Jean-Dominique Bourzat

PREPARATION OF 7-MODIFIED DOCETAXEL ANALOGS USING ELECTROCHEMISTRY

The electrochemical reduction of 7α-iodo docetaxel at E-1.3V vs. SCE in methanol in the presence of lithium chloride and hydrochloric acid leads predominantly to 7-deoxy-docetaxel 9. When the electroreduction is conducted at E-1.7V vs. SCE in the presence of sodium acetate and acetic acid, the cyclopropanol-containing taxoid 10 is formed in good yield. Electrochemical reduction of 7-deoxy-docetaxel at C-10 is also reported. All these docetaxel analogs retain biological activity.

Direct access to 2-debenzoyl taxoids by electrochemistry, synthesis of 2-modified docetaxel analogs

Abstract A new route to semisynthetic 2-modified docetaxel analogs is described using electrochemical cleavage of the 2-benzoate as the key reaction. Subsequent reacylation at C-2 followed by sequential deprotections afforded the title analogs. Biological results of selected 2-docetaxel analogs are presented.

Electrochemical reduction of taxoids: Selective preparation of 9-dihydro-, 10-deoxy- and 10-deacetoxy-taxoids

The electrochemical reduction of docetaxel in methanol in the presence of ammonium chloride leads to 9α-dihydro-docetaxel 3 and 9β-dihydro-docetaxel 4. Under the same conditions, the electrochemical reduction of paclitaxel gives 10-deacetoxy-paclitaxel 7. Calcium chloride as well as magnesium and cerium chloride, and to some extent strontium and lithium chloride, favor 10-dehydroxylation in the docetaxel series. All these docetaxel analogs retain biological activity.

Partial synthesis of major human metabolites of docetaxel

Abstract The structures and synthesis of the four major human metabolites of docetaxel are reported. These metabolites, i.e. compounds 3, 4ab and 5, are side-chain oxidation derivatives. They were prepared by partial synthesis from the previously described amino-taxoid 8 using mixed-carbonates as acylation reagents. In vitro biological activities are detailed.

Improved access to 19-nor-7β, 8β-methylene-taxoids and formation of a 7-membered C-ring analog of doxetaxel by electrochemistry

Abstract A new route to semisynthetic 19-nor-7β, 8β-methylene taxoids, such as compound 8 , from the 7-O-trifluoromethanesulfonyl derivative 6 is reported. Evidence for a dissociation of the triflate to form a carbocation at C-7 under the reaction conditions is presented. Electrochemical reduction of the cyclopropane taxoid 8 gives, besides the expected 10-dehydroxy-cyclopropane analog 10 , the 7-membered C-ring derivative 11 .

Semisynthesis of RPR 121056A, a major metabolite of irinotecan (CPT-11)

Abstract The semisynthesis of RPR 121056A ( 4 0, a major metabolite of irinotecan (CPT-11, 2 ), is reported starting from SN-38 ( 3 ) and an appropriate side-chain precusor, and using a 2-step sequence. This semisynthesis is based on the 10-O-acylation of SN-38 with the conveniently protected carbamoylchloride derivative 10 followed by cleavage of the benzylic protecting groups by hydrogenolysis. Preliminary in vitro results show that RPR 121056A displays no cytotoxicity.

Synthesis and biological activity of Para-substituted 3′-phenyl docetaxel analogs

Abstract An expedient route for semisynthetic para -modified 3′-phenyl docetaxel analogs is described using the initial regioselective iodination of the oxazolidinecarboxylate 3 . Palladium catalyzed coupling reactions of the iodo intermediate 4 with alkenyl and aryl boronic acids and alkynes led after alkaline hydrolysis to a series of N,O-protected para -substituted phenylisoserines 6 . Coupling with 10-deacetyl-7, 10-O-diTroc-baccatin III followed by standard deprotections and acylation afforded the title analogs.

From Random Screening of Chemical Libraries to the Optimization of FPP-Competitive Inhibitors of Farnesyltransferase

Together with gene alterations of the p53 tumor suppressor gene, mutations of the ras genes represent the most frequent gene modification umancancers. Ras mutations are found in at least 90% of pancreas, 50% of colon, and 30% of both lung and thyroid cancers (1,2).