Sakurai M, Higashida S, Sugano M, Nishi T, Saito F, Ohata Y, Handa H, Komai T, Yagi R, Nishigaki T
Bioscience Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Chem Pharm Bull (Tokyo). 1993 Aug;41(8):1378-86. doi: 10.1248/cpb.41.1378.
Human immunodeficiency virus type 1 (HIV-1) protease inhibitors containing four types of hydroxyethylene dipeptide isosteres were designed and synthesized. These inhibitors consist of eight stereoisomers of phenylalanylproline (Phe-psi[H.E.]-Pro), four stereoisomers of phenylalanylalanine [Phe-psi[H.E.]-Ala), and one stereoisomer each of phenylalanylglycine (Phe-psi[H.E.]-Gly) and cyclohexylalanylalanine (Cha-psi[H.E.]-Ala) hydroxyethylene dipeptide isosteres. For the synthesis of the latter two isosteres, a newly developed synthetic method for gamma-lactone was applied. The inhibitory activities of these peptides were evaluated by cleavage assay of partially purified gag proteins or purified synthetic peptide. Of the inhibitors examined, compounds 2c (Z-Asn-(2S,3R,4S,5S)-Phe-psi[H.E.]-Pro-NHB(un); Bu(n) = n-butyl, Ki = 0.50 microM), 21a (Z-Asn-(2R,4S,5S)-Phe-psi[H.E.]-Ala- NHBu(n), Ki = 0.34 microM) and 23 (Z-Asn-(2R,4S,5S)-Cha-psi[H.E.]-Ala- NHBu(n), Ki = 0.46 microM) were moderately potent inhibitors. The results revealed that the alkyl substituent at C2 is essential, and the stereochemistry of the hydroxyethylene dipeptide isosteres greatly affected their inhibitory activities.
设计并合成了含有四种羟乙烯二肽类似物的1型人类免疫缺陷病毒（HIV-1）蛋白酶抑制剂。这些抑制剂由苯丙氨酰脯氨酸（Phe-ψ[H.E.]-Pro）的八种立体异构体、苯丙氨酰丙氨酸[Phe-ψ[H.E.]-Ala]的四种立体异构体以及苯丙氨酰甘氨酸（Phe-ψ[H.E.]-Gly）和环己基丙氨酰丙氨酸（Cha-ψ[H.E.]-Ala）羟乙烯二肽类似物的各一种立体异构体组成。对于后两种类似物的合成，应用了一种新开发的γ-内酯合成方法。通过对部分纯化的gag蛋白或纯化的合成肽进行切割试验来评估这些肽的抑制活性。在所检测的抑制剂中，化合物2c（Z-Asn-(2S,3R,4S,5S)-Phe-ψ[H.E.]-Pro-NHB(un)；Bu(n)=正丁基，Ki = 0.50微摩尔）、21a（Z-Asn-(2R,4S,5S)-Phe-ψ[H.E.]-Ala-NHBu(n)，Ki = 0.34微摩尔）和23（Z-Asn-(2R,4S,5S)-Cha-ψ[H.E.]-Ala-NHBu(n)，Ki = 0.46微摩尔）是中等效力的抑制剂。结果表明，C2处的烷基取代基至关重要，且羟乙烯二肽类似物的立体化学极大地影响了它们的抑制活性。
