Bovine Serum Amine Oxidase and Polyamine Analogues: Chemical Synthesis and Biological Evaluation Integrated with Molecular Docking and 3‑D QSAR Studies

Natural polyamines (PAs) are key players in cellular homeostasis by regulating cell growth and proliferation. Several observations highlight that PAs are also implicated in pathways regulating cell death. Indeed, the PA accumulation cytotoxic effect, maximized with the use of bovine serum amine oxidase (BSAO) enzyme, represents a valuable strategy against tumor progression. In the present study, along with the design, synthesis, and biological evaluation of a series of new spermine (Spm) analogues (1–23), a mixed structure-based (SB) and ligand-based (LB) protocol was applied. Binding modes of BSAO-PA modeled complexes led to clarify electrostatic and steric features likely affecting the BSAO-PA biochemical kinetics. LB and SB three-dimensional quantitative structure–activity relationship (Py-CoMFA and Py-ComBinE) models were developed by means of the 3d-qsar.com portal, and their analysis represents a strong basis for future design and synthesis of PA BSAO substrates for potential application in oxidative stress-induced chemotherapy.天然多胺（polyamines, PAs）通过调控细胞生长与增殖，是维持细胞稳态的关键因子。多项研究表明，多胺亦参与调控细胞死亡的信号通路。事实上，借助牛血清胺氧化酶（bovine serum amine oxidase, BSAO）强化多胺积累的细胞毒性效应，可作为对抗肿瘤进展的有效策略。本研究在设计、合成并生物学评价一系列新型精胺（spermine, Spm）类似物（1~23）的同时，采用了基于结构（structure-based, SB）与基于配体（ligand-based, LB）的混合研究策略。通过对BSAO-PA建模复合物的结合模式进行分析，阐明了可能影响BSAO-PA生化动力学的静电与空间位阻特征。借助3d-qsar.com在线平台构建了基于配体与基于结构的三维定量构效关系（three-dimensional quantitative structure–activity relationship, Py-CoMFA与Py-ComBinE）模型，对这些模型的分析可为未来设计、合成可应用于氧化应激诱导化疗的多胺BSAO底物提供坚实基础。