Synthesis and biological evaluation of novel all-hydrocarbon cross-linked aza-stapled peptides

Luo, Zhihong; Xu, Lei; Tang, Xiaomin; Zhao, Xuejun; He, Tong; Lubell, William D.; Zhang, Jinqiang

doi:10.1039/d2ob01496c

Cited by 2 publications

(1 citation statement)

References 58 publications

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“…The conformational preferences of azaamino acid residues have been studied theoretically [ 15 , 16 , 17 , 18 , 19 , 20 , 21 ] and experimentally [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. The results showed that the preferred dihedral angles of the backbone of these azaamino acid residues are in the range of ϕ = ±90° ± 30°, ψ = 0° or ±180° ± 30°, which is appeared to be the polyproline II (β P ), and β-turn motif (α R , α L , δ R , or δ L conformation) [ 15 , 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Computational Investigation of Conformational Properties of Short Azapeptides: Insights from DFT Study and NBO Analysis

et al. 2023

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Azapeptides have gained much attention due to their ability to enhance the stability and bioavailability of peptide drugs. Their structural preferences, essential to understanding their function and potential application in the peptide drug design, remain largely unknown. In this work, we systematically investigated the conformational preferences of three azaamino acid residues in tripeptide models, Ac-azaXaa-Pro-NHMe [Xaa = Asn (4), Asp (5), Ala (6)], using the popular DFT functionals, B3LYP and B3LYP-D3. A solvation model density (SMD) was used to mimic the solvation effect on the conformational behaviors of azapeptides in water. During the calculation, we considered the impact of the amide bond in the azapeptide models on the conformational preferences of models 4–6. We analyzed the effect of the HB between the side-chain main chain and main-chain main-chain on the conformational behaviors of azapeptides 4–6. We found that the predicted lowest energy conformation for the three models differs depending on the calculation methods. In the gas phase, B3LYP functional indicates that the conformers tttANP-1 and tttADP-1 of azapeptides 4 and 5 correspond to the type I of β-turn, the lowest energy conformation with all-trans amide bonds. Considering the dispersion correction, B3LYP-D3 functional predicts the conformers tctANP-2 and tctADP-3 of azapeptide 4 and 5, which contain the cis amide bond preceding the Pro residue, as the lowest energy conformation in the gas phase. The results imply that azaAsx and Pro residues may involve cis-trans isomerization in the gas phase. In water, the predicted lowest energy conformer of azapeptides 4 and 5 differs from the gas phase results and depends on the calculational method. For azapeptide 6, regardless of calculation methods and phases, tttAAP-1 (β-I turn) is predicted as the lowest energy conformer. The results imply that the effect of the side chain that can form HBs on the conformational preferences of azapeptides 4 and 5 may not be negligible. We compared the theoretical results of azaXaa-Pro models with those of Pro-azaXaa models, showing that incorporating azaamino acid residue in peptides at different positions can significantly impact the folding patterns and stability of azapeptides.

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Section: Introductionmentioning

confidence: 99%

Computational Investigation of Conformational Properties of Short Azapeptides: Insights from DFT Study and NBO Analysis

et al. 2023

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N-Heterocyclic Carbene-Catalyzed Synthesis of Pentafluorophenyl Sulfides

Xia,

Luo,

et al. 2024

Chinese Journal of Organic Chemistry

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An efficient method for the construction of C(sp 2 )-S bond has been developed. The stable N-heterocyclic carbene 1,3-bis(2,6-dissopropylphenyl)-imidazole-2-ylidene can activate the C -Si bond of pentafluorophenyl trimethylsilicon effectively to initiate the nucleophilic substitution reaction with thiosulfonic ester, producing pentafluorophenyl sulfide products in 34%～98% yields. Keywords N-heterocyclic carbene; C-S bond; pentafluorophenyl sulfide 碳-硫(C-S)键广泛存在于天然产物、生物活性化合物、药物以及功能材料中, 因此 C-S 键的构建一直是有机合成领域中的研究热点 [1] . 在过去几十年中, 过渡金属催化的交叉偶联反应、插入反应、硫代羰基化、亲核加成反应等已经被广泛地用于 C-S 键的构建 [2] . 另外, 多氟芳烃很多为重要的结构单元, 广泛存在于药物分子和聚合物中, 因此合成五氟芳基硫醚化合物在有机化学中具有重要意义 [3] . 在过去的几十年里, 化学家发展了几种合成五氟苯基硫醚化合物的方法. Kita 课题组 [4] 在 2001 年通过 TMSOTf 催化富电子芳烃与醌单-O,S-缩醛的亚磺酰化和亲核加成反应获得了五氟苯基硫醚化合物, 但该反应需要在低温条件下进行(Scheme 1a). Shi 课题组 [5] 用 Cu(I)催化五氟苯与二芳基二硫醚发生交叉偶联反应(Scheme 1b), 得到相应的五氟苯基硫醚, Peng 课题组 [6] 用 Ni(0)催化硫醇和芳基碘化物分子间交叉偶联反应快速地合成了多种五氟苯基硫醚(Scheme 1b), Sakai 课题组 [7] 用 Pd(II)/Cu(II)催化二芳基二硫醚与芳烃的交叉偶联反应(Scheme 1b), 得到五氟苯基硫醚化合物. 此外, Shibata 课题组 [8] 通过活化的 α-亚甲基酮、环状 1,3-二酮、内酰胺和内酯与 C 6 F 5 -DAST 的脱酰基五氟苯基硫化反应(Scheme 1b), 得到五氟苯基环硫醚衍生物. 然而这些方法一般都需要过渡金属催化剂催化, 有的还需要高温等较为苛刻的反应条件. 我们课题组 [9] 前期利用膦腈碱 t-Bu-P 4 作为强有机 Lewis 碱催化剂, 实现了有机小分子催化下五氟苯基硅试剂与硫代磺酸酯的亲核取代反应(Scheme 1c), 制备了多种五氟苯基硫醚化合物, 但膦腈碱催化剂价格非常昂贵, 在实验室制备困难, 且该催化剂对水和空气高度敏感, 实验操作需要极其严苛的无水无氧条件. 因此, 该方法的实际应用受到了一定的限制. 鉴于 C-S 键构筑和五氟芳基硫醚化合物的重要性, 发展高效、廉价且易于操作的催化合成方法来制备五氟芳基硫醚化合物仍具有重要意义.氮杂环卡宾(NHCs)作为一种重要的小分子有机催化剂, 在有机合成中具有广泛的应用 [10] . 该催化剂可以

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Synthesis and biological evaluation of novel all-hydrocarbon cross-linked aza-stapled peptides

Abstract: Novel all-hydrocarbon cross-linked aza-stapled peptides were designed and synthesized by ring-closing metathesis between two aza-alkenylglycine residues. Three aza-stapled peptidic analogues based on the peptide dual inhibitor of p53-MDM2/MDMX interactions were...

Cited by 2 publications

References 58 publications

Computational Investigation of Conformational Properties of Short Azapeptides: Insights from DFT Study and NBO Analysis

Computational Investigation of Conformational Properties of Short Azapeptides: Insights from DFT Study and NBO Analysis

N-Heterocyclic Carbene-Catalyzed Synthesis of Pentafluorophenyl Sulfides

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