Search

An efficient synthesis to enable the full evaluation of cycloproparadicicol as a candidate for further advancement was developed. Results of these studies are in conjunction with the earlier demonstration that cycloproparadicicol binds to Hsp90 at ca. 160 nM.

Extensive glycosylation of HIV envelope proteins were considered to be one of the major impedients to the development of an HIV vaccine. This 'glycan shield' was perceived to confer protection from antibodies, which can recognize the peptide backbone of the gp120 trimer surface.

The Ru-catalyzed synthesis of novel C14 position of the baccatin moiety and the ortho position of C3'N-benzoyl group (C14-C3'BzN)-linked macrocyclic taxoids (SB-T-2053) and (SB-T-2054) that mimic the 'REDOR-taxol' structure, paclitaxel is described. The results revealed that SB-T-2054 is the most active compound that exhibited similar potency and structure as that of paclitaxel.

The design and synthesis of multivalent glycopeptide constructs that do not contain any relation to a native gp120 peptide sequence, yet still mimic gp120's binding to 2G12, are presented. These constructs have suitable functional handles for attachment to a carrier protein, thus facilitating their use in vaccines.

A program currently ongoing in our laboratory envisions natural macrolide radicicol-based inhibitors targeting the molecular chaperone Hsp90. Such inhibitors can be potential anticancer agents due to their ability to induce the breakdown of a variety of oncogenic proteins. In this account, we first concern ourselves with a vastly important total synthesis of such an inhibitor. We accomplished this via a new approach, which we term the "ynolide method", directed to the synthesis of resorcinylic macrolides, including cycloproparadicicol and aigialomycin D. The key features of the syntheses involve cobalt-complexation- promoted ring-closing metathesis (ACM) to generate ynolides, followed by Diels-Alder reaction with dimedone-derived bis-siloxy dienes to elaborate the benzo system. A number of interesting analogues were synthesized using this protocol. They were evaluated for their inhibitory activity against the growth of breast cancer cell line, MCF-7. The potency of their cytotoxicity was found to be consistent with their ability to degrade the oncogenic protein, Her2. From these assays, cycloproparadicicol was identified as a most promising candidate for further development. [ABSTRACT FROM AUTHOR]