Syntheses of cyclic prodrugs of RGD peptidomimetics with various macrocyclic ring sizes: evaluation of physicochemical, transport and antithrombic properties.
Syntheses of cyclic prodrugs of RGD peptidomimetics with various macrocyclic ring sizes: evaluation of physicochemical, transport and antithrombic properties.
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具有不同大环尺寸的 RGD 肽模拟物的环状前药的合成：物理化学、转运和抗血栓特性的评估。
DOI：
10.1034/j.1399-3011.2003.00062.x
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Siahaan,TJ
中科院分区：
文献类型：
--
作者：
He,HT;Xu,CR;Song,X;Siahaan,TJ
本工作的目的是合成不同环大小(n[CH2] = 1、3、5和7)的RGD多肽2a-d的环状前体药物1a-d，并评价环大小对其转运、物理化学、酶稳定性和抗血栓性能的影响。将两个关键中间体Boc-Phe-O-CH2-OCO-OpNP(5)和H2N-(CH2)n-CO-Asp(OBzl)-OTce(8a-d)聚合，得到线性前体Boc-Phe-O-CH2-OCO-HN-(CH2)n-CO-Asp(OBzl)-OTce(9a-d)，从而合成了环状前体药物1a-d。将N-端和C-端保护基团从9a-d去掉，得到10a-d。线性前体10a-d环化，剩余的Bzl-保护基去掉，得到总收率约20%的环状前体药物1a-DIN。采用标准的Boc-氨基酸化学，采用溶液相法合成了线性RGD多肽模拟物(2a-d)。通过增加亚甲基来增加环的大小也增加了环状前体药物和母体RGD多肽类药物的疏水性。环状前体药1and1d的转运性能分别是母体化合物2and2d的2.6倍和4.4倍。这些结果表明，增加环状前体药物和母体RGD模拟肽的疏水性增强了它们的转运性能。环状前体药物的流体动力学半径也小于它们各自母体化合物的流体动力学半径，这表明尺寸的变化可能有助于它们的传输特性。环状前体药物的化学稳定性受环大小的影响，环大小(1d)的环状前药比环小(1a)的环状前药更稳定。所有的环状前药在pH为4的条件下比在pH为7和10的条件下更稳定。分离的酯酶和人血浆中的酯酶都能诱导前体药物向药物的转化。随着亚甲基(n[CH2] = 1，3，5，7)长度的增加，前体药物和母体化合物的抗血栓活性增强。综上所述，环状前体药物的环大小影响它们的转运、物理化学和抗血栓性能。
The objective of this work was to synthesize cyclic prodrugs1a–dof RGD peptidomimetics2a–dwith various ring sizes (n[CH2] = 1, 3, 5 and 7) and to evaluate the effect of ring size on their transport, physicochemical, enzymatic stability, and antithrombic properties. The syntheses of cyclic prodrugs1a–dwere achieved by converging two key intermediates, Boc‐Phe‐O‐CH2‐OCO‐OpNP (5) and H2N‐(CH2)n‐CO‐Asp(OBzl)‐OTce (8a–d), to give linear precursors Boc‐Phe‐O‐CH2‐OCO‐HN‐(CH2)n‐CO‐Asp(OBzl)‐OTce (9a–d). The N‐ and C‐terminus protecting groups were removed from9a–dto give10a–d. Linear precursors10a–dwere cyclized, and the remaining Bzl‐protecting group was removed to produce cyclic prodrugs1a–din around 20% overall yield. The linear RGD peptidomimetics (2a–d) were synthesized using standard Boc‐amino acid chemistry by solution‐phase method. Increasing the ring size by adding methylene groups also increases the hydrophobicity of the cyclic prodrugs and parent RGD peptidomimetics. The transport properties of cyclic prodrugs1cand1dwere 2.6‐ and 4.4‐fold better than those of parent compounds2cand2d, respectively. These results suggest that increasing the hydrophobicity of the cyclic prodrugs and parent RGD peptidomimetics enhanced their transport properties. The hydrodynamic radii of the cyclic prodrugs were also smaller than those of their respective parent compounds, suggesting that the change in size may contribute to their transport properties. The chemical stability of the cyclic prodrugs was affected by the ring size, and the cyclic prodrug with the larger ring size (i.e.1d) was more stable than the smaller one (i.e.1a). All the cyclic prodrugs were more stable at pH 4 than at pH 7 and 10. Prodrug‐to‐drug conversion could be induced by isolated esterase as well as esterase found in human plasma. An increase in the length of methylene group (n[CH2] = 1, 3, 5, 7) enhanced the antithrombic activity of the prodrugs and the parent compounds. In summary, the ring size of cyclic prodrugs affected their transport, physicochemical, and antithrombic properties.
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具有改善膜渗透性的新型香豆素基酯酶敏感的拟肽 RGD 类似物环状前药的合成和评估。
影响因子：
1.7
作者：
Binghe Wang;Wei Wang;Gian P. Camenisch;J. Elmo;Huijuan Zhang;Ronald T. Borchardt
通讯作者：
Ronald T. Borchardt
影响因子：
5.2
作者：
Yasunori Tsuchiya;S. Sawada;K. Tsukada;I. Saiki
通讯作者：
Yasunori Tsuchiya;S. Sawada;K. Tsukada;I. Saiki
DOI：
10.1034/j.1399-3011.1999.00052.x
发表时间：
1999-05-01
期刊：
JOURNAL OF PEPTIDE RESEARCH
影响因子：
--
作者：
Bogdanowich-Knipp, SJ;Chakrabarti, S;Siahaan, TJ
通讯作者：
Siahaan, TJ
DOI：
10.1034/j.1399-3011.1999.00076.x
发表时间：
1999-04-01
期刊：
JOURNAL OF PEPTIDE RESEARCH
影响因子：
--
作者：
Gudmundsson, OS;Jois, SDS;Borchardt, RT
通讯作者：
Borchardt, RT
影响因子：
4.4
作者：
S. Jois;U. S. Tambunan;S. Chakrabarti;T. Siahaan
通讯作者：
S. Jois;U. S. Tambunan;S. Chakrabarti;T. Siahaan