Bioorganic & medicinal chemistry letters
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Versatile intermediates 12'-iodovinblastine, 12'-iodovincristine and 11'-iodovinorelbine were utilized as substrates for transition metal based chemistry which led to the preparation of novel analogues of the vinca alkaloids. The synthesis of key iodo intermediates, their transformation into final products, and the SAR based upon HeLa and MCF-7 cell toxicity assays is presented. Selected analogues 27 and 36 show promising anticancer activity in the P388 murine leukemia model.
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Bioorg. Med. Chem. Lett. · Feb 2009
Synthesis and SAR of potent LXR agonists containing an indole pharmacophore.
A novel series of 1H-indol-1-yl tertiary amine LXR agonists has been designed. Compounds from this series were potent agonists with good rat pharmacokinetic parameters. In addition, the crystal structure of an LXR agonist bound to LXRalpha will be disclosed.
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Bioorg. Med. Chem. Lett. · Feb 2009
Design and synthesis of a beta-lactamase activated 5-fluorouracil prodrug.
An efficient synthesis of a 5-fluorouracil-cephalosporin prodrug is described for use against colorectal and other cancers in antibody and gene-directed therapies. The compound shows stability in aqueous media until specifically activated by beta-lactamase (betaL). The kinetic parameters of the 5-fluorouracil-cephalosporin conjugate were determined in the presence of Enterobacter cloacae P99 betaL (ECl betaL) revealing a K(m)=95.4 microM and V(max)=3.21 microMol min(-1) mg(-1). The data compare favorably to related systems that have been reported and enable testing of this prodrug against cancer cell lines in vitro and in vivo.