition of nNOS activity.

Reactions of Allyl and Propargyl/Allenic Organometallics with Imines and Iminium Ions

Gilman and Eisch were the first to recognize that allyl organometallic reagents possess superior reactivity relative to ordinary, nonresonance-stabilized organometallic reagents in imine addition reactions.1

Chapter 30. Polyamine Spider Toxins: Unique Pharmacological Tools

Publisher Summary The polyamine toxins, obtained from the venom of a variety of orb-weaver spiders are rapidly emerging as unique tools for understanding excitatory amino acid (EM) transmission and related pharmacology or physiology. In this chapter, the chemistry and pharmacology of Araneidae polyamine spider venom toxins is reviewed and a brief discussion of the venom from the funnel-web spider is also included. The chemistry involved in the preparation of many of the naturally occurring polyamines has been discussed in the chapter. Polyamine spider venoms have highly polar hydroxyaryl and amino acid residues. Interest in the polyamine spider toxins is a result of the observation that these molecules affect those synapses, at which an excitatory amino acid (EAA) is the neurotransmitter. Compounds that affect EAA function, particularly those that antagonize the action of such transmitters, are therefore of considerable agricultural (insect control) and therapeutic interest. Blockade of neuromuscular transmission in invertebrates by polyamin spider toxins reveals their glutamate antagonist activity. Polyamine spider venoms also act on glutaminergic synapses in vertebrate systems. Partially purified JSTX blocks the responses of CA1 pyramidal neurons in rat hippocampus both to stimulation of the appropriate afferent neurons and to direct the application of glutamate. A variety of venoms have been screened for their ability to block synaptic transmission at glutaminergic synapses in the chick cochlear nucleus. A number of toxins from the funnel-web spider Agelenopsis aperta paralyze insects. These toxins contain low molecular weight acylpolyamine constituents, at least six amino acid residue peptides, and several larger polypeptides. Two classes of toxins from Agelenopsis aperta venom that block the transmission in the chick cochlear nucleus assay have also been discussed in the chapter. The results of these studies suggest that considerable structural and functional diversity exists within the polyamine toxin class and that these compounds differ significantly from previously-known classes of EAA and calcium antagonists.