Design, Synthesis, Anti-TMV Activity, and Structure–Activity Relationships of Seco-pregnane C21 Steroids and Their Derivatives,Journal of Agricultural and Food Chemistry

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Design, Synthesis, Anti-TMV Activity, and Structure–Activity Relationships of Seco-pregnane C21 Steroids and Their Derivatives
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2024-09-18 , DOI: 10.1021/acs.jafc.4c03946
Ying Yan _{1,

2} , Pan Tang ₁ , Siyu He ₁ , Xiangkai Kong ₁ , Rong-Hua Wang ₁ , Jing Shi ₁ , Tianyuan Zhang ₁ , Ying-Tong Di ₃ , Lei Tang ₁ , Xiao-Jiang Hao ₃

Affiliation

seco-pregnane C₂₁ steroids exhibit high antiviral activity against the tobacco mosaic virus (TMV). However, the structural modification of seco-pregnane C₂₁ steroids and the structure–activity relationship (SAR) of the modified compounds remain unevaluated. Hence, the present study investigated how variations in the original skeletons of natural seco-pregnane C₂₁ steroids affect their antiviral activity. A series of glaucogenin C and A derivatives were designed and synthesized for the first time, and their anti-TMV activity was evaluated. Bioassay results showed that most of the newly designed derivatives exhibited good to excellent antiviral activity; among these derivatives, 5g, 5j, and 5l with higher antiviral activity than that of ningnanmycin emerged as new antiviral candidates. Reverse transcription-polymerase chain reaction and Western blotting assay revealed reduced levels of TMV coat protein (TMV-CP) gene transcription and TMV-CP protein expression, which confirmed the antiviral activity of these derivatives. These compounds also downregulated the expression of NtHsp70-1 and NtHsp70-061. Computational simulations indicated that 5l displayed strong van der Waals energy and electrostatic with the TMV coat protein, affording a lower binding energy (Δ_Gbind = −56.2 kcal/mol) compared with Ribavirin (Δ_Gbind = −47.6 kcal/mol). The SAR of these compounds was also evaluated, which demonstrated for the first time that substitutions at C-3 and double bonds of C-5/C-6 and C-13/C-18 are crucial for maintaining high anti-TMV activity.

中文翻译：

Seco-pregnane C21 类固醇及其衍生物的设计、合成、抗TMV 活性及构效关系

seco -pregnane C _{21 类}固醇对烟草花叶病毒 (TMV) 表现出高抗病毒活性。然而，仲孕烷C _{21 类}固醇的结构修饰和修饰化合物的构效关系（SAR）仍未得到评估。因此，本研究调查了天然环孕烷C ₂₁类固醇的原始骨架的变化如何影响其抗病毒活性。首次设计合成了一系列glaucogenin C和A衍生物，并对其抗TMV活性进行了评价。生物测定结果表明，大多数新设计的衍生物表现出良好至优异的抗病毒活性；在这些衍生物中，比宁南霉素具有更高抗病毒活性的5g 、 5j和5l成为新的抗病毒候选药物。逆转录聚合酶链反应和蛋白质印迹测定显示TMV外壳蛋白（TMV-CP）基因转录和TMV-CP蛋白表达水平降低，这证实了这些衍生物的抗病毒活性。这些化合物还下调NtHsp70-1和NtHsp70-061的表达。计算模拟表明， 5l与 TMV 外壳蛋白表现出很强的范德华能量和静电，与利巴韦林 (Δ _Gbind = -47.6 kcal/mol) 相比，提供较低的结合能 (Δ _Gbind = -56.2 kcal/mol)。还评估了这些化合物的 SAR，首次证明 C-3 以及 C-5/C-6 和 C-13/C-18 双键的取代对于维持高抗 TMV 活性至关重要。

更新日期：2024-09-19

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