ABSTRACT
5-Aminolevulinic acid (ALA) and its derivatives, serving as the endogenous precursor of the photosensitizer (PS) protoporphyrin IX (PpIX), successfully applied in tumor imaging and photodynamic therapy (PDT). ALA and its derivatives have been used to treat actinic keratosis (AK), basal cell carcinoma (BCC), and improve the detection of superficial bladder cancer. However, the high hydrophilicity of ALA and the conversion of PpIX to heme have limited the accumulation of PpIX, hindering the efficiency and potential application of ALA-PDT. This study aims to evaluate the PDT activity of three rationally designed series of ALA-HPO prodrugs, which were based on enhancing the lipophilicity of the prodrugs and reducing the labile iron pool (LIP) through HPO iron chelators to promote PpIX accumulation. Twenty-four ALA-HPO conjugates, incorporating amide, amino acid, and ester linkages, were synthesized. Most of the conjugates, exhibited no dark-toxicity to cells, according to bioactivity evaluation. Ester conjugates 19a-g showed promoted phototoxicity when tested on tumor cell lines, and this increased phototoxicity was strongly correlated with elevated PpIX levels. Among them, conjugate 19c emerged as the most promising (HeLa, IC50 = 24.25 ± 1.43 µM; MCF-7, IC50 = 43.30 ± 1.76 µM; A375, IC50 = 28.03 ± 1.00 µM), displaying superior photodynamic anticancer activity to ALA (IC50 > 100 µM). At a concentration of 80 µM, the fluorescence intensity of PpIX induced by compound 19c in HeLa, MCF-7, and A375 cells was 18.9, 5.3, and 2.8 times higher, respectively, than that induced by ALA. In conclusion, cellular phototoxicity showed a strong correlation with intracellular PpIX fluorescence levels, indicating the potential application of ALA-HPO conjugates in ALA-PDT.
Subject(s)
Aminolevulinic Acid , Antineoplastic Agents , Drug Screening Assays, Antitumor , Photochemotherapy , Photosensitizing Agents , Humans , Aminolevulinic Acid/pharmacology , Aminolevulinic Acid/chemistry , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , Photosensitizing Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Structure-Activity Relationship , Molecular Structure , Pyridones/pharmacology , Pyridones/chemistry , Pyridones/chemical synthesis , Cell Line, Tumor , Protoporphyrins/chemistry , Protoporphyrins/pharmacology , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Cell Survival/drug effects , Prodrugs/pharmacology , Prodrugs/chemistry , Prodrugs/chemical synthesisABSTRACT
The rapid enantioselective synthesis of valuable building blocks and pharmaceutically important compounds from easily accessible precursors is one of the major areas of focus in organic chemistry. In this context, 2-activated 1,3-enyne has emerged as a powerful synthon in recent years for the efficient synthesis of enantioenriched furans, allenes, 4-H-pyrans, and 4-isoxazolines, which are privileged scaffolds in bioactive compounds and natural products. This review will cover the history of the development of 2-activated 1,3-enyne in enantioselective synthesis along with the corresponding mechanisms, which may motivate further development in this area to forge more complex and valuable molecules.