Vitamin B9 derivatives as carriers of bioactive cations for musculoskeletal regeneration applications: Synthesis, characterization and biological evaluation
Vitamin B9 derivatives as carriers of bioactive cations for musculoskeletal regeneration applications: Synthesis, characterization and biological evaluation
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DOI：
10.1016/j.ejmech.2021.113152
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发表时间：
2021-01-13
影响因子：
6.7
通讯作者：
Rojo, Luis
中科院分区：
文献类型：
--
作者：
Fernandez-Villa, Daniel;Asensio, Gerardo;Rojo, Luis
在过去的几十年里，用于肌肉骨骼再生的新药的开发引起了人们的广泛关注。本文介绍了三种新型含二价阳离子（ZnFO、MgFO和MnFO）的维生素B9（叶酸）衍生物，并给出了它们的合成机理和理化性质。此外，使用人间充质干细胞（hMSC）评估其生物学特性（以及我们之前报道的SrFO）也得到了重视。在所有情况下，纯叶酸衍生物（MFOs）在金属和叶酸阴离子之间具有双齿配位模式，并具有1:1的化学计量，获得了高产率。所有mfo的非细胞毒性剂量（50 μ g/mL）被证明在基础条件下通过其自身的mRNA谱向成骨样或纤维软骨样表型调节。此外，在基础条件下，ZnFO提高了碱性磷酸酶活性，而在骨诱导条件下，ZnFO和MnFO均提高了基质矿化程度。因此，我们已经证明了这些新化合物的生物活性和进一步研究它们在体内肌肉骨骼再生应用的适用性。(C) 2021 Elsevier Masson SAS。版权所有。
The development of new drugs for musculoskeletal regeneration purposes has attracted much attention in the last decades. In this work, we present three novel vitamin B9 (folic acid)-derivatives bearing divalent cations (ZnFO, MgFO and MnFO), providing their synthesis mechanism and physicochemical characterization. In addition, a strong emphasis has been placed on evaluating their biological properties (along with our previously reported SrFO) using human mesenchymal stem cells (hMSC). In all the cases, pure folate derivatives (MFOs) with a bidentate coordination mode between the metal and the folate anion, and a 1:1 stoichiometry, were obtained in high yields. A non-cytotoxic dose of all the MFOs (50 mu g/mL) was demonstrated to modulate by their own the mRNA profiles towards osteogenic-like or fibrocartilaginous-like phenotypes in basal conditions. Moreover, ZnFO increased the alkaline phosphatase activity in basal conditions, while both ZnFO and MnFO increased the matrix mineralization degree in osteoinductive conditions. Thus, we have demonstrated the bioactivity of these novel compounds and the suitability to further studied them in vivo for musculoskeletal regeneration applications. (C) 2021 Elsevier Masson SAS. All rights reserved.