Jianmei Wei

Taxol structure-activity relationships: Synthesis and biological evaluation of 2-deoxytaxol

2-Deoxy taxol 2 was prepared in nine steps from baccatin III; the key step of the synthesis is a Barton-type deoxygenation at C-2. The compound was found to possess much reduced antitumor activity with respect to taxol.

The chemistry of taxanes: reaction of taxol and baccatin derivatives with Lewis acids in aprotic and protic media

Abstract Several Lewis acids were shown to cleanly open the oxetane ring of taxol and baccatin derivatives. The reaction is shown to proceed via anchimeric assistance by the C-4 acetate group. Several minor products, including a novel derivative possessing a bridged C-ring, were also isolated. A mechanistic rationale is provided for all compounds formed. When taxol derivatives were treated with Lewis acids in methanol, ester cleavage reactions were observed. We provide conditions that are selective for C-10 acetate cleavage and for C-13 side-chain methanolysis.

Structure-activity relationships of taxol®: synthesis and biological evaluation of C2 taxol analogs

Abstract Red-Al was used to selectively remove the C 2 benzoate of 7,13-bisTES baccatin ( 8 ). Derivatization of the resulting C 2 hydroxy compound provided the corresponding p-nitrophenyl carbamate, the p-methoxy and p-nitrobenzoates, and cyclohexyl ester. Attachment of the taxol side chain to the above four analogs via lactam ( 15 ) followed by desilylation provided five analogs of taxol modified at the C 2 position, including a C 1,2 cyclic carbonate. These five analogs were less potent than taxol in a tubulin polymerization assay and a cytotoxicity assay against human colon cancer cell line.

NOVEL C-4 PACLITAXEL (TAXOL) ANALOGS : POTENT ANTITUMOR AGENTS

Abstract A large number of C-4 paclitaxel analogs have been prepared in the course of our systematic C-4 modification. These include C-4 esters, carbonates, carbamates as well as a C-4 deacetyl derivative. All of these analogs were evaluated in a tubulin polymerization assay as well as in a cytotoxicity assay against a human colon cancer cell line. The potent analogs emerging from these in vitro assays were further evaluated in vivo. With the exception of paclitaxel side chain bearing C-4 carbamates and C-4 aromatic esters, most of the C-4 aliphatic esters and carbonates were found to possess comparable or superior activity to paclitaxel in vitro. Several C-4 aliphatic esters and carbonates also exhibited in vivo activities against i.p. implanted murine M-109 lung carcinoma.

Taxol® structure-activity relationships: synthesis and biological evaluation of taxol analogs modified at C-7

Abstract A series of taxol derivatives, modified at C-7, is described. This includes sulfonate, silylether, ester, carbonate, carbamate, fluoro, dehydro and deoxy derivatives. Biological evaluation shows that these modifications do not usually significantly compromise activity. However, none of the C-7 analogs prepared thus far have been shown to be better than taxol in both in vitro and in vivo assays.

An approach to the identification of potent inhibitors of influenza virus fusion using parallel synthesis methodology

Structure-activity studies associated with the salicylic acid-derived inhibitor of influenza fusion, BMY-27709, were examined using a parallel synthesis approach. This SAR survey led to the discovery of potent influenza inhibitory activity in a series of aromatic amides and thioamides derived from 1,3,3-trimethyl-5-hydroxycyclohexylmethylamine. Select compounds were characterized as inhibitors of the H1 subtype of influenza A viruses that act by preventing the pH-induced fusion process, thereby blocking viral entry into host cells. In a plaque-reduction assay, the most potent inhibitors displayed EC(50) values of 0.02-0.14 microg/mL.

Salicylamide inhibitors of influenza virus fusion

Structural variation of the quinolizidine heterocycle of the influenza fusion inhibitor BMY-27709 was examined by several topological dissections in order to illuminate the critical features of the ring system. This exercise resulted in the identification of a series of synthetically more accessible decahydroquinolines that retained the structural elements of BMY-27709 important for antiviral activity. The 2-methyl-cis-decahydroquinoline 6f was the most potent influenza inhibitor identified that demonstrated an EC50 of 90 ng/mL in a plaque reduction assay.

A facile synthesis of 7,10-dideoxy taxol and 7-epi-10-deoxy taxol

Abstract 7,10-Dideoxy taxol 2 was prepared from baccatin III in 4 steps via the Barton deoxygenation reaction. Similarly, 7-epi-10-deoxy taxol 3 was prepared in one step from 7-epi taxol in high yield. The key reaction was the tributyllin hydride- mediated direct reduction of the C 10 acetate.