Kobayakawa Takuya, Matsuzaki Yudai, Hozumi Kentaro, Nomura Wataru, Nomizu Motoyoshi, Tamamura Hirokazu
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan.
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-039, Japan.
ACS Med Chem Lett. 2017 Dec 27;9(1):6-10. doi: 10.1021/acsmedchemlett.7b00234. eCollection 2018 Jan 11.
The first rapid and efficient chemical synthesis of a cyclic Arg-Gly-Asp (RGD) peptide containing a chloroalkene dipeptide isostere (CADI) is reported. By a developed synthetic method, an --butylsulfonyl protected CADI was obtained utilizing diastereoselective allylic alkylation as a key reaction. This CADI was also transformed into an -Fmoc protected CADI in a few steps. The CADI was used in Fmoc-based solid-phase peptide synthesis. The first synthesis of a CADI-containing cyclic RGD peptide was successful, and the synthesized CADI-containing peptidomimetic was found to be a more potent inhibitor against integrin-mediated cell attachment than the parent cyclic peptide.
报道了含氯代烯烃二肽类似物（CADI）的环状精氨酸-甘氨酸-天冬氨酸（RGD）肽的首次快速高效化学合成。通过一种改进的合成方法，以非对映选择性烯丙基烷基化作为关键反应，得到了叔丁基磺酰基保护的CADI。该CADI也可通过几步反应转化为芴甲氧羰基（Fmoc）保护的CADI。CADI用于基于Fmoc的固相肽合成。含CADI的环状RGD肽首次合成成功，并且发现合成的含CADI的拟肽对整合素介导的细胞黏附的抑制作用比母体环状肽更强。
