ABSTRACT
High photodynamic activity was observed for hexadeca-cationic zinc, magnesium, and metal-free phthalocyanines (Pcs) and tetrapyrazinoporphyrazines with EC50 values as low as 5 nM (MCF-7 cells) for the best compound; this activity was several times better than that of clinically established photosensitizers verteporfin, temoporfin, S3AlOHPc, or protoporphyrin IX. This lead compound was characterized by low dark toxicity (TC50 = 369 µM), high efficiency against other cell lines (HCT 116 and HeLa), and possible activation by light above 680 nm. The excellent photodynamic activity resulted from the rigid spatial arrangement of the quaternized triazole moieties above and below the Pc core, as confirmed by X-ray crystallography. The triazole moieties thus formed two "cationic donuts" that protected the hydrophobic core against aggregation in water. The lysosomes were found to be the site of subcellular localization and were consequently the primary targets of photodynamic injury, resulting in predominantly necrotic cell death.
Subject(s)
Indoles/chemistry , Photosensitizing Agents/chemistry , Porphyrins/chemistry , Pyrazoles/chemistry , Triazoles/chemistry , Cell Line, Tumor , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Humans , Indoles/chemical synthesis , Indoles/pharmacology , Isoindoles , Lysosomes/metabolism , Molecular Conformation , Necrosis , Photochemotherapy , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/pharmacology , Porphyrins/chemical synthesis , Porphyrins/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/pharmacologyABSTRACT
The new 1,3,4-oxadiazolylquinoxaline ring system was synthesized by the condensation of the quinoxaline 1,4-dioxide acid hydrazide 6 with acetyl chloride in one-pot synthesis. In which the hydrazide was refluxed in excess of acetyl chloride, acetic anhydride or acetic acid in the presence of phosphorus oxychloride forming the 1,3,4-oxadiazolylquinoxaline ring system. Molecular modeling studies have been performed to evaluate their recognition at the hDHFR binding-pocket as potential hDHFR inhibitors. The antibacterial properties of these compounds showed reasonable activities towards gram negative bacteria, Escherichia coli. Compound 20 performed appropriate complementarity study rather well; the conserved amino acids of hDHFR enzyme imitating the MTX docking pattern. Besides, compound 20 showed highest antibacterial activity against E. coli in comparison with the well known bacteriostatic chloramphenicol; the pyrazolyl analogues also have moderate affinity toward the applied bacteria.
