Kang Changyu, Kim Jaejeong, Ju Sanghyun, Cho Heeyeong, Kim Hyun Young, Yoon In-Soo, Yoo Jin-Wook, Jung Yunjin
College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea.
Biotechnology & Therapeutic Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
Pharmaceutics. 2022 Dec 22;15(1):41. doi: 10.3390/pharmaceutics15010041.
We designed colon-targeted trans-cinnamic acid (tCA) and synthesized its conjugates with glutamic acid (tCA-GA) and aspartic acid (tCA-AA). We evaluated the anti-colitic activity of colon-targeted tCA using a dinitrobenzenesulfonic acid-induced rat colitis model. The conjugates lowered the distribution coefficient and Caco-2 cell permeability of tCA and converted to tCA in the cecum, with higher rates and percentages with tCA-GA than with tCA-AA. Following oral gavage, tCA-GA delivered a higher amount of tCA to the cecum and exhibited better anti-colitic effects than tCA and sulfasalazine (SSZ), which is the current treatment for inflammatory bowel disease. In the cellular assay, tCA acted as a full agonist of GPR109A (EC50: 530 µM). The anti-colitic effects of tCA-GA were significantly compromised by the co-administration of the GPR109A antagonist, mepenzolate. Collectively, colon-targeted tCA potentiated the anti-colitic activity of tCA by effectively activating GPR109A in the inflamed colon, enabling tCA to elicit therapeutic superiority over SSZ.
我们设计了结肠靶向的反式肉桂酸（tCA），并合成了其与谷氨酸（tCA-GA）和天冬氨酸（tCA-AA）的共轭物。我们使用二硝基苯磺酸诱导的大鼠结肠炎模型评估了结肠靶向tCA的抗结肠炎活性。这些共轭物降低了tCA的分配系数和Caco-2细胞通透性，并在盲肠中转化为tCA，tCA-GA的转化率和转化百分比高于tCA-AA。经口灌胃后，tCA-GA向盲肠输送了更高量的tCA，并且比tCA和柳氮磺胺吡啶（SSZ，目前用于治疗炎症性肠病的药物）表现出更好的抗结肠炎效果。在细胞试验中，tCA作为GPR109A的完全激动剂（半数有效浓度：530µM）。GPR109A拮抗剂甲哌卡因共同给药显著削弱了tCA-GA的抗结肠炎作用。总体而言，结肠靶向的tCA通过有效激活炎症结肠中的GPR109A增强了tCA的抗结肠炎活性，使tCA能够展现出优于SSZ的治疗优势。
