Design, Synthesis, Mechanism And Biological Activity Of Chlorin-type Photosensitizer

Photodynamic therapy(PDT)had developed into one of the mainstream of cancer treatment,photosensitizer is the core.Chlorin the second generation of photosensitizer are receiving considerable attention owing to their intense absorption in near infrared region,low dark toxicities,rapid clearance from normal tissue and low cutaneous phototoxicity etc.In our previous studies,a series of novel chlorin-type PSs were designed and synthesized using crude chlorophyll extracts from Chinese traditional herb named silkworm excrement as the starting material.The main contents of this dissertation were taken purple-18 as the lead compound,designed and synthesized 26 new compounds,and the results showed that several compounds having excellent photodynamic antitumor activity in virto.1.Design,Synthesis,Mechanism and Biological Activity of Chlorin P6-based Water-soluble DerivativesIn our previous research,a plurality of chlorin class lead compounds were obtained by degradation of silkworm excrement.Based on these,and according with the designed strategies of marketed drugs verteporfin and talaporfin,a series of new water-soluble amino acid conjugates of chlorin P6 dimethylester(5)and BCPD-18MA(11)containing glutamyl or aspartyl residues were synthesized and investigated for PDT antitumor efficacy.Results indicated that the phototoxicity of photosensitizer which had modified with amino acid rediues had a certain degree of reduction,but the dark toxicity was decreased greater.In particular,7b is a promising photosensitizer for PDT applications due to its strong absorption in the phototherapeutic window relatively high 1O2 quantum yield,hightest dark cytotoxicity/phototoxicity ratio,good water-solubility and excellent in vivo PDT antitumor efficacy.In addition,structure-activity relationship studies showed that aspartic acid superior to glutamic acid.2.Design,Synthesis and Antitumor Activity of Chlorin DerivativesA large number of research data and our previous studied results all showed that introduction of ether groups into chorin photosensitizer molecule can effectively improve their antitumor activity.So we introduced different ethers into purple-18 and Chlorin p6 dimethylester containing glutamyl or aspartyl residues,and had synthesized 20 compounds.In vitro antitumor activity tests showed that most of the compounds have potent phototoxicity,especially compounds 14 d,15d and 17 h possess high dark cytotoxicity/phototoxicity ratio,which superior to verteporfin.In summary,we through modified purple-18,designed and synthesized 26 new compounds.The noveltly of this work lies in that:(1)Taking silkworm excrements as raw materials,realized the utilization of waste products;(2)Introducing amino into photosensitizer,greatly improved aqueous solubility and significantly reduced dark toxicity of photosensitizer;(3)A new promising photosensitizer was designed and synthesized,which showed more phototoxic,less dark toxic and better in vivo photodynamic antitumor efficacy than verteporfin.The results from the present thesis laid a foundation for the development of new photosensitizer drug candidates.