Darwish Shaban, Parang Keykavous, Marshall John, Goebel Dennis J, Tiwari Rakesh
Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, California 92618, USA.
Organometallic and Organometalloid Chemistry Department, National Research Centre, El Bohouth st., Dokki, Giza, Egypt.
Tetrahedron Lett. 2017 Aug 2;58(31):3053-3056. doi: 10.1016/j.tetlet.2017.06.066. Epub 2017 Jun 23.
CN2097 (RCs-sCYK[KTE(β-Ala)]V) is a rationally designed peptidomimetic that shows effectiveness in preclinical models for the treatment of neurological disorders, such as Angelman syndrome, traumatic brain injury (TBI) and stroke. Because of its therapeutic activity for the treatment of human CNS disorders, there was an urgent need to develop an efficient strategy for large-scale synthesis of CN2097. The synthesis of CN2097 was accomplished using Fmoc/tBu solid phase chemistry in multiple steps. Two different peptide fragments (activated polyarginine peptide Npys-sCR and CYK[KTE(β-Ala)]V) were synthesized, followed by solution phase coupling in water. Activation of the polyarginine (CR) was achieved in situ during cleavage of protected peptide (C(Trt)R(Pbf)) from the Rink amide resin using 5 equiv. of 2,2-dithopyridine in TFA:TIS:HO (95:2.5:2.5, v/v/v) for 4 h. The disulfide coupling was efficient which provided a 60% yield.
CN2097（RCs-sCYK[KTE(β-丙氨酸)]V）是一种经过合理设计的拟肽，在治疗神经系统疾病（如天使综合征、创伤性脑损伤（TBI）和中风）的临床前模型中显示出有效性。由于其对治疗人类中枢神经系统疾病的治疗活性，迫切需要开发一种高效的大规模合成CN2097的策略。CN2097的合成通过多步Fmoc/tBu固相化学完成。合成了两个不同的肽片段（活化的聚精氨酸肽Npys-sCR和CYK[KTE(β-丙氨酸)]V），然后在水中进行溶液相偶联。使用5当量的2,2-二硫代吡啶在TFA:TIS:HO（95:2.5:2.5，v/v/v）中从Rink酰胺树脂上切割保护肽（C(Trt)R(Pbf)）时，聚精氨酸（CR）原位活化4小时。二硫键偶联效率高，产率为60%。
