Cai R Z, Reile H, Armatis P, Schally A V
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, LA 70146.
Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12664-8. doi: 10.1073/pnas.91.26.12664.
Various pseudononapeptide bombesin (BN)-(6-14) antagonists with a reduced peptide bond (CH2-NH) between positions 13 and 14 can suppress the mitogenic activity of BN or gastrin-releasing peptide in 3T3 fibroblast cells and small cell lung carcinoma. In the search for more potent BN antagonists, 10 modified nonapeptide BN antagonists containing N-terminal D-Phe, D-Cpa, and D- or L-Tpi and C-terminal Leu-psi(CH2-N)-Tac-NH2, Leu-psi(CH2-N)-MeTac-NH2, or Leu-psi(CH2-N)-Me2Tac-NH2 have been synthesized by incubating [13 psi 14,CH2-NH,Cys14]BN-(6-14) or [13 psi 14-CH2-NH,Pen14]BN-(6-14) with formaldehyde or acetaldehyde (Cpa = 4-chlorophenylalanine, Tac = thiazolidine-4-carboxylic acid, Tpi = 2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-3-carboxylic acid, and Pen = penicillamine). The biological activities of these compounds were then evaluated. [D-Phe6,13 psi 14,CH2-N,Tac14]BN-(6-14) (RC-3950-II) and [D-Phe6,13 psi 14,CH2-N,Me2Tac14]BN-(6-14) (RC-3985-II) exhibited greater potency in inhibition of 125I-labeled [Tyr4]BN binding to Swiss 3T3 cells than their parent compounds [D-Phe6,13 psi 14,CH2-NH,Cys14]BN-(6-14) (RC-3950-I) and [D-Phe6,13 psi 14,CH2-NH,Pen14]BN-(6-14) (RC-3985-I). The order of binding affinities of these compounds was as follows: [13 psi 14,CH2-N,Tac14]BN-(6-14) > [13 psi 14,CH2-N,Me2Tac14]BN-(6-14) > [13 psi 14,CH2-N,MeTac14]BN-(6-14). In most cases, the analogs with C-terminal Leu-psi(CH2-N)-Tac-NH2 were also more potent growth inhibitors of 3T3 cells than compounds containing C-terminal Leu-psi(CH2-N)-Me2Tac-NH2 or Leu-psi(CH2-N)-MeTac-NH2. The best BN antagonists of this series, RC-3950-II and [D-Cpa6,13 psi 14,CH2-N,Tac14]BN- (6-14) (RC-3925-II), inhibited gastrin-releasing peptide-stimulated growth of Swiss 3T3 cells with IC50 values of 1 nM and 6 nM, respectively. Since antagonists of this class inhibit growth of various tumors in animal cancer models, some of them may have clinical applications.
各种在13位和14位之间具有减少肽键（CH2-NH）的拟九肽蛙皮素（BN）-（6-14）拮抗剂可抑制BN或胃泌素释放肽在3T3成纤维细胞和小细胞肺癌中的促有丝分裂活性。为了寻找更有效的BN拮抗剂，通过将[13ψ14，CH2-NH，Cys14]BN-（6-14）或[13ψ14-CH2-NH，Pen14]BN-（6-14）与甲醛或乙醛孵育，合成了10种修饰的九肽BN拮抗剂，其N端为D-Phe、D-Cpa和D-或L-Tpi，C端为Leu-ψ（CH2-N）-Tac-NH2、Leu-ψ（CH2-N）-MeTac-NH2或Leu-ψ（CH2-N）-Me2Tac-NH2（Cpa = 4-氯苯丙氨酸，Tac = 噻唑烷-4-羧酸，Tpi = 2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸，Pen = 青霉胺）。然后评估了这些化合物的生物活性。[D-Phe6，13ψ14，CH2-N，Tac14]BN-（6-14）（RC-3950-II）和[D-Phe6，13ψ14，CH2-N，Me2Tac14]BN-（6-14）（RC-3985-II）在抑制125I标记的[Tyr4]BN与瑞士3T3细胞结合方面比其母体化合物[D-Phe6，13ψ14，CH2-NH，Cys14]BN-（6-14）（RC-3950-I）和[D-Phe6，13ψ14，CH2-NH，Pen14]BN-（6-14）（RC-3985-I）表现出更高的效力。这些化合物的结合亲和力顺序如下：[13ψ14，CH2-N，Tac14]BN-（6-14）>[13ψ14，CH2-N，Me2Tac14]BN-（6-14）>[13ψ14，CH2-N，MeTac14]BN-（6-14）。在大多数情况下，具有C端Leu-ψ（CH2-N）-Tac-NH2的类似物也是比含有C端Leu-ψ（CH2-N）-Me2Tac-NH2或Leu-ψ（CH2-N）-MeTac-NH2的化合物更有效的3T3细胞生长抑制剂。该系列中最好的BN拮抗剂，RC-3950-II和[D-Cpa6，13ψ14，CH2-N，Tac14]BN-（6-14）（RC-3925-II），分别以1 nM和6 nM的IC50值抑制胃泌素释放肽刺激的瑞士3T3细胞生长。由于这类拮抗剂在动物癌症模型中可抑制各种肿瘤的生长，其中一些可能具有临床应用价值。
