Design and synthesis of a combinatorial chemistry library of 7-acyl, 10-acyl, and 7,10-diacyl analogues of paclitaxel (taxol) using solid phase synthesis.
A series of 10-acyl and 7,10-diacyl paclitaxel analogues (7a-7e and 9a-9u) have been synthesized using a solid phase combinatorial chemistry approach, and a second series of 7-acyl-10-deacetylpaclitaxel analogues have been prepared by conventional chemistry. In the first series, 10-deacetylpaclitaxel (4) was linked through its 2'-hydroxyl group using 1% polystyrene-divinyl benzene resin functionalized with butyldiethylsilane linker (PS-DES) and then acylated at the C-10 hydroxyl group with various anhydrides and dialkyl dicarbonates in the presence of CeCl(3). The resin-bound C-10 acylated paclitaxel derivatives (6a-6e) were then treated with various carboxylic acids in the presence of 1,3-diisopropylcarbodiimide in toluene to provide polymer-supported 7,10-diacylpaclitaxels (8a-8u). These 7-acyl- and 7,10-diacylpaclitaxels (6a-6e and 8a-8u) were cleaved from the resin to give the 24 paclitaxel analogues 7a-7e and 9a-9u. Nine 7-acyl-10-deacetylpaclitaxel analogues were also prepared by conventional chemistry. Methodology to determine the tubulin-assembly activity of compounds prepared in small quantities by a combinatorial approach has been developed, and four analogues with improved tubulin-assembly activity as compared with paclitaxel were found, together with two analogues with improved cytotoxicity.
Department of Chemistry, M/C 0212, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA.
Prakash G
PG
Jagtap
Erkan
E
Baloglu
Donna M
DM
Barron
Susan
S
Bane
David G I
DG
Kingston
D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy; D008869:Microtubule-Associated Proteins / Q000187:drug effects; D015394:Molecular Structure; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000972:Antineoplastic Agents, Phytogenic; D008869:Microtubule-Associated Proteins; D017239:Paclitaxel