Todd C. Somers

A Regio- and stereocontrolled total synthesis of (-)-indolactam-V

Abstract (-)-Indolactam-V (IL-V) ( 1 ) -was prepared in 10 steps from L-tryptophan methyl ester in 17.1% overall yield. The key steps involve regiospecific thallation of the acylindole intermediate ( 4 ), followed by azide displacement and reduction to introduce the 13-amino group. Control of the C-ll stereocenter was achieved by S N 2 displacement of the chiral inflate ( 10 ), derived from D-valine. The thallium mediated closure of dipeptide ( 17 ) did not provide an alternative route to IL-V.

Benzodiazepine peptidomimetic inhibitors of farnesyltransferase.

A structural survey of protein Zn2+ binding geometries was instigated based upon the functional requirement of Ras farnesyltransferase for Zn2+. The Cys-X-X-Cys motif found in Zn(2+)-binding proteins such as aspartate transcarbamylase was used as a template to devise a bidentate-coordination model for Cys-A1-A2-X peptide inhibitors. Accordingly, replacement of the central dipeptide with the hydrophobic scaffold 3-amino-1-carboxymethyl-2,3-dihydro-5- phenyl-1H-1,4-benzodiazepin-2-one (BZA) yielded a peptidomimetic inhibitor, Cys(BZA)Met, of moderate potency (IC50 = 400 nM). N-Methylation of the cysteine amide improved potency almost 100-fold (IC50 = 0.3-1 nM). The increased affinity presumably correlates with a preferred conformation of the inhibitor which maximizes a hydrophobic interaction between the scaffold and the enzyme, and the proper presentation of cysteine and methionine to allow bidentate coordination at Zn2+. These non-peptide inhibitors have been shown to block farnesylation of the Ras protein in intact cells and provide lead compounds for the development of new cancer therapeutic agents.

Preparation and biological activity of novel tricyclic GPIIb/IIIa antagonists

Antagonists of the glycoprotein GPIIb/IIIa are a promising class of antithrombotic agents offering potential advantages over present antiplatelet agents (i.e., aspirin and ticlopidine). Novel tricyclic nonpeptidal GPIIb/IIIa antagonists have been prepared and evaluated in vitro as antagonists of fibrinogen binding to the purified GPIIb/IIIa receptor and as inhibitors of platelet aggregation. The work presented demonstrates the robustness of the benzodiazepinedione (BZDD) scaffold, which can be functionalized at the N1-C2 amide as well as at C7, to provide structural diversity and allow optimization of the physiochemical and pharmacological properties of the BZDD based GPIIb/IIIa antagonists. In addition, the resulting new class of tricyclic GPIIb/IIIa antagonists could be used to probe for additional binding interactions on the GPIIb/IIIa receptor and perhaps lead to BZDD based GPIIb/IIIa antagonists with increased potency. The tricyclic molecules reported herein demonstrate that a heterocyclic ring can be fused to the benzodiazepinedione scaffold with retention of anti-aggregatory potency and in the case of tetrazole 30i, increased potency relative to the bicyclic analogue 1c.

Stereochemistry of the benzodiazepine based Ras farnesyltransferase inhibitors

Abstract Chiral benzodiazepine I is the preferred dipeptide turn mimic enantiomer employed in a series of Ras farnesyltransferase inhibitors. It was resolved as the camphorsulfonic acid salt of its methyl ester via a directed crystallization process. Crystallographic analysis of a derivative established R stereochemistry at C-3. The stereochemistry of the additional two chiral centers in derived inhibitor II is addressed.

Peptidomimetic inhibitors of Ras farnesylation

The Ras protein and related members of the growing superfamily of small molecular weight GTP-binding proteins have been the subject of intense study over the past decade 111. First discovered as the product of the transforming gene of a sarcoma virus, the Ras protein forms part of the intracellular network responsible for the control of cell growth and differentiation. In response to the binding of extracellular growth factors to specific cell surface receptors, Ras functions as a ‘molecular switch, interconverting between an active and an inactive form through the binding and hydrolysis of GTP. The transforming activity of Ras is induced by a single point mutation which reduces the GTPase activity of the protein, so that it remains locked in the active or GTP-bound state. The resulting unregulated stimulation of cell growth is thought to contribute to the development of malignant tumors. Mutations in Ras are associated with -50% of colon tumors and -90% of pancreatic carcinomas, making it a suitable target for the development of new therapeutic agents.