H-Asp(OBn)-Phe-NH2 trifluoroacetate | 60058-91-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: H-Asp(OBn)-Phe-NH2 trifluoroacetate
• 英文别名: H-Asp(OBzl)-Phe-NH2*TFA；TFA*H-Asp(OBzl)-Phe-NH2；H-Asp(OBn)-OH；benzyl (3S)-3-amino-4-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-4-oxobutanoate;2,2,2-trifluoroacetic acid
• CAS: 60058-91-5
• 化学式: C₂HF₃O₂*C₂₀H₂₃N₃O₄
• 分子量: 483.444
• InChiKey: OMEROALAGPWLQP-QJHJCNPRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.29
• 重原子数：
  34.0
• 可旋转键数：
  9.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  161.81
• 氢给体数：
  4.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  H-Asp(OBn)-Phe-NH2 trifluoroacetate 、 (tert-butyloxycarbonyl)-L-tryptophyl-L-leucinal 在 sodium cyanoborohydride 作用下， 以 甲醇 、 溶剂黄146 为溶剂， 反应 1.0h， 以65%的产率得到(tert-butyloxycarbonyl)-L-tryptophyl-L-leucyl-ψ(CH2-NH)-β-benzyl-L-aspartyl-L-phenylalanine amide
  参考文献：
  名称：

  Synthesis and biological activities of some pseudo-peptide analogs of tetragastrin: the importance of the peptide backbone

  摘要：

  Pseudo-peptide analogues of the C-terminal tetrapeptide of gastrin, in which a peptide bond has been replaced by a CH2-NH bond, i.e. (tert-butyloxycarbonyl)-L-tryptophyl-psi (CH2-NH)-L-leucyl-L-aspartyl-L-phenylalanine amide (8), (tert-butyloxycarbonyl)-L-tryptophyl-L-leucyl-psi (CH2-NH)-L-aspartyl-L-phenylalanine amide (13), (tert-butyloxycarbonyl)-L-tryptophyl-L-leucyl-L-aspartyl-psi (CH2NH)-L-phenylalanine amide (20), were synthesized. The pseudo-peptides 8 and 13 were shown to have the same affinity as (tert-butyloxycarbonyl)-L-tryptophyl-L-leucyl-L-aspartyl-L-phenylalanine amide (21) for the gastrin receptor on isolated mucosal cells. The pseudo-peptide 20 exhibited lower affinity (IC50 congruent to 10(-5) M). The biological activity of these pseudo-peptides was studied on acid secretion in the anesthetized rat. Compound 8 stimulated acid secretion, identically with that of 21. Compound 13 did not exhibit any agonist activity but was able to antagonize the action of gastrin (ED50 = 0.3 mg/kg). Compound 20 did not show any agonist activity but was able to inhibit gastrin-induced acid secretion, with lower potency (ED50 = 15 mg/kg). The importance of the peptide bonds in the mode of action of gastrin is discussed, and a hypothetical approach of the mechanism of action is presented.

  DOI：

  10.1021/jm00150a020
• 作为产物：
  描述：

  L-苯丙氨酰胺盐酸盐 在 N-羟基丁二酰亚胺 、 三乙胺 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 H-Asp(OBn)-Phe-NH2 trifluoroacetate
  参考文献：
  名称：

  CCK-B agonist or antagonist activities of structurally hindered and peptidase-resistant Boc-CCK4 derivatives

