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

Abstract

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.

Modern Natural Products Drug Discovery and Its Relevance to Biodiversity Conservation

“…Examples include the synthesis of a library of betulinic acid derivatives as HIV-2 inhibitors, 136,137 a library of 3,17-hydroxysteroid dehydrogenase inhibitors, 138 a library based on a tambjamine template, 139 and several libraries based on paclitaxel. [140][141][142][143] Natural Products and Biodiversity Conservation. The ratification of the Convention on Biological Diversity marked a turning point in the search for drugs from natural sources.…”

“…Although natural products have served as the inspiration for the design of many combinatorial libraries, ,− there are relatively few examples of the use of combinatorial chemistry to prepare libraries from actual natural product scaffolds, as opposed to natural product-like scaffolds. Examples include the synthesis of a library of betulinic acid derivatives as HIV-2 inhibitors, , a library of 3,17-hydroxysteroid dehydrogenase inhibitors, a library based on a tambjamine template, and several libraries based on paclitaxel. − …”

Natural Product‐Like Combinatorial Libraries

“…Nevertheless, the steric hindrance caused by THP ether linker or related alkoxy linkers precluded the synthesis of analogues with a normal N-benzoyl function. To overcome this limitation Kingston and co-workers 132 used as alternative solid-support a polystyrene-divinyl benzene resin functionalized with a butyldiethylchlorosilane linker (93) (Figure 34). Treatment of 93 with 10-deacetylpaclitaxel (92) provided the resinbound compound 94, which was converted to the correspondent 10-acyl analogues 95 using Holton's method.…”

Topics on Specific Synthetic Applications of Phosgenation Reactions

“…The design and synthesis by solid-phase methods of a combinatorial chemistry library of C-7 acyl, C-10 acyl, and C-7,10 diacyl analogues of paclitaxel (taxol) has been described [196]. In this connection, a patent application on ''Methods and useful intermediates for paclitaxel [taxol] synthesis from C-7,10 di-Cbz 10-deacetylbaccatin III'' is worthy of mention [197].…”