Lo Concordia C L, Joaquin Daniel, Moyá Diego A, Ramos Alexander, Kastner David W, White Stephen M, Christensen Blake L, Naglich Joseph G, Degnen William J, Castle Steven L
Department of Chemistry and Biochemistry, Brigham Young University Provo UT 84602 USA
Bristol Myers Squibb, Research & Early Development, Mechanistic Pharmacology-Leads Discovery & Optimization Rte 206 & Province Line Rd Princeton NJ 08543 USA.
Chem Sci. 2022 Jan 3;13(7):1899-1905. doi: 10.1039/d1sc05992k. eCollection 2022 Feb 16.
Two full-length analogs of the anticancer peptide yaku'amide A (1a) and four partial structures have been synthesized. These analogs were identified by computational studies in which the three - and -ΔIle residues of the natural product were replaced by the more accessible dehydroamino acids ΔVal and ΔEnv. Of the eight possible analogs, modeling showed that the targeted structures 2a and 2b most closely resembled the three-dimensional structure of 1a. Synthesis of 2a and 2b followed a convergent route that was streamlined by the absence of ΔIle in the targets. Screening of the compounds against various cancer cell lines revealed that 2a and 2b mimic the potent anticancer activity of 1a, thereby validating the computational studies.
已合成了抗癌肽矢车酰胺A（1a）的两种全长类似物和四种部分结构。通过计算研究鉴定了这些类似物，其中天然产物的三个-ΔIle残基被更容易获得的脱氢氨基酸ΔVal和ΔEnv取代。在八种可能的类似物中，建模显示目标结构2a和2b与1a的三维结构最为相似。2a和2b的合成采用了一种收敛路线，由于目标中不存在ΔIle，该路线得到了简化。针对各种癌细胞系对这些化合物进行筛选，结果表明2a和2b模拟了1a的强效抗癌活性，从而验证了计算研究的结果。
