Design And Synthesis Of Boronic Acid-based Two-photon Absorption Photosensitizers And Peptide Boronates Proteasome Inhibitors

It is known that cell-surface carbohydrates have been associated with the development and progression of many types of cancers. One most specific example associated with the development and progression of human carcinomas is their ability to express fucosylated carbohydrates, which are important components of ligands involved in selectin-mediated cell adhesion and inflammatory responses. Recently, there has been a great deal of interest in using boronic acid compounds for the development of fluorescent sensors targeting monosaccharides and cell surface fucosylated carbohydrate structures. Photodynamic therapy (PDT) is a local light-activate treatment to destroy tumor tissues, particularly skin, esophageal, and lung cancers. The disadvantage of currently available PDT is the low penetration depth of the visible light because of the absorption and the scattering of biological tissues, meaning that this method cannot be applied to the treatment of deep cancers. Due to its merits of highly localized nonlinear excitation, intrinsic three-dimensional resolution and the possibility of an increased penetration depth in tissue, the use of two-photon absorption (2PA) in PDT becomes attractive.Consequently, in this thesis, the design and synthesis of a novel kind of boronic acid-based two-photon absorption photosensitizers targeting cell surface fucosylated carbohydrate has been described.Besides, Computer-aided drug design (CADD) has been employed to study the structure-activity relationship (SAR) of peptide boronates proteasome inhibitors. Based on the research result, two series of peptide boronates proteasome inhibitors have been designed and synthesized and in vitro antitumor tests against the tumor cells of MDA-MB-231 of the compounds have been evaluated in chapter 3. The details of this paper are as follows: 1. 34 new boronic acid-based two-photon absorption compouds targeting cell surface fucosylated carbohydrate has been designed, synthesized and characterized by NMR and MS spectrum.2. The binding affinities with D-glucose, D-galactose, L-fucose, D-frucose, D-xylose, has been examined; Also examined is the recognition of cell surface fucosylated carbohydrate.3. Single- and two-photon properties of compounds have been systematically investigated, the effect of molecular structure and solvent has also been discussed. With the strengthen of the donor, the single-photon absorption peaks, the single -photon fluorescence peaks and the two-photon fluorescence peaks all have redshifts, and the two-photon absorption cross-sections become bigger.4. Molecular field analysis (MFA) method was employed to construct peptide boronates proteasome inhibitors's 3D-QSAR model. The model was proved to be high-predictive by statistical data (q2 = 0.714) and accurate prediction of the compounds. Base on carefully analysis of protein-inhibitor interactions, also the results of references, we identified the character of peptide boronates proteasome inhibitors: the boronic acid was the key pharmacophore, good result may be obtained by the introduction of large hydrophobic moieties at the P2 site, alterations of the P1 and P3 sites may significantly change the binding properties of the inhibitor to the respective proteolytically active sites.5. Based on the character of peptide boronates proteasome inhibitors, two series of peptide boronates proteasome inhibitors have been designed, synthesized and characterized by NMR and MS spectrum. In vitro tests show that compounds exhibit no cytotoxicity against the tumor cells of MDA-MB-231. Work is in progress to evaluate the inhibitory effects of compounds 1-20 for proteasome.