Medicinal chemistry of natural compound inspired scaffolds
Development of new compounds with antimetastatic activity
Metastasis accounts for more than 90% of cancer-related deaths. Despite recent advances in cancer therapies, the majority of patients with advanced-stage solid tumors die as a result of metastatic disease. Mechanisms of cancer cell migration and invasion have been intensively studied, nevertheless, cancer therapies are developed based on antiproliferative effect only. Migrastatics represent a new concept of drugs with a great potential to improve the outcome of the current cancer treatment strategies by inhibiting metastatic behavior of cancer cells.
Cytochalasans are natural actin-targeting compounds that have been thoroughly studied as possible cytostatics but they also show anti-metastatic effect at low concentrations. Our goal is to use rational design to prepare new synthetic cytochalasan analogues with antimetastatic activity. Based on molecular modelling, cytochalasan scaffold is modified at different parts in order to simplify its synthesis while keeping strong actin binding of new analogues. Then, we study structure-activity relationship. Antimetastatic activity screening of the new compounds is performed in collaboration with Brábek group at BIOCEV (Vestec).
As cytochalasans are poorly water-soluble, prodrug approach is applied in order to improve the water solubility of cytochalasans. Prodrug moieties bearing polar groups are attached to various sites of the cytochalasan scaffold and stability and solubility of these compounds is studied.
Our research is focused on development of migrastatics in a long term using natural product inspired scaffolds. In our projects we are combining synthesis of complex molecules and medicinal chemistry.
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