Synthesis and bio-evaluation of novel hypocrellin derivatives: Potential photosensitizers for photodynamic therapy of age-related macular degeneration

• Two hypocrellin derivatives 3 and 4 were designed and synthesized for PDT of AMD.
• They exhibited the maximal absorption around yellow-orange light.
• 4 exhibited more photodynamic activity than 3 or its parent in vitro or in vivo.
• The vascular leakage of 4 was close to its parent.
• 4 is more suitable for PDT of AMD than 3.

The phototherapeutic window from 600 to 900 nm is necessary for photodynamic therapy (PDT) of solid tumors, but may not suitable for PDT of some microvascular diseases, like age-related macular degeneration (AMD), because of its deep penetration. Moreover, absorption of some neighboring photoreceptors should be avoided for PDT of AMD. Considering these, yellow-orange light may be a proper phototherapeutic window of AMD. Herein, two novel amino-alkyl-sulfonic acid-substituted hypocrellin B derivatives, 3 and 4 were designed and synthesized. They exhibited the maximal absorption at yellow-orange light, and possessed higher PDT activity than 2, proved by the in vitro or in vivo experiments. Besides, 4 showed much higher PDT activity than 3, ascribed to its higher cellular uptake suggested by its optimized amphiphilicity and liposome–mimic results. And the vascular leakage of 4 was close to 2. Consequently, 4 has great potential for PDT of AMD or other superficial diseases.