Synthesis and Structure-activity Relationship Study of 2,4-dioxothiazolidin-5-ylidene Derivatives for 15-hydroxyprostaglandin Dehydrogenase Inhibitory Activity, Prostaglandin E2 Release, and Wound Healing Effect

• Published in: Biotechnology and bioprocess engineering 2021-12, Vol.26 (6), p.933-955
• Main Authors: Yoon, EunJeong, Choi, DuBok, Yu, InSun, Cho, Hoon
• Format: Article
• Language: English
• Subjects: 15-Hydroxyprostaglandin dehydrogenase (NAD+); Biotechnology; Cell culture; Chemistry; Chemistry and Materials Science; Dehydrogenase; Dehydrogenases; Disease management; Growth factors; Industrial and Production Engineering; Phosphonates; Prostaglandin E2; Regeneration; Research Paper; Synthesis; Transforming growth factor-b1; Wound healing
• ISSN: 1226-8372; 1976-3816
• DOI: 10.1007/s12257-021-0071-8

The aim of this study was to investigate the synthesis and structure-activity relationship of 2,4-dioxothiazolidin-5-ylidene derivatives for 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitory activity, prostaglandin E 2 (PGE 2 ) release, and wound healing effect. Of the synthesized compounds, compound 29 was identified as the best 15-PGDH inhibitor, with an IC 50 value of 0.0131 µM. To determine whether the synthesized inhibitors increased the intracellular amount of PGE 2 , the PGE 2 concentration in A549 cells was measured. The compound that resulted in the highest increase in PGE 2 concentration was (Z)-4-(2,4-dioxothiazolidin-5-ylidene)methyl-2-methyl-2-methylphenyl-4-phosphonate (compound 59; increase = 579%). Compound 89 resulted in the second highest increase of 389.2%, followed by compounds 14 and 29 (third and fourth, respectively). Compounds 59, 89, 14, and 29 caused evidently faster cell regeneration than the negative control after 24 h of culture, and the cells treated with the compounds grew as much as those treated with the cell growth factor, TGF-β1, which served as the positive control. In fact, cells treated with the compounds were found to grow approximately 5.0-fold larger than cells treated with the negative control. When cells were treated with different concentrations of compounds 59 and 89, the scratches could be recovered with concentrations below 5.0 µM. In fact, the recovery was approximately 2.5-fold higher than that with the negative control. Collectively, these results confirm that compounds 59 and 89 could inactivate 15-PGDH and increase PGE 2 levels to aid in wound healing. Therefore, they could be employed in the therapeutic management of diseases requiring elevated PGE 2 levels.