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

A large number of C-4 paclitaxel analogs have been prepared in the cou rse of our systematic C-4 modification. These include C-4 esters, carb onates, 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 pote nt analogs emerging from these in vitro assays were further evaluated in vivo. With the exception of paclitaxel side chain bearing C-4 carba mates and C-4 aromatic esters, most of the C-4 aliphatic esters and ca rbonates were found to possess comparable or superior activity to pacl itaxel in vitro. Several C-4 aliphatic esters and carbonates also exhi bited in vivo activities against i.p. implanted murine M-109 lung carc inoma.