School of Pharmacy, Guangdong Medical University, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China; Institute of Biomedicine, College of Life Science & Technology, Jinan University, Guangzhou, Guangdong, 510632, China.
School of Pharmacy, Guangdong Medical University, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China.
Eur J Med Chem. 2019 Jul 15;174:181-197. doi: 10.1016/j.ejmech.2019.04.042. Epub 2019 Apr 22.
The scarcity of hematopoietic stem cells (HSCs) significantly hindered their clinical potentials. Umbilical cord blood (UCB) has become the leading source of HSCs for both research and clinical applications. But the low content of HSCs in a single UCB unit limited its use only to pediatric patients. Various cytokines and small molecules have demonstrated strong abilities in promoting HSC ex vivo expansion, of which UM171 is the newest and by far the most potent HSC ex vivo expansion agent. In this study, we synthesized 37 pyrimidoindole analogs and identified 6 compounds to be potent in promoting HSC ex vivo expansion. In particular, analog 11 was found to be the most effective in stimulating ex vivo expansion of UCB CD34 cells and CD34CD38 cells. Initial data indicated that compound 11 promoted the absolute number of long term HSCs and inhibited their differentiation. UCB HSCs expanded with 11 retained adequate multi-lineage differentiation capacity. In addition, compound 11 is not cytotoxic at its test concentrations, suggesting that it merits further investigation for potential clinical applications.
造血干细胞（HSCs）的稀缺性极大地限制了其临床应用潜力。脐带血（UCB）已成为 HSCs 在研究和临床应用中的主要来源。但是，单个 UCB 单位中 HSCs 的含量较低，这限制了其仅用于儿科患者。各种细胞因子和小分子已被证明具有很强的促进 HSC 体外扩增的能力，其中 UM171 是最新的、迄今为止最有效的 HSC 体外扩增剂。在这项研究中，我们合成了 37 种嘧啶并吲哚类似物，并鉴定出 6 种具有促进 HSC 体外扩增能力的化合物。特别是，类似物 11 被发现能够最有效地刺激 UCB CD34 细胞和 CD34CD38 细胞的体外扩增。初步数据表明，化合物 11 可促进长期 HSCs 的绝对数量，并抑制其分化。用 11 扩增的 UCB HSCs 保持了足够的多谱系分化能力。此外，化合物 11 在其测试浓度下没有细胞毒性，这表明它值得进一步研究，以探索其在潜在临床应用中的价值。
