Design, Synthesis, And Photodynamic Property Studies Of Novel Hypocrellin Derivatives

Naturally occurring hypocrellins, including hypocrellin A (HA) and hypocrellin B (HB), are promising non-porphyrin type of photodynamic sensitizers. However, poor water solubility, small extinction coefficients in phototherapeutic window (600-900 nm), negligible affinity to biomolecules, and low photodynamic activity in hypoxic conditions limit their application in photodynamic therapy (PDT). In this dissertation, different strategies were applied to chemically modify HA and HB, and the resultant derivatives exhibit greatly improved photodynamic properties than the parent HA and HB. The detailed results are summarized as follows.1, Fifteen complexes of HA with rare earth trivalent ions (except Pm3+) along with the complex of HA with Sc3+ were prepared. All complexes exhibit red shifted absorption spectrum, increased absorbance above 600 nm, improved water solubility, and enhanced affinity to calf thymus DNA (CT DNA) over the parent HA. For ions that possess low energy excited states, including Ce3+, Pr3+, Nd3+, Sm3+, Eu3+, Tb3+, Dy3+, Ho3+, Er3+, Tm3+, and Yb3+, the corresponding complexes show undetectable or nearly undetectable fluorescence, triplet excited state lifetime, generation of reactive oxygen species (ROS), and photodamage onto CT DNA. In contrast, for ions that do not possess low energy excited states, including Sc3+, Y3+, La3+, Gd3+, and Lu3+, the corresponding complexes exhibit higher photodamage abilities onto CT DNA with respect to HA, benefited from both their comparable or even higher 1O2 quantum yields than HA and their electrostatic affinity to DNA.2, Three long-wavelength absorbing dipeptide-modified HB derivatives, Gly-HB, Tyr-HB, and Trp-HB, were designed and prepared. Tyr-HB and Trp-HB distinguish themselves from Gly-HB and HB remarkably by their significantly improved efficiencies to generate semiquinone anion radicals, superoxide anion radicals, and hydroxyl radicals, as well as their affinity to CT DNA, as the result of the electron-donating properties and intercalating abilities of tyrosine and tryptophan groups. Tyr-HB and Trp-HB show remarkably enhanced photodamage capabilities on CT DNA than their parent HB in aerobic conditions. Moreover, they possess moderate photodamage abilities on CT DNA even in anaerobic conditions, indicating the role of Type I mechanism in their photodynamic behaviors.3, A ferrocene-modified hypocrellin B (Fc-HB) was designed and synthesized. It is found that the roles of the ferrocene functionality are threefold: (1) improving the water solubility of Fc-HB via the supramolecular interaction with 2-hydroxypropyl-β-cyclodextrin; (2) facilitating the generation of semiquinone anion radical and superoxide anion radical via the photoinduced intramolecular electron transfer from ferrocene to hypocrellin B moieties; and (3) promoting the transformation of the superoxide anion radical to hydroxyl radical via the catalysis of the in-situ generated ferrocenium ions. Accordingly, Fc-HB can photodamage CT DNA more efficiently than HB in both aerobic and anaerobic conditions.4, Fourω-amino acid modified HB derivatives were designed and synthesized. Compared to HB, their water solubility is enhanced significantly, and more importantly, their lipophilic and hydrophilic features can be effectively tuned by simply varying the length of the saturated aliphatic chain involved inω-amino acids. Above mentioned chemical modification strategies may provide guidelines for further improvements of photodynamic activities of not only hypocrellins but also other types of photosensitizers.