  摘要：

  Replacement of Met31 by (N-Me)Nle in CCK8 or CCK4 has been shown to improve the affinity and selectivity for CCK-B receptors. In order to obtain molecules with enhanced bioavailability, two novel series of protected tetrapeptides of the general formula Boc-Trp30-X-Asp-Y33 have been developed. Introduction of (N-Me)Nle and the bulky, aromatic naphthylalaninamide (Nal-NH2) in positions X and Y, respectively, does not greatly modify the affinity for guinea pig brain CCK-B receptors. In contrast, incorporation of hindering N-methyl amino acids such as (N-Me)Phe, (N-Me)Phg, or (N-Me)Chg, but not their non-methylated counterparts, in position X induced a large decrease in affinity for the CCK-B binding sites. Among the various peptides synthesized, Boc-[(N-Me)Nle31,1Nal-NH233]CCK4 (2) (K(I) = 2.8 nM), Boc-[Phg31,1Nal-NH233]CCK4 (15) (K(I) = 14 nM), and Boc-[Phg31,1Nal-N(CH3)233]CCK4 (17) (K(I) = 39 nM) displayed good affinities for brain CCK-B receptors and had good selectivity ratios. These pseudopeptides, in which the presence of unnatural and hydrophobic residues is expected to improve their penetration of the central nervous system, were shown to be very resistant to brain peptidases. Interestingly, whereas compounds 2 and 15 proved to be full agonists for rat hippocampal CCK-B receptors when measured in an electrophysiological assay, compound 17 behaved as a potent antagonist in the same test and displayed a good affinity in rat brain K(I)(CCK-B) = 51 nM as compared to the Merck antagonist L365,260, K(I)(CCK-B) = 12 nM. This illustrates a simple means to obtain CCK-B antagonists and suggests that the free, CONH2 group plays a critical role in the recognition of the agonist date of brain CCK-B receptors.

  DOI：

  10.1021/jm00053a022

文献信息

• Boc-Trp-Orn(Z)-Asp-NH2 and derivatives: a new family of CCK antagonists
  作者：R. Gonzalez-Muniz、F. Bergeron、I. Marseigne、C. Durieux、Bernard P. Roques

  DOI：10.1021/jm00174a016

  日期：1990.12

  (Z) and of the N-terminal tripeptide moiety in the antagonist properties of the cholecystokinin CCK8 analogue Boc-[Nle28,Orn(Z)31]CCK27-33 (Marseigne et al. J. Med. Chem. 1988, 31, 966.) were studied with the following derivatives: Boc-[Nle28,Orn(X)31]CCK27-33, Boc[Nle28,Orn(X)31]CCK27-32, Boc-[Orn(X)31]CCK30-33, and Boc-[Orn(X)31]CCK30-32 (X = Z, Boc, H). These derivatives, the synthesis of eight of

  苄氧羰基（Z）和N端三肽部分在胆囊收缩素CCK8类似物Boc- [Nle28，Orn（Z）31] CCK27-33的拮抗特性中的各自作用（Marseigne et al.J.Med。 Chem。1988，31，966.）研究了以下衍生物：Boc- [Nle28，Orn（X）31] CCK27-33，Boc [Nle28，Orn（X）31] CCK27-32，Boc- [Orn（ X）31] CCK30-33和Boc- [Orn（X）31] CCK30-32（X = Z，Boc，H）。测试了这些衍生物的合成，此处报道了其中的八种衍生物的合成，以测试它们抑制[3H] pCCK8与豚鼠胰腺和脑膜结合的能力，以及刺激豚鼠胰腺痤疮淀粉酶释放的能力。Z衍生物均不产生淀粉酶分泌，但它们竞争性拮抗CCK8诱导的刺激。N末端三肽和/或Phe-NH2（33）残基的缺失在识别外周受体和这些肽的活性中不发挥关键作
• A study on endocrine disorder in patients with chronic renal failure. I. Synthesis and biological activity of human gastrin I.
  作者：TAKASHI ABIKO、IKUKO ONODERA、HIROSHI SEKINO

  DOI：10.1248/cpb.30.2604

  日期：——

  A heptadecapeptide amide, H-Pyr-Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2, corresponding to the entire amino acid sequence of human gastric I, was synthesized by the solution method. This peptide inhibited lactate dehydrogenase activity by 87.6% at a concentration of 300 pg/ml. This peptide was tested for suppression of PHA-induced lymphocyte proliferation, but showed no significant activity.

