Synthesis of [1-8-NαC]-zanriorb A1, alanine-containing analogues, and their cytotoxic and anti-inflammatory activity,Journal of Peptide Science

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Synthesis of [1-8-NαC]-zanriorb A1, alanine-containing analogues, and their cytotoxic and anti-inflammatory activity
Journal of Peptide Science ( IF 1.8 ) Pub Date : 2022-01-23 , DOI: 10.1002/psc.3405
Muhammad Nadeem-Ul-Haque ₁ , Anila Bashir ₁ , Humira Karim ₁ , Sadiq Noor Khan ₁ , Zafar Ali Shah ₂ , Almas Jabeen ₃ , Shaista Qayyum ₃ , A Ganesan ₄ , M Iqbal Choudhary _{1,

3,

5} , Farzana Shaheen ₁

Affiliation

The synthesis of the orbitide[1-8-NαC]-zanriorb A1, isolated from the medicinal plant Zanthoxylum riedelianum, was investigated by solution-phase macrocyclization of a linear peptide and on-resin solid-phase macrocyclization with an acylsulfonamide safety-catch linker. The solution-phase route produced a mixture of proline rotamers, and the main component was assigned as the trans, cis rotamer, identical to the natural product. The on-resin cyclization was less successful, producing mainly a linear peptide, and minor cyclic products as rotameric mixtures. Although the natural product was reported to be significantly cytotoxic against Jurkat leukemia T cells, our synthetic peptides were inactive, suggesting the presence of other rotamers or impurities in the naturally isolated material. Additional analogues of zanriorb A1 were synthesized in which proline and glycine residues were replaced with alanine. While these analogues were not cytotoxic, several of them inhibited the production of nitric oxide in lipopolysaccharide (LPS)-stimulated macrophages. The most active compound, cyclic[Ala^5,6,8]-zanriorb A1 had an IC₅₀ of 22 μM and was more potent compared with the standard NG-monomethyl-l-arginine acetate (L-NMMA) with an IC₅₀ of 98 μM, indicating their strong anti-inflammatory potential.

中文翻译：

[1-8-NαC]-zanriorb A1、含丙氨酸类似物的合成及其细胞毒和抗炎活性

从药用植物Zanthoxylum riedelianum中分离出的 orbitide[1-8-NαC]-zanriorb A1 的合成通过线性肽的溶液相大环化和使用酰基磺酰胺安全捕获接头的树脂固相大环化来研究. 溶液相路线产生脯氨酸旋转异构体的混合物，主要成分为反式、顺式旋转异构体，与天然产物相同。树脂上环化不太成功，主要产生线性肽，以及作为旋转异构体混合物的少量环状产物。尽管据报道该天然产物对 Jurkat 白血病 T 细胞具有显着的细胞毒性，但我们的合成肽是无活性的，这表明天然分离的材料中存在其他旋转异构体或杂质。还合成了 zanriorb A1 的其他类似物，其中脯氨酸和甘氨酸残基被丙氨酸取代。虽然这些类似物没有细胞毒性，但其中一些抑制了脂多糖 (LPS) 刺激的巨噬细胞中一氧化氮的产生。最活跃的化合物环状[Ala ^5,6,8 ]-zanriorb A1 的 IC_{为 50}22 μM，与标准 NG-单甲基-l-精氨酸乙酸盐 (L-NMMA) 相比更有效，IC ₅₀为 98 μM，表明它们具有强大的抗炎潜力。

更新日期：2022-01-23

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