Synthesis and antitumor activity of peptide‐paclitaxel conjugates

Paclitaxel (Pac) is the most important anticancer drug used mainly in treatment of breast, lung, and ovarian cancer and is being investigated for use as a single agent for treatment of lung cancer, advanced head and neck cancers, and adenocarcinomas of the upper gastrointestinal tract. In this work, we present the synthesis of five 2′-paclitaxel-substituted analogs in which paclitaxel was covalently bound to peptides or as multiple copies to synthetic carriers. Ac-Cys(CH2CO-2′-Pac)-Arg-Gly-Asp-Arg-NH2, Folyl-Cys(CH2CO-2′-Pac)-Arg-Gly-Asp-Ser-NH2, Ac-[Lys-Aib-Cys(CH2CO-2′-Pac)]2-NH2, Ac-[Lys-Aib-Cys(CH2CO-2′-Pac)]3-NH2 and Ac-[Lys-Aib-Cys(CH2CO-2′-Pac)]4-NH2 were synthesized using 2′-halogeno-acetylated paclitaxel derivatives. Paclitaxel conjugates showed greater solubility in water than paclitaxel and inhibited the proliferation of human breast, prostate, and cervical cancer cell lines. Although all synthesized compounds had an antiproliferative activity, the Ac-[Lys-Aib-Cys(CH2CO-2′-Pac)]4-NH2 derivative showed improved biological activity in comparison with paclitaxel in cervical and prostate human cancer cells. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd.