化学学报 ›› 2021, Vol. 79 ›› Issue (11): 1385-1393.DOI: 10.6023/A21060282 上一篇    下一篇

研究论文

Salan钛双齿配合物的Sonogashira合成后修饰反应研究

赵添堃*(), 王鹏, 姬明宇, 李善家, 杨明俊, 蒲秀瑛   

  1. 兰州理工大学生命科学与工程学院 兰州 730050
  • 投稿日期:2021-06-21 发布日期:2021-08-16
  • 通讯作者: 赵添堃
  • 基金资助:
    甘肃省自然科学基金(20JR5RA470)

Post-Synthetic Modification Research of Salan Titanium bis-Chelates via Sonogashira Reaction

Tiankun Zhao(), Peng Wang, Mingyu Ji, Shanjia Li, Mingjun Yang, Xiuying Pu   

  1. College of Life Science and Engineering, Lanzhou University of Technology, Lanzhou 730050
  • Received:2021-06-21 Published:2021-08-16
  • Contact: Tiankun Zhao
  • Supported by:
    Natural Science Foundation of Gansu Province(20JR5RA470)

报道了一种通过钯催化Sonogashira反应对具抗癌活性的ONNO型“Salan”、“2,6-吡啶二甲酸”双配位钛化合物进行高效后修饰的方法学研究. 通过Sonogashira反应直接向两个配体引入不同炔烃功能基团, 共制备了20个新型的钛配合物. 进一步通过该方法学向钛配合物引入三苯乙炔基及癌细胞靶向分子雌炔醇. 通过1H NMR和13C NMR、HRMS、UV-vis和IR等手段对所有配合物进行了结构表征. 多数炔基活化的钛配合物对HeLa S3和Hep G2癌细胞在微摩尔范围内表现出显著提升的抑制活性, 其中配合物3j [Salan2,4-dimethylTi(IV)Dipic4-(3-(dimethylamino)prop-1-yn-1-yl)]的IC50值较顺铂提升约一个数量级, 是本研究中活性最强的Salan钛双齿配合物[3j, HeLa S3: IC50=(0.5±0.1) μmol/L, Hep G2: IC50=(0.7±0.2) μmol/L; 顺铂, HeLa S3: IC50=(3.3±0.2) μmol/L, Hep G2: IC50=(6.0±1.1) μmol/L]. 针对芳炔和脂肪炔取代不同配体的代表配合物2a2f3a3j开展的稳定性研究表明, 向2位无取代Salan引入的炔基可通过电负性改变配合物的水稳定性, 2a2f水解出无抗癌活性的炔基Salan配体1a*, 半数水解时间(t1/2)分别为5和10 h. 炔基功能化2,6-吡啶二甲酸的配合物3a3j含有2位甲基取代的Salan配体, 它们在水环境中保持稳定. 此外, 本文总结和阐释了这类新型炔基功能化钛配合物的“结构-活性”关系, 并对后续开发此类钛配合物的前景和策略做出了分析与展望.

关键词: Sonogashira反应, [SalanTi(IV)Dipic]配合物, 抗癌活性, 炔基功能化, 水稳定性

A palladium-catalyzed Sonogashira reaction has been developed for the highly efficient post-modification of ONNO “Salan” ligand and 2,6-dipicolinic acid stabilized titanium bis-chelates with anticancer activity. Different alkynyl substituents were introduced to “Salan” and 2,6-dipicolinic acid, respectively. In total 20 novel titanium complexes containing mono-, di- and tri-alkynyl substituents as well as a complex containing tumor targeting ethinylestradiol were synthesized, all complexes were characterized by 1H NMR and 13C NMR, HRMS, UV-vis and IR spectroscopy. The nature of obtained titanium complexes that losing solvent molecules fast when exposed to air makes it hard to obtain satisfactory single crystals for X-ray diffraction measurement. Most alkynyl titanium complexes exhibit enhanced inhibitory activity against HeLa S3 and Hep G2 tumor cells in the micromole range. The introduction of alkynyl group to the Salan demonstrated less significant contribution to the anti-tumoral activity. However, the anti-tumoral activity alters with different alkynyl substituents on the 2,6-dipicolinic acid. Of all complexes, 3j [Salan2,4-dimethylTi(IV) Dipic4-(3-(dimethylamino)-prop-1-yn-1-yl)] showed excellent inhibitory activity, its IC50 value is an order of magnitude higher than that of Cisplatin, which is the most active anti-tumoral Salan titanium compound in this study [3j, HeLa S3: IC50=(0.5±0.1) μmol/L, Hep G2: IC50=(0.7±0.2) μmol/L; Cisplatin, HeLa S3: IC50=(3.3±0.2) μmol/L, Hep G2: IC50=(6.0±1.1) μmol/L]. In general, aromatic alkynyl substitution containing electron withdrawing moiety proved to have a positive influence on complex’s anti-tumoral activity than those containing electron donating moiety. Short chain aliphatic alkynyl substituents benefit the complex’s inhibitory activity. However, increased aliphatic chain length results in fast loss of complexes’ activity. Stability study on the representative aromatic alkynyl 2a, 3a and aliphatic alkynyl 2f, 3j suggests that the alkynyl’s electron nature can alter the complex stability. 2a and 2f, with substitutions on the Salan (2 position non-substituted), their half hydrolyzation time (t1/2) are 5 and 10 h, respectively. The hydrolysate of 2a was characterized to be the non-toxic alkynyl Salan ligand 1a*. For 3a and 3j, the 2 position of Salan are occupied by methyl groups, their protective effect to the titanium center resulted in a stable behavior of both in the presence of an aqueous media. In addition, the “structure-activity” relationship and development prospects of these novel alkynyl Salan titanium bis-chelates are summarized and prospected.

Key words: Sonogashira reaction, [SalanTi(IV)Dipic] complexes, antitumor activity, alkyne functionalization, aqueous stability