Neuropilin-1 drives tumor-specific uptake of chlorotoxin.

Background: Chlorotoxin (Cltx) isolated from scorpion venom is an established tumor targeting and antiangiogenic peptide. Radiolabeled Cltx therapeutic (I-TM601) yielded promising results in human glioma clinical studies, and the imaging agent tozuleristide, is under investigation in CNS cancer studies. Several binding targets have previously been proposed for Cltx but none effectively explain its pleiotropic effects; its true target remains ambiguous and is the focus of this study.

Total synthesis of ipomoeassin F.

The first total synthesis of ipomoeassin F was carried out using a convergent approach that relied upon the use of Schmidt glycosidation technology for the coupling of two suitably protected monosaccharide fragments. After two steps, ring-closing metathesis was used to form the macrocyclic ring, and seven more steps then furnished ipomoeassin F. In vitro inhibitory activity against a four-panel cell line showed low nanomolar inhibitory activity.

RCM-based synthesis of a variety of beta-C-glycosides and their in vitro anti-solid tumor activity.

The synthesis of a number of biologically relevant C-glycosides has been carried out through the use of an esterification-ring-closing metathesis (RCM) strategy. The required acid precursors were readily prepared via a number of standard chemical transformations followed by dehydrative coupling of these acids with several olefin alcohols 1 to yield the precursor esters 3 in excellent yield. Methylenation of the esters 3 was followed by RCM and in situ hydroboration-oxidation of the formed glycals to furnish the protected beta-C-glycosides 6 in good overall yield.

First synthesis of a branched beta-C-tetrasaccharide using a triple ring closing metathesis cyclization.

The first synthesis of a branched beta-C-tetrasaccharide has been carried out through the use of an esterification-ring closing metathesis (RCM) strategy. The precursor triacid 2a was readily prepared via standard chemical methods from a known starting material, and dehydrative coupling with an excess of olefin alcohol 1a gave triester 3a in excellent yield. Methylenation of the triester 3a and subsequent triple RCM reaction was followed by an in situ hydroboration-oxidation to furnish the branched beta-C-tetrasaccharide 6a in good overall yield.

Synthesis and partial biological evaluation of a small library of differentially-linked beta-C-disaccharides.

The synthesis of a small library of differentially-linked beta-C-disaccharides has been carried out through the use of a radical allylation-RCM strategy. Acids 6 were prepared by Keck allylation of a suitable carbohydrate-based radical precursor, followed by oxidative cleavage of the formed alkene. Dehydrative coupling of these acids with the known olefin alcohol 5 then gave the precursor esters 7 in excellent yield.

Synthesis of some biologically relevant beta-C-glycoconjugates.

[reaction: see text] An esterification-RCM approach to a variety of biologically relevant beta-C-glycoconjugates is reported herein. A range of carboxylic acids were coupled with several different olefin alcohols 1 to provide esters 3. The esters were then converted to the final ring-closed product 6 in three steps in 49-60% overall yield.