Cai R Z, Radulovic S, Pinski J, Nagy A, Redding T W, Olsen D B, Schally A V
Endocrine, Polypeptide and Cancer Institute, Veterans Administration Medical Center, New Orleans, LA 70146.
Peptides. 1992 Mar-Apr;13(2):267-71. doi: 10.1016/0196-9781(92)90107-e.
Seven new antagonists of bombesin (Bn)/gastrin-releasing peptide (GRP) containing C-terminal Trp or Tpi (2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3-carboxylic acid) in a reduced peptide bond were synthesized by solid phase methods and evaluated biologically. The reduced bond in four [Leu13 psi(CH2NH)Trp14]Bn(6-14) analogs was formed by reductive alkylation at the dipeptide stage. In the case of three [Leu13 psi(CH2N)Tpi14]Bn(6-14) analogs, the Trp dipeptide with reduced bond was reacted with formaldehyde to form the corresponding Tpi derivative. These Tpi-containing analogs have a new reduced bond which is structurally more constrained. Leu13 psi(CH2N)Tpi14 analogs inhibit [125I][Tyr4]bombesin binding to Swiss 3T3 cells with IC50 values of 2-4 nM, compared to 5-10 nM for Leu13 psi(CH2NH)Trp14 analogs. Leu13 psi(CH2N)Tpi14 analogs are also more potent than Leu13 psi(CH2NH)Trp14 analogs in growth inhibition studies using Swiss 3T3 cells. The two best bombesin antagonists of this series, [D-Trp6,Leu13 psi(CH2N)Tpi14]Bn(6-14) (RC-3415) and [Tpi6,Leu13 psi(CH2N)Tpi14]Bn(6-14) (RC-3440), inhibited GRP-stimulated growth of Swiss 3T3 cells with IC50 values less than 1 nM. RC-3440 was also active in vivo, suppressing GRP(14-27)-stimulated serum gastrin secretion in rats. Bombesin/GRP antagonists, such as RC-3440, containing the new reduced bond (CH2N) reported herein are very potent.
通过固相法合成了7种新的含有C端色氨酸或Tpi（2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸）且肽键还原的蛙皮素（Bn）/胃泌素释放肽（GRP）拮抗剂，并进行了生物学评估。4种[Leu13 ψ(CH2NH)Trp14]Bn(6-14)类似物中的还原键是在二肽阶段通过还原烷基化形成的。对于3种[Leu13 ψ(CH2N)Tpi14]Bn(6-14)类似物，将具有还原键的色氨酸二肽与甲醛反应形成相应的Tpi衍生物。这些含Tpi的类似物具有一个结构上更受限的新还原键。Leu13 ψ(CH2N)Tpi14类似物抑制[125I][Tyr4]蛙皮素与瑞士3T3细胞结合的IC50值为2-4 nM，而Leu13 ψ(CH2NH)Trp14类似物的IC50值为5-10 nM。在使用瑞士3T3细胞的生长抑制研究中，Leu13 ψ(CH2N)Tpi14类似物也比Leu13 ψ(CH2NH)Trp14类似物更有效。该系列中两种最佳的蛙皮素拮抗剂，[D-Trp6,Leu13 ψ(CH2N)Tpi14]Bn(6-14)（RC-3415）和[Tpi6,Leu13 ψ(CH2N)Tpi14]Bn(6-14)（RC-3440），抑制瑞士3T3细胞中GRP刺激生长的IC50值小于1 nM。RC-3440在体内也有活性，可抑制大鼠中GRP(14-27)刺激的血清胃泌素分泌。本文报道的含有新还原键（CH2N）的蛙皮素/GRP拮抗剂，如RC-3440，非常有效。
