Karwowski Boleslaw T
Nucleic Acids Damage Laboratory, Faculty of Pharmacy, Medical University of Lodz, ul. Muszynskiego 1, 90-151 Lodz, Poland.
Molecules. 2025 Aug 14;30(16):3377. doi: 10.3390/molecules30163377.
Adenosine deaminase (ADA) is one of the most important enzymes in nucleoside metabolism, regulating the levels of adenosine and deoxyadenosine triphosphate (ADT/dATP) on either side of the cell membrane. This small protein (weighing approximately 40 kDa) exhibits deamination properties towards other pharmaceuticals built on adenine as the leading structure, which requires co-administration of ADA inhibitors. 3'-deoxyadenosine (Cordycepin, Cord) is an active compound isolated from the fungus , which has been used in traditional Chinese medicine for over 2000 years. Its anticancer activity is likely related to the inhibition of primer elongation of lagging strands during genetic information replication. Unfortunately, Cord is rapidly deaminated by ADA into inactive 3'-deoxyinosine, necessitating its co-administration with ADA inhibitors. Here, for the first time, the synthesis and discussion of the oxidised form of Cord are presented. The 7,8-dihydro-8-oxo-3'-deoxyadenosine (Cord) exhibits high resistance to ADA because of its conformation, as shown experimentally by UV spectroscopy and RP-HPLC monitoring. Theoretical Density Functional based Tight Binding (DFTB) studies of the Michaelis complex ADA-Cord have revealed significant distance increases between the "active" HO molecule and C6 of the 8-oxo-adenine moiety of Cord, i.e., 4 Å as opposed to 2.7 Å in the cases of ADA-dAdo and Cord. In conclusion, it can be postulated that the conversion of Cord to Cord enhances its therapeutic potential; however, this needs to be verified in vitro and in vivo. It should be emphasised that the therapeutic effect, if any, can be achieved theoretically without ADA inhibitors, e.g., pentostatin, thus reducing adverse effects. These promising preliminary results, presented here, warrant further investigations.
腺苷脱氨酶（ADA）是核苷代谢中最重要的酶之一，可调节细胞膜两侧的腺苷和脱氧腺苷三磷酸（ADT/dATP）水平。这种小蛋白（约40 kDa）对以腺嘌呤为主要结构的其他药物具有脱氨特性，这需要联合使用ADA抑制剂。3'-脱氧腺苷（虫草素，Cord）是从真菌中分离出的一种活性化合物，已在传统中药中使用了2000多年。其抗癌活性可能与遗传信息复制过程中滞后链引物延伸的抑制有关。不幸的是，Cord会被ADA迅速脱氨为无活性的3'-脱氧肌苷，因此需要与ADA抑制剂联合使用。在此，首次介绍了Cord氧化形式的合成与讨论。7,8-二氢-8-氧代-3'-脱氧腺苷（Cord）由于其构象而对ADA具有高抗性，通过紫外光谱和反相高效液相色谱监测实验证明了这一点。基于密度泛函理论的紧束缚（DFTB）对米氏复合物ADA-Cord的研究表明，“活性”HO分子与Cord的8-氧代腺嘌呤部分的C6之间的距离显著增加，即4 Å，而ADA-dAdo和Cord的情况为2.7 Å。总之，可以推测Cord向Cord的转化增强了其治疗潜力；然而，这需要在体外和体内进行验证。应该强调的是，理论上无需ADA抑制剂（如喷司他丁）即可实现治疗效果，从而减少不良反应。此处呈现的这些有前景的初步结果值得进一步研究。
