State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources , Guangxi Normal University , Guilin , Guangxi 541004 , P. R. China.
Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease , China Pharmaceutical University , Nanjing , Jiangsu 210009 , P. R. China.
J Med Chem. 2019 Dec 12;62(23):10630-10644. doi: 10.1021/acs.jmedchem.9b00939. Epub 2019 Nov 21.
It is a great challenge to design drugs that penetrate the blood-brain barrier to inhibit brain tumor growth by acting against multiple targets and also improve their delivery efficacy and targeting ability to cancer cells. To overcome the above problems, we designed a multitarget metal agent for treating brain tumors based on an human serum albumin (HSA)-cell penetrating peptide conjugate. Thus, we rationally screened copper (Cu) and 2-acetyl-3-ethylpyrazine thiosemicarbazones to synthesize six compounds, and we investigated their structure-activity relationships and confirmed multiple mechanisms for brain glioma cells. The HSA- complex structure indicated that binds to the IIA subdomain of HSA and His242 replaces the Br ligand in in coordination with Cu. In vivo data suggested that both and the HSA--peptide conjugate penetrate the blood-brain barrier and inhibit brain tumor growth with few side effects. Furthermore, the HSA-peptide conjugate also improved the delivery efficacy and targeting ability of in vivo.
设计能够穿透血脑屏障的药物来抑制脑肿瘤生长，同时针对多个靶点，并提高其向癌细胞的输送效果和靶向能力，这是一项巨大的挑战。为了克服上述问题，我们基于人血清白蛋白（HSA）-细胞穿透肽偶联物，设计了一种用于治疗脑肿瘤的多靶金属试剂。因此，我们合理筛选了铜（Cu）和 2-乙酰基-3-乙基吡嗪硫代卡巴腙，以合成了六种化合物，并研究了它们的构效关系，确认了对脑胶质瘤细胞的多种作用机制。HSA-配合物结构表明，[CuL1]（L1 为 2-乙酰基-3-乙基吡嗪硫代卡巴腙）结合到 HSA 的 IIA 亚域，His242 取代配位的 Br 配体与 Cu 配位。体内数据表明，[CuL1]和 HSA--肽缀合物均能穿透血脑屏障，抑制脑肿瘤生长，且副作用较小。此外，HSA-肽缀合物还提高了[CuL1]在体内的输送效果和靶向能力。
