Biotechnology and Bioprocess Engineering 2021; 26(6): 933-955  
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
EunJeong Yoon, DuBok Choi, InSun Yu, and Hoon Cho
EunJeong Yoon, InSun Yu, Hoon Cho*
Department of Biochemical & Polymer Engineering, Chosun University, Gwangju 61452, Korea
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Dubok Choi
Faculty of Advanced Industry Convergence, Chosun University, Gwangju 61452, Korea
Eunjeong Yoon and Dubok Choi equally contributed to this paper as first authors
Received: March 24, 2021; Revised: May 24, 2021; Accepted: May 30, 2021; Published online: December 31, 2021.
© The Korean Society for Biotechnology and Bioengineering. All rights reserved.

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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 E2 (PGE2) release, and wound healing effect. Of the synthesized compounds, compound 29 was identified as the best 15-PGDH inhibitor, with an IC50 value of 0.0131 μM. To determine whether the synthesized inhibitors increased the intracellular amount of PGE2, the PGE2 concentration in A549 cells was measured. The compound that resulted in the highest increase in PGE2 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 PGE2 levels to aid in wound healing. Therefore, they could be employed in the therapeutic management of diseases requiring elevated PGE2 levels.
Keywords: 2,4-dioxothiazolidin-5-ylidene, structure-activity relationship study, PGE2, wound healing activity

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