세포 내의 PGE₂농도 조절을 위한 2,4-dioxothiazolidin-5-ylidene 유도체 합성 및 활성평가

Abstract

The prostaglandins (PGs) are a group of important lipid compound mediators and have been found in almost every cell in human body. They are synthesized from arachidonic acid (AA) released from the cell membrane when the cell is activated by a physical or chemical stimulation. The released AA is metabolized into PGH2 and then to different derivatives by various enzymes. The prostaglandin E₂(PGE2) among them is known to have an important role in body function as an important factor for reproduction, inflammatory regulation, wound healing, peptic ulcer, neuroendocrine and immune system regulation, contraction and expansion of blood vessel and regulation of blood pressure. However, as PGE₂is quickly metabolized by 15-PGDH using NAD+ as the accessory factor, it has a very short half-life in the body. Therefore, 15-PGDH must be inhibited for the therapeutic management of diseases requiring elevated PGE2 levels. In this study, I synthesized various 15-PGDH inhibitors based on thiazolidinedione, which is known to inhibit 15-PGDH, and conducted activity evaluation. The activity evaluation showed, while most synthesized compounds had good inhibiting effects, the best 15-PGDH inhibitor was the compound 29 (Z)-2-bromo-4 -((2,4-dioxothiazolidin-5-ylidene)methyl)phenyl 4-phenylbutanoate with the IC50 value of 0.0145. To check whether the synthesized inhibitor increases the amount of PGE2 inside a cell, PGE2 concentration in the A549 cell was measured. The most effective compound for increasing the PGE2 concentration was the compound 44 which increased the concentration to 579% level. A scratch would healing assay using the HaCaT cell was conducted to check whether the compounds that's howed outstanding inhibiting effect and PGE2 concentration improvement could also treat the wound well. The assay confirmed that the compound promoted the cell proliferation after 24 hours and was effective in wound healing. The results confirmed that the compounds inactivated 15-PGDH and increased the PGE2 level to help wound healing and was expected to help therapeutic management of diseases requiring elevated prostaglandin E2 levels.