  一种十七肽酰胺H-Pyr-Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2，对应于人胃泌素I的整个氨基酸序列，通过溶液法合成。该肽在300 pg/ml的浓度下抑制乳酸脱氢酶活性达87.6%。该肽被测试用于抑制PHA诱导的淋巴细胞增殖，但未显示出显著活性。
• Investigation of peripheral cholecystokinin receptor heterogeneity by cyclic and related linear analogs of CCK26-33. Synthesis and biological properties
  作者：Bruno Charpentier、Christiane Durieux、Isabelle Menant、Bernard P. Roques

  DOI：10.1021/jm00389a002

  日期：1987.6

  by a D-Lys residue in Boc[Nle28,31]CCK27-33, a derivative as active as CCK8. The linear peptide Boc-Asp-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 was cyclized through amide bond formation between the side chains of Asp26 and D-Lys29 to give the peptide Boc-Asp-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2. Analogues 1 and 2 were shown to stimulate secretion of amylase from rat pancreas with a potency that

  通过替换柔性Gly29残基，研究了CCK26-33 [Asp-Tyr（SO3H）-Met-Gly-Trp-Met-Asp-Phe-NH2]（CCK8）周围受体的可能异质性在CCK8折叠中，通过Boc [Nle28，31] CCK27-33中的D-Lys残基，具有与CCK8同样活性的衍生物。线性肽Boc-Asp-Tyr（SO3H）-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2通过Asp26和D-Lys29侧链之间的酰胺键形成环化，得到肽Boc-Asp -Tyr（SO3H）-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2。已显示类似物1和2刺激大鼠胰腺淀粉酶的分泌，其效力分别比CCK8低40和80倍。相反，两种肽均作为CCK8诱导的豚鼠回肠收缩的弱拮抗剂（EC50约为10（-5）M）。尽管它们的C末端Asp32残基发生酰胺化，但从1和2中除去苯丙氨酸获得的肽3和4在所
• Schoen, Istvan; Szirtes, Tamas; Rill, Attila, Journal of the Chemical Society. Perkin transactions I, 1991, # 12, p. 3213 - 3223
  作者：Schoen, Istvan、Szirtes, Tamas、Rill, Attila、Balogh, Gabor、Vadasz, Zsolt、et al.

  DOI：——

  日期：——
• Synthesis and biological activity of CCK heptapeptide analogs. Effects of conformational constraints and standard modifications on receptor subtype selectivity, functional activity in vitro, and appetite suppression in vivo
  作者：Mark W. Holladay、Michael J. Bennett、Michael D. Tufano、C. W. Lin、Karen E. Asin、David G. Witte、Thomas R. Miller、Bruce R. Bianchi、A. L. Nikkel

  DOI：10.1021/jm00094a001

  日期：1992.8

  A series of modifications of the CCK7 analogue (des-NH2)Tyr(SO3-)-Nle-Gly-Trp-Nle-Asp-Phe-NH2 was prepared and tested for binding to guinea pig CCK-A and CCK-B receptors and in CCK-A-mediated functional assays. Selected analogues also were tested for appetite suppressant activity in rats. Several conformationally restricted residues in the C-terminal tetrapeptide region, including DELTA(Z)-Phe33, (N-Me)Phe33, (N-Me)Asp32, (N-Me)Leu31, and 3PP31 (3PP = trans-3-n-propyl-L-proline) were found to be acceptable modifications at one or both receptor subtypes. The (N-Me)Asp32 and (N-Me)Leu31 modifications afforded potent and selective CCK-A and CCK-B ligands, respectively. SAR studies in the N-terminal acyldipeptide region examined structural requirements for the side chain at position 28, where Gly and Pro replacements were found to possess high affinity at both receptor subtypes. Other conformationally restrictive modifications were less active. All of the analogues that showed high affinity (<10 nM) for the CCK-A receptor also were full agonists in amylase release and most were full or nearly full agonists in the phosphoinositide (PI) turnover assay, the most notable exception being the DELTA(Z)-Phe33 analogue, which showed 69% of the maximal response in the PI assay. Potent activity in suppression of food intake in rats was found for selected analogues.