New sensitizers for photodynamic therapy. Controlled synthesis of purpurins and their effect on normal tissue

Abstract

Purpurins are a class of porphyrin derivative that have been shown to have good in vivo cytotoxicity to N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) induced rat bladder tumors (AY-27) implanted into Fisher 344 rats. The synthesis of purpurins from etioporphyrin I and coproporphyrin I proceeds in high yield and with a high degree of regioselectivity. Product formation can be rationalized in terms of relief of steric strain about the periphery of the purpurin macrocycle. The effect of therapeutic light doses using the rat footpad model suggests that, at therapeutic sensitizer doses, normal tissue damage is within acceptable limits, particularly for metalated purpurins.

Separation of porphyrin-based photosensitizer isomers by laser-induced fluorescence capillary electrophoresis

“…The stock solutions were stored at 47C in the dark to prevent their degradation and photobleaching during storage. Tin ethyl etiopurpurin (SnET2, 5) was synthesized as described by Morgan et al [34,35]. A stock solution was prepared by weighting 1.0 mg of 5 and dissolving it in 1.0 mL DMSO.…”

Tin ethyl etiopurpurin significantly inhibits vascular smooth muscle cell proliferation in vivo

“…These compounds are initially delivered to all cells of the recipient. After a latency period, the photosensitizers tend to accumulate in rapidly proliferating cells while they are cleared from cells with a normal metabolic rate (Luna et al 1994;Morgan et al 1989;Manyak et al 1988). This dichotomy produces elevated levels of the photosensitizer in hyperproliferating cells, often 5-to 10-fold higher than in normal cells, which can be exploited in a selective therapy.…”

Stability of Tin Etiopurpurin¶

“…The tin etiopurpurin (SnET2) is a well‐known photosensitizing agent with documented efficacy against a variety of malignant cell types (1–6). SnET2 localizes in lysosomes and the endoplasmic reticulum (ER), and subsequent photodamage results in the rapid initiation of apoptosis (7, 8).…”

“…Synthetic procedures Synthesis of SnET2 (Fig. 1) was carried out using a modification of published procedures (1–6), as described in Fig. 2.…”