Structural Modification Of Camptothecin As Antitumor Agents

With increasing incidence and mortality, cancer is the leading cause of death in China and is a major public health problem. Much of the rising burden is attributable to population growth and ageing and to sociodemographic changes. Limited efficacy in terms of impact on overall patient survival, toxicity and drug resistance is the major limitation and challenge of present chemotherapy. Therefore, development of novel antineoplastic drugs is urgently needed. As a result, approximately 60-70% of anticancer chemotherapeutic agents are natural products or derived from them, suggesting that by structural modification of natural products, it is still an efficient mean of finding clinical candidate compounds.Because of its unique anti-tumor mechanisms (DNA topoisomerase I inhibitor), camptothecin has been widespread interest, three camptothecin analogues (irinotecan, topotecan and belotecan) have been approved for clinical treatment, and a number of camptothecin derivatives are at various stages of clinical trials. But the disadvantage of CPT (low solubility in water and rapid inactivation due to the lactone ring opening at physiological pH) have not been overcame properly.Based on previous work of our laboratory group, a safe, economical method for the preparation of 2-amino-5-methoxylpropiophenone had been developed using 5-hydroxy-2-nitrobenzoic acid as starting material. Meanwhile, a novel series of homocamptothecin derivatives with a-OMe substituted E-rings had been designed and synthesized. All 15 derivatives showed comparable or superior cytotoxic activities to that of SN-38. Additionally, the water soluble compound WL-15 showed increased lactone stability and demonstrated a significant antitumor activity in a xenograft model. On the basis of these positive results, WL-15 displayed as a potential anticancer clinical trial candidate.Besides, microwave-promoted Suzuki coupling reaction was applied for the facile synthesis of 7-heteroarylcamptothecins, the in vitro antirumor activity results suggested that introduction of a proper heteroaryl group at 7-positions of CPT could promote potency to some extent. Finally, malignant tumor cells have been found to have high levels of reactive oxygen species such as hydrogen peroxide (H2O2), supporting the hypothesis that a prodrug could be activated by intracellular H2O2 and lead to a potential antitumor therapy. The 7-ethyl-10-boronic acid camptothecin Bl was synthesized for the first time, as prodrug of SN-38. Prodrug exhibited significant in vitro and in vivo antitumor activities, this strategy would be applied to the research and development of natural products.