Cytoprotective Effects of Water Soluble Dihydropyrimidinthione Derivative Against UV-B Induced Human Corneal Epithelial Cell Photodamage

Abstract

Excessive UV-B exposure is well known to be a risk factor for corneal phototoxicity including direct DNA damage and disturbances in the antioxidant balance. Here, we showed a successful synthesis of a water-soluble and biocompatible small molecule DHPM 1 with dihydropyrimidinthione skeleton, which could effectively protect human corneal epithelial (HCE-2) cells from UV-B damage. In separate experiments, DHPM 1 absorbed UV-B rays and exhibited scavenging activity against intracellular ROS induced by UV-B radiation, thereby reducing the levels of DNA fragmentation. Additionally, UV-B exposure increased the expression of cleaved caspase-3, as well as the ratio of Bax/Bcl-2 at protein levels, while pretreatment with DHPM 1 significantly reversed these changes. To the best of our knowledge, this is the first report of a study based on dihydropyrimidinthione derivatives to develop a promising eye drops, which may well find extensive applications in UV-B caused corneal damage.

Efficient Synthesis and Evaluation of Novel Sulfonated Dihydropyrimidinthione Derivatives for the Treatment of UV‐B‐Induced Corneal Damage

“…Cell viability analysis showed 6 showed remarkable protective effect (70% at 0.1 mg mL −1 ). Encouragingly, 0.2 mg mL −1 6 can keep cell viability at 93%, which was equivalent to that of cis ‐UCA (0.1 mg mL −1 ) or DHPM 1 (0.5 mg mL −1 ) (18,23). The molar concentrations of 0.2 mg mL −1 6 , 0.1 mg mL −1 cis ‐UCA and 0.5 mg mL −1 DHPM 1 are 540, 724 and 562 μM, respectively, suggesting compound 6 has a better UV‐B resistance capacities than cis ‐UCA .…”

“…With raw materials 1 , 2b and 3 , Biginelli reaction was comparatively clean under the conditions of acetic acid (both as acid catalyst agent and solvent), anhydrous magnesium chloride (as desiccant) and sealed tube reaction to 100°C for 2 h. The work‐up process to get 4b was achieved by preparative HPLC. For the synthesis of 6 , the key intermediate 5 was synthesized following our previously reported procedure (18). Then, taurine was condensed with intermediate 5 in the presence of HATU.…”

“…In order to find potential anticorneal photodamage agents, we designed two novel sulfonated DHPMs 4b and 6 , which were prepared by simple and convenient methods. The structural stability was also enhanced to some extent compared to that of DHPM 1 and cis ‐UCA , which contain unstable phosphate group and cis double bond, respectively (9,18). The presence of sulfonic acid group onto phenyl ring causes a significant improvement in the solubility of compound 4b (>50 mg mL −1 in PBS) but moderate biocompatibility (57% at 5.0 mg mL −1 ).…”

“…HRMS calcd for C Synthesis of compound 6. Compound 5 was synthesized following our previously reported procedure (18). To a solution of 5 (0.5 g, 1.9 mmol) in DMF (10 mL), Taurine (0.4 g, 3.2 mmol), HATU (1.4 g, 3.7 mmol) and DIEA (0.5 g, 3.9 mmol) was added, then the resulting mixture was stirred at room temperature for 2 h. After completion, the mixture was concentrated and the residue was then purified by HPLC to afford the product 6 (0.…”

“…1) as an alternative option to provide the excellent protection in UV‐B damage on ocular surface. DHPM 1 could protect the exposed HCE‐2 cells in a dose‐dependent manner, especially ~100% protection at 0.5 mg mL −1 (18). However, DHPM 1 solution needs to be prepared immediately before its use, which is attributed to the molecular structure of unstable phosphotyrosine.…”