Anti-cancer Drug Paclitaxel And Immunostimulants Muramic Acid Peptide Conjugate Of Chemical Biology Research

Taxol^? (Paclitaxel) has shown great clinical promise against a wide variety of tumors, especially against ovarian, breast, and lung cancers. However, reports have also indicated that the limitations of taxol due to lower aqueous insolubility, dose-limiting toxicity, multidrug-resistance (MDR) and immunosuppression render it less than an ideal drug. To overcome these problems, it is necessary searching for novel promising taxol analogues as anticancer drug candidates. Taxol acts not only by preventing the assembly of tubulin into microtubules, but also approved as lipopolysaccharide (LPS) mimetic targeting at macrophages, which does enhance murine macrophage cells to produce TNF-α in both normal host and tumor-bearing host. On the basis of the research acheivements on MDP in our group, we hypothesize that a synergism between MDP and taxol must occur when both of them meet macrophage. We then considered to chemically conjugating both MDP and paclitaxel and wish that we could discover a molecule in combination of chemotherapy and immunotherapy for cancer treatment. As far as we know, there is no report of both biology and chemistry through chemical conjugation of them.The structure-activity relationships (SAR) of taxol have been extensively studied. Knowledge of the SAR of taxol will help in the design and synthesis of new analogues with improved physical, chemical and biological properties. According to these knowledge, there are three sites on paclitaxel where can potentially link MDP. Our interest for chemistry, herein, is in developing a highly efficient method of synthesis of MDP and paclitaxel conjugates. In this thesis, we are reporting for the first time the synthesis of the most promising new conjugates with both "taxol-like" and "MDP-like" activity. Taxol was bound via its hydroxyl group or amino group to Muramyl dipeptide (MDP) by means of a succinic acid linker and an amino acid "spacer", the linker was introduced into the 2'- or 7-hydroxyl group of the paclitaxel through an ester bond and 3'-amino group through an amide bond. The total synthesis of the three series of muramyl dipeptide (MDP) and taxol conjugates has been...