Design,Synthesis And Bioactivities Of Phenalenone And Azobenzene Photoresponsive Compounds

As an external physical stimulus,light participates in the regulation of a variety of chemical and life processes.In the field of medicine,the main researches are focued on photodynamic therapy and photopharmacology.Photodynamic therapy can utilize photosensitizers to absorb light energy and transfer it to oxygen to produce singlet oxygen,thereby exhibiting anti-tumor,insecticidal,and bactericidal activities.Photodynamics relies on the formation of reactive oxygen species and has no selectivity for specific molecular targets.So,its application is limited to situations where cell death must be evoked.The principle of photopharmacology is to introduce light switch molecules,such as azobenzene,into biologically active molecules,and the isomerization of light will change the molecular shape and size,etc.,so as to achieve the purpose of photoswitchable biological activity.This method is usually aimed at specific targets,using light to precisely control biologically active targets in time and space.Hence,in this paper,on the one hand,based on the structure of phenalenone,new structural photosensitizers were developed.On the other hand,photoisomerization active molecules were synthesized based on the azobenzene and their photoisomerization properties and biological activities were studied.1.As an efficient type Ⅱ photosensitizer,the singlet oxygen quantum yield of phenalenone(PN)is almost 100%,however its excitation wave length is very short and located in the ultraviolet region.Since the structure of carbonyl-phenacen-2,3-dicarboxylic imides is similar to phenalenone,we believe these compounds can also be used as photosensitizers.In this chapter,a series of compounds containing carbonyl-phenacen-2,3-dicarboxylic imide was synthesized and their photosensitive properties were investigated.Compared with PN,the excitation wavelength of synthetic compounds was red shifted by the closed conjugation system that located in the visible region(>430 nm).And their phototoxicity bioassay activities against 4th Aedes aegypti were tested.The phototoxicity of 4th Aedes aegypti indicated that the phototoxicity of compound A5(LCso=2.08 μg mL-1)was slightly higher compare with PN(LC50=3.10 μg mL-1),but its dark toxicity(LC50>100 μg mL-1)was much lower than that of PN(LC50=16 μg mL-1),indicating the increased security and selectivity.Thus,the difference of phototoxicity between light and dark makes these molecules as potential type Ⅱphotosensitizer.2.In this chapter,based on the similarity of phenalenone structure,oxoisoaporphines and their derivatives may be considered as photosensitizers for singlet oxygen production.Here 6 closed cyclic oxoisoaporphines derivatives were synthesized.And the photosensitive properties and biological activities of the compounds were studied.Photophysical and chemical properties tests indicated these compounds can be efficient type Ⅱ photosensitizers.The experiment on 4th Aedes aegypti mosquito larvae showed that phototoxicities of B1(LC50=0.88 μg mL-1),B4(LC50=0.88 μg mL-1)and B6(LC50=0.19 μg mL-1)were better than that of PN(LC50=3.10μg mL-1).In addition,the phototoxicities are not affected by mosquito resistance,and the phototoxicities of these compounds could also be excited under sunlight.Due to the high fluorescence quantum of B6 is 0.70,which means this compound can be used as a fluorescent indicator to observe the changes of intestinal tissue in Aedes aegypti larvae before and after illumination.The photodynamic cell experiments in vitro also showed that these compounds have excellent phototoxicity and can be used as a kind of potential effective photosensitive agents.Especially for B5,the IC50 to HeLa was 1.26 μM under light stimulation,and the fluorescence quantum yield(ΦF)is 0.60 in water,which means this molecule can be as theranostic agent for simultaneous fluorescence imaging and photodynamic therapy photosensitizer.This provides a new idea for the development of functional photosensitizer that integrated diagnosis and therapy.3.Sorafenib is a kind of diarylureas multikinase inhibitors.In the chapter,the C ring of sorafenib is replaced with an azobenzene structure containing different substituents.19 compounds were synthesized and their photoisomerization properties studied.It was expected that intramolecular hydrogen bond interactions could be formed between diarylureas and azobenzene substituents in trans state.The azobenzene could be isomerized by light to cis state and the intramolecular hydrogen bonding force was disappeared.In this way,the purpose of light-regulated biological activity could be achieved.However,the cis conversion and half-time of ortho azobenzene introduced into diarylureas is low since the intramolecular hydrogen bonding force.And the introduction of meta-azobenzene has little interference to the whole molecule.While the introduction of meta-azobenzene has too little interference to the whole molecule;the half life of para-azobenzene in cis state is too short(<48 h).None of them achieves the purpose of photoswitchable biological activity.4.In view of the fact that the introduction of azobenzene into the C-ring of sorafenib did not achieve the purpose of photocontrolled biological activity,11 compounds were synthesized by introducing azobenzene with different substituents directly into the hydrophobic part of Aring of sorafenib.Besides their photoisomerization properties and cell viabilities in vitro were tested.Among them,the activities of compound F7 substituted by meta-2,6-difluoroazobenzene were significantly different before and after irradiation at the cellular level.The IC50 value of trans-F7 on HepG2 cells was 12.74 μM,higher than that of cis-F7(2.74 μM).The activity difference between cis and trans isomers could be 4.6 times,indicating the purpose of regulating biological activity by light of compound F7.