Synthesis and Characterization of Three Novel Amphiphilic Aminated Hypocrellins as Photodynamic Therapeutic Agents¶

Abstract

To improve the amphiphilicities and red absorption of the hypocrellins, three novel 2‐amino‐2‐demethoxy‐hypocrellins were synthesized by the mild reactions of hypocrellin B with 4‐(2‐amino‐ethyl)morpholine, N,N‐dimethylethylenediamine and 1‐(2‐amino‐ethyl)piperazine, respectively. The structures of these derivatives were characterized with proton nuclear magnetic resonance, infrared and mass spectra (MS). The ultraviolet–visible absorption and fluorescence spectra of the derivatives were measured and the new amino‐substituted hypocrellins showed strong absorption in the domain of the phototherapeutic window (600–900 nm). Their amphiphilicities evaluated via the partition coefficients between n‐octanol and phosphate‐buffered saline buffer improved remarkably. Electron paramagnetic resonance spin‐trapping measurements were used to investigate the photodynamic action of the three compounds in the presence of oxygen. Singlet oxygen (1O2) and superoxide anion radical (O2•−) generated by illuminating the hypocrellin derivatives in aerobic solution were observed.

A novel elsinochrome A derivative: a study of drug delivery and photodynamic activity

“…Many hypocrellin derivatives have been synthesized to improve water-solubility, mainly by modification of the chemical structures. Among these, 13-sulfonated, 15 5-sulfonic acid-, 16 5,8-glycoside-, 17 5,8mercaptoacetic acid-, 18 5,8-sodium-cysteine- 19 and 5-cyclodextrin-20 substituted hypocrellins are almost completely water-soluble but lose PDT activity in vivo due to poor cellular uptake, 21 while 5-mercaptoacetic-acid-and 5-/5,8-mercaptoethanol-, 22,23 5-/5,8-cysteamine-, 24 2-amino-, 25 4,9-amino-, 26 17-amino-, 27 2-cyclohexylamino-, 28 2-butylamino-, 29 2-phenylmethylamino-, 30 2-morpholine/dimethylethylenediamine/piperazine-, 31 2-/2,17ethanolamino-, 32 2,17-peptide-, 33 2-diamino-34, 35 and 13/17-amino acid-36,37 substituted hypocrellins are PDT active but have water solubilities that are too low to enable drug solutions at clinically acceptable concentrations. In contrast, a bromine-substituted derivative has been reported for EA 38 but this did not show any improvement in solubility.…”

Near‐Infrared Hypocrellin Derivatives for Synergistic Photodynamic and Photothermal Therapy

“…In previous studies, functional groups, such as halogen, aliphatic amine, and amino acids, were introduced to a specific site in HB [25,30–36] . Different chemical modifications on HB induce variations in absorption properties and 1 O 2 yields [37–42] . Amino‐substituted HB derivatives at position 2 could remarkably enhance longer‐wavelength absorption bands near 600 nm compared with that of HB (Scheme 1).…”

Drug-delivery and multifunction possibilities of hypocrellin photosensitizers

“…48 Previously, a theoretical method was developed to evaluate the amphiphilicity of hypocrellin derivatives and a concept of quantitative amphiphilicity was proposed. 49 Evaluated based on this idea, mercapto, amino-acid, ethanolamine, morpholine, piperazine and dipeptide substituted hypocrellin derivatives exhibited higher solubility than their parents, [50][51][52][53][54] but the solubility was lower than the threshold of clinically required concentration as mentioned above. On the other hand, aliphatic amine, aromatic amine or bisamine substituted hypocrellin derivatives were even more lipophilic than their parents.…”