Reconstitution, Structural Modification And Targeting Design Of Diindolyl Alkaloids

Vinblastine-type alkaloids are indolyl dimer of alkaloids, such as vinblastinewhich was isolated firstly from Catharanthus roseus. So far, there are hundreds ofdiindolyl-type alkaloids isolated from nature products or synthesized artificially.Many of them, are very effective to treat cancer, such as vinblastine, vincristine,vindesine and vinorelbine，which have been used for many years in the treatment oftumor in clinic. However, their severe side effects such as neurotoxicity and tissuedamage have limited their clinical application. Therefore, it is very significant tosearch for compounds with high effectiveness and low toxicity by structuralmodification. This dissertation is consisted of two parts.In part one, structural modification and reconstitution of vinblastine have beencarried on. Based on the common structural characteristics of vinca alkaloids, bothcatharanthine-catharanthine and vindoline-vindoline dimers have been designed. Thecatharanthine-catharanthine dimer was successfully synthesized through the couplingreaction between catharanthine and hydrogenated catharanthine under the catalysis ofFeCl3. An effective method for selective reduction of catharanthine has also beendeveloped. In the meantime, ring enlargement of vindoline and vinblastine have alsobeen investigated. Totally12compounds have been synthesized in this part, in whichfive of them are diindolyl alkaloids.In part two, six Z-GP-NHNH vinca alkaloid adducts have been designed andsynthesized using vinblastine, vincristine, vinorelbine, vinflunine, catharanthine andvindoline as starting materials respectively. The introduction of Z-GP fragment is inthe purpose of reducing the toxic side effects of parent compounds, which wassuggested for targeting the adducts to the tumor specific express enzyme, namely theFAPα. In this part, totally17compounds, including6targeting compounds have beensynthesized. The preliminary in vitro pharmacological investigations discloses that allthe adducts are able to be targeted to FAPα resulted in the decrease of theircytotoxicities.