Brusatol, a quassinoid natural product, is effective against multiple diseases including hematologic malignancies, as we reported recently by targeting the PI3Kγ isoform, but toxicity limits its further development. Herein, we report the synthesis of a series of conjugates of brusatol with amino acids and short peptides at its enolic hydroxyl at C-3. A number of conjugates with smaller amino acids and peptides demonstrated activities comparable to brusatol. Through in vitro and in vivo evaluations, we identified UPB-26, a conjugate of brusatol with a L- β-homoalanine, which exhibits good chemical stability at physiological pH's (SGF and SIF), moderate rate of conversion to brusatol in both human and rat plasmas, improved mouse liver microsomal stability, and most encouragingly, enhanced safety compared to brusatol in mice upon IP administration.

如我们最近以PI3Kγ亚型为靶点报道的那样，一种类天然天然产物Brusatol可有效抵抗多种疾病，包括血液系统恶性肿瘤，但毒性限制了它的进一步发展。在本文中，我们报道了在C-3的烯醇羟基处合成一系列Brusatol与氨基酸和短肽的缀合物。许多具有较小氨基酸和肽的结合物显示出与Brusatol相当的活性。通过体外和体内评估，我们确定了UPB-26，这是一种Brusatol与L-β-高丙氨酸的共轭物，在生理pH值（SGF和SIF）下表现出良好的化学稳定性，在人和人体内都具有中等的向Brusatol的转化率大鼠血浆，改善了小鼠肝脏微粒体的稳定性，最令人鼓舞的是，