Salan钛双齿配合物的Sonogashira合成后修饰反应研究

doi:10.6023/A21060282

摘要/Abstract

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 [Salan^2,4-dimethylTi^(IV)Dipic^{4-(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2a、2f、3a和3j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, 2a和2f水解出无抗癌活性的炔基Salan配体1a*, 半数水解时间(t_1/2)分别为5和10 h. 炔基功能化2,6-吡啶二甲酸的配合物3a和3j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 [Salan^2,4-dimethylTi^(IV)Dipic^{4-(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 (t_1/2) 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

引用此文

赵添堃, 王鹏, 姬明宇, 李善家, 杨明俊, 蒲秀瑛. Salan钛双齿配合物的Sonogashira合成后修饰反应研究[J]. 化学学报, 2021, 79(11): 1385-1393.

Tiankun Zhao, Peng Wang, Mingyu Ji, Shanjia Li, Mingjun Yang, Xiuying Pu. Post-Synthetic Modification Research of Salan Titanium bis-Chelates via Sonogashira Reaction[J]. Acta Chimica Sinica, 2021, 79(11): 1385-1393.

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图/表 10

图式1. 具抗癌活性钛配合物发展及合成后修饰研究

Scheme 1. Development and post-synthetic modification of anti-tumoral titanium complexes

图1. 碘代[SalanTi(IV)Dipic] 1a~1c的合成

Figure 1. Synthesis of iodine-substituted [SalanTi(IV)Dipic] 1a~1c

Entry^a	Catalyst	CuI	Base	Yield^b/%
1	PdCl₂(PPh₃)₂	—	(ⁱPr)₂NH	Trace^c
2	PdCl₂(PPh₃)₂	10%	(ⁱPr)₂NH	76
3	PdCl₂(PPh₃)₂	2.5%	(ⁱPr)₂NH	84
4	Pd-DPPF	2.5%	(ⁱPr)₂NH	76
5	Pd(PPh₃)₄	2.5%	(ⁱPr)₂NH	Trace^c
6	PdCl₂(PPh₃)₂	2.5%	Et₃N	Trace^c
7	PdCl₂(PPh₃)₂	2.5%	Pyridine	Trace^c
8	PdCl₂(PPh₃)₂	2.5%	K₂CO₃	trace^c
9^d	PdCl₂(PPh₃)₂	2.5%	(ⁱPr)₂NH	74
10^e	PdCl₂(PPh₃)₂	2.5%	(ⁱPr)₂NH	65

表1. Sonogashira反应条件筛选

Table 1. Screening of Sonogashira reaction conditions

Entry^a	R	Time/h	Yield^b/%	Complex
1	Ph	10	84	2a
2	p-PhF	10	72	2b
3	p-PhBr	12	78	2c
4	p-PhEt	11	70	2d
5	p-PhOMe	12	82	2e
6^c	n-C₃H₇	12	82	2f
7^c	n-C₆H₁₃	7	76	2g
8^c	TMS	11	80	2h
9	CH₂OH	72	trace^d	2i
10	CH₂NMe₂	72	trace^d	2j

表2. 钛配合物2a~2j的合成

Table 2. Synthesis of titanium complexes 2a~2j

Entry^a	R	Time/h	Yield^b/%	Complex
1	Ph	7	>99	3a
2	p-PhF	8	88	3b
3	p-PhBr	23	84	3c
4	p-PhEt	24	86	3d
5	p-PhOMe	7	91	3e
6^c	n-C₃H₇	30	91	3f
7^c	n-C₁₄H₂₉	48	92	3g
8^c	TMS	24	77	3h
9	CH₂OH	72	64^d	3i
10	CH₂NMe₂	72	74	3j

表3. 钛配合物3a~3j的合成

Table 3. Synthesis of titanium complexes 3a~3j

图2. 碘代[SalanTi(IV)Dipic]的Sonogashira后续功能化反应

Figure 2. Further functionalization of iodine containing [SalanTi(IV)Dipic] via Sonogashira reaction Path a: 1b (347 mg, 0.5 mmol), ethinylestradiol (177.8 mg, 1.2 equiv.), PdCl2(PPh3)2 (0.05 mmol), CuI (0.025 mmol), (iPr)2NH (3.0 equiv.) in 4 mL THF at r.t. for 20 h, yield 89%. Path b: 1c (445 mg, 0.5 mmol), phenylacetylene (0.2 mL, 3.6 equiv.), PdCl2(PPh3)2 (0.075 mmol), CuI (0.025 mmol), (iPr)2NH (6.0 equiv.) in 4 mL THF at r.t. for 9 h, yield 86%

Entry^a	HeLa S3	Hep G2	Complex	Entry^a	HeLa S3	Hep G2	Complex
1	0.9±0.2	4.1±0.9	2a	12	59.1±6.2	Non toxic	3d
2	1.1±0.2	3.2±0.4	2b	13	Non toxic	Non toxic	3e
3	3.8±0.8	10.7±1	2c	14	10.6±2	26.1±3.3	3f
4	3.2±0.4	3.6±0.5	2d	15	Non toxic	Non toxic	3g
5	7.1±1.3	16.8±2.4	2e	16	5.9±0.4	30.2±5.7	3h
6	2.1±0.3	7.1±0.7	2f	17	0.8±0.2	1.46±0.7	3i
7	11.8±2.6	27.7±6.3	2g	18	0.5±0.1	0.7±0.2	3j
8	0.6±0.1	0.8±0.1	2h	19	Non toxic	Non toxic	4a
9	1.9±2.6	58.6±16	3a	20	11.8±1.1	Non-toxic	4b
10	1.1±0.2	6.5±1.3	3b	20	3.3±0.2	6.0±1.1	Cisplatin
11	1.6±0.3	17.7±7.6	3c	21^[27]	4.4±0.4	3.4±0.2	[L₂Ti^(IV)Dipic]

表4. [L2Ti(IV)Dipic]、顺铂和2a~4b对HeLa S3和Hep G2细胞的IC50值

Table 4. IC50 values of [L2Ti(IV)Dipic], Cisplatin and 2a~4b against HeLa S3 and Hep G2 cells

图式2. 含炔基Salan钛配合物对Hela S3细胞抑制活性的位阻效应和电子效应分析

Scheme 2. Steric effect and electron effect analysis of inhibition activity of alkynyl Salan Ti(IV) bis-chelates against Hela S3 cells

图3. (a) 2a在1000 equiv. D2O中的水解1HNMR谱图(红色: 2a信号A、D, 蓝色: 1a*信号C、E). (b) 2a、2f、3a和3j在1000 equiv. D2O中的水解速率

Figure 3. (a) Hydrolyzation 1H NMR spectra of 2a in 1000 equiv. D2O (red region: signals of 2a, A and D, blue region: signals of 1a*, C and E). (b) Hydrolyzation rate of 2a, 2f, 3a and 3j in 1000 equiv. D2O

图4. 2a在1000 equiv. D2O中的水解产物及配体1a*的直接合成

Figure 4. Hydrolyzation of 2a in 1000 equiv. D2O and synthesis of 1a*Path a: 1000 equiv. D2O, d8-THF 0.4 mL. Path b: L1 (300 mg, 0.6 mmol), phenylacetylene (2.5 equiv.), PdCl2(PPh3)2 (0.03~0.06 mmol), CuI (0.015~0.03 mmol), PPh3 (0.03~0.06 mmol) and (iPr)2NH (3.0 equiv.) in 3 mL THF at r.t.

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