The Research Of Novel Chlorin Photosensitizers And Cyclohexalipopeptide Of Antifungal Agents

In this thesis, our research work are independently composed of two parts. Firstly, funded by the National "863" Program of China(N0.2002AA233091), our research work is performed on the total synthesis of cyclohexalipopeptide antifungal agents. A total synthesis approach of novel cyclohexalipopeptidyl bisamine compounds is designed and high potent lead compounds are successfully synthesized. Secondly, granted by the National Natural Science Foundation of China(NO. 3037 1737), our reseach work is performed on the semisynthesis of novel chlorin photosensitizers for PDT treatment of cancer using low-cost silkworm excrement crude chlorophyll extracts as starting material and several novel high potent photosensitizing antitumor benzochloroporphyrin derivatives(BCPD) are successfully synthesized. Among them, 3 target compounds show much the same photodynamic efficacy in vitro on liver cancer BEL-7402 cells as Verteporfin and nearly 100-fold decrease of their dark toxicity than Verteporfin. In conclusion, our research work will contribute to the development of high potent, low toxic novel antifungal and photosensitizing antitumor drugs with exclusive ownership of intellectual property rights.1. The studies on total synthesis of novel cyclohexalipopeptides antifungal agentsFungal infection in human, especially life-threatening deep fungi infections, has been increasing. The patients under long-term treatment with broad-spectrum antibiotics or glucocorticosteroids , immunocompromised patients who have received cancer chemotherapy and immunosuppressive therapy for organ transplants, and AIDS patients are particularly susceptible to fungal infections. Considering the difficulty to treat serious deep fungi infections, fungi resistance to the available drugs, limited antifungal spectrum and side effects of clinical antifungal agents, it is necessory for researchers to search for novel, high potent, low toxic fungicidal agents with broad-spectrum and good selectivity,which are of novel modes of action and new target of action. 1,3-Glucan synthetase of fungal cell wall is one of such new targets.P-l,3-Glucan is present as the major structural carbo-hydrate component in the cell wall of many pathogenic fungi. The producing enzyme, 1,3-glucan synthetase, is a membrane-bound protein utilizing UDP-glucose as the substrate for polymer synthesis. Along with other components, including a GDP-binding protein, this complex extrudes glucan microfibrils into the interstitial space of the cell where other glycosyltransferases complete the crosslinking steps required to construct the growing cell wall. It has been shown that interference of this process leads to a weakened cell wall and sub-sequent cell content leakage due to the internal osmoticpressure ultimately results in cell death.p-l,3-Glucan is one of the components primarily responsible for the structure of the fungal cell wall and is not present in mammalian cells, and it is therefore an attractive target for antifungal agents. Indeed, natural product such as cyclohexalipopeptide pneumocandins and echinocandins as well as the glycolipid papulacandins, which are known p-l,3-glucan synthase inhibitors, show high potent antifungal activity against Candida albicans and Aspergillus fumigatus and have been evaluated as potential therapeutics for the last two decades. As a result, MK-0991 (caspofungin acetate; Cancidas) and FK463 (Micafungin; Funguard), two semisynthetic analogues of pneumocandin Bo and pneumocandin Ao, have been developed as broad-spectrum parenteral drugs for the treatment of aspergillosis and candidiasis.Because of the limitation of the studies on semisynthesis of echinocandins and pneumocandins, we set out to investigate the total synthesis of cyclohexalipopeptides in order to futher elucidate the structure-activity relationship. Accorging to the known structure-activity relationship of echinocandins and pneumocandins, and based on the structural characteristic of caspofungin, a total synthesis approach of caspofungin analogues- novel cyclo...