Citation: Geng Xu, Ju Guo, Zheng Yan, Nan Wang, Zhan-Zhu Liu. Synthesis and cytotoxicity of dinuclear platinum(Ⅱ) complexes of (1S, 3S)-1, 2, 3, 4-tetrahydroisoquinolines[J]. Chinese Chemical Letters, ;2013, 24(3): 186-188. shu

Synthesis and cytotoxicity of dinuclear platinum(Ⅱ) complexes of (1S, 3S)-1, 2, 3, 4-tetrahydroisoquinolines

Geng Xu ^a ,
Ju Guo ^a ,
Zheng Yan ^b ,
Nan Wang ^b ,
Zhan-Zhu Liu ^a,b,,

1.
a State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China;
2.
b Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China

Corresponding author: Zhan-Zhu Liu,
Received Date: 21 December 2012
Available Online: 4 February 2013

A series of novel dinuclear platinum(Ⅱ) complexes with (1S, 3S)-1,2,3,4-tetrahydroisoquinolines as the ligands were synthesized as potential anticancer agents in several steps starting from commercially available L-DOPA. The cytotoxicities of the series of dinuclear platinum(Ⅱ) complexes of tetrahydroisoquinoline were tested against HCT-8, BEL-7402, A2780, MCF-7, Hela, A549 and BGC-823 cell lines by the MTT test. These complexes showed selective inhibition activity against cisplatin-insensitive cell line Skov3.
- Dinuclear platinum(Ⅱ) complexes,
- Antitumor activity,
- Tetrahydroisoquinolines,
- Synthesis
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  [14] Data of ligands 7a-e. 7a: White solid, mp > 250℃, [α]_D²⁴-33.3 (c 0.81 CH₃OH) ¹H NMR (300 MHz, DMSO-d₆): δ 1.38 (s, 4H, C-C₂H₄-C), 1.71 (s, 4H, C-CH₂-C×2), 2.90-3.10 (m, 6H, CH₂-Ar×2), 3.20-3.30 (m, 2H, CH₂-N×2), 3.44 (s, 6H, -OCH₃×2), 3.78 (s, 6H, -OCH₃×2), 4.10 (m, 2H, CH-Ar×2), 5.74 (d, 2H, J = 6.6, Ar-CH-Ar×2), 6.07 (s, 2H, Ar-H×2), 6.85 (s, 2H, Ar-H×2), 7.50 (s, 10H, Ar-H×2), 9.58 (br, 4H, -NH×2), 10.07 (br, 2H, -NH×2), 10.27 (br, 2H, -NH×2). ESI-MS: 679 (m/z + 1); HRMS (ESI) Calcd. for C₄₂H₅₅N₄O₄: 679.4217, found: 679.4224. 7b: White solid, mp 190-192℃, [α]_D²⁴- -35.2 (c 0.31 CH₃OH) ¹H NMR (300 M Hz, DMSO-d₆): δ 1.35 (s, 6H, C-C₃H₆-C), 1.70 (s, 4H, C-CH₂-C×2), 2.90-3.10 (m, 6H, CH₂-Ar×2), 3.20-3.30 (m, 2H, CH₂-N×2), 3.44 (s, 6H, -OCH₃×2), 3.78 (s, 6H, -OCH₃×2), 4.10 (m, 2H, CH-Ar×2), 5.72 (m, 2H, Ar-CH-Ar×2), 6.07 (s, 2H, Ar-H×2), 6.85 (s, 2H, Ar-H×2), 7.49 (m, 10H, Ar-H×2), 9.65 (br, 4H, -NH×2), 10.17 (br, 2H, -NH×2), 10.33 (br, 2H, -NH×2). ESI-MS: 693 (m/z + 1); HRMS (ESI) Calcd. for C₄₃H₅₇N₄O₄: 693.4374, found: 693.4365. 7c: White solid, mp 237-239℃, [α]_D²⁴-34.7 (c 0.39 CH₃OH) ¹H NMR (300 MHz, DMSO-d₆): δ 1.32 (s, 8H, C-C₄H₈-C), 1.68 (m, 4H, C-CH₂-C×2), 2.90-3.10 (m, 4H, CH₂-Ar×2), 3.20-3.30 (m, 8H, CH₂-N-CH₂×2), 3.44 (s, 6H, -OCH₃×2), 3.78 (s, 6H, -OCH₃×2), 4.09 (m, 2H, N-CH-C×2), 5.72 (m, 2H, Ar-CH-Ar×2), 6.07 (s, 2H, Ar-H×2), 6.85 (s, 2H, Ar-H×2), 7.49 (m, 10H, Ar-H×2), 9.62 (br, 4H, -NH×2), 10.10 (br, 2H, -NH×2), 10.33 (br, 2H, -NH×2). ¹³C NMR (75 MHz, DMSO-d₆): δ 148.64, 147.52, 136.17, 130.19, 129.47, 128.65, 124.13, 123.51, 111.41, 110.54, 60.63, 55.57, 55.46, 51.54, 48.09, 47.16, 29.19, 28.04, 25.66, 25.26. ESI-MS: 707 (m/z + 1); HRMS (ESI) Calcd. for C₄₄H₅₉N₄O₄: 707.4536, found: 707.4553. 7d: Yellowish solid, mp 185-187℃, [α]_D²⁴-27.9 (c 0.57 CH₃OH) ¹H NMR (300 MHz, DMSO-d₆): δ 1.28 (s, 10H, C-C₅H₁₀-C), 1.65 (m, 4H, C-CH₂-C×2), 2.90-3.10 (m, 6H, CH₂-Ar×2), 3.20-3.30 (m, 2H, CH₂-N×2), 3.35 (s, 6H, -OCH₃×2), 3.77 (s, 6H, -OCH₃×2), 4.09 (m, 2H, CH-Ar×2), 5.71 (m, 2H, Ar-CH-Ar×2), 6.06 (s, 2H, Ar-H×2), 6.83 (s, 2H, Ar-H×2), 7.48 (m, 10H, Ar-H×2), 9.63 (br, 4H, -NH×2), 10.15 (br, 2H, -NH×2), 10.32 (br, 2H, -NH×2). ESI-MS: 721 (m/z + 1); HRMS (ESI) Calcd. for C₄₅H₆₁N₄O₄: 721.4687, found: 721.4692. 7e: Yellowish solid, mp 209-211℃, [α]_D²⁴-30.9 (c 0.58 CH₃OH) ¹H NMR (300 MHz, DMSO-d₆): δ 1.27 (s, 16H, C-C₈H₁₆-C), 1.66 (m, 4H, C-CH₂-C×2), 2.90-3.10 (m, 6H, CH₂-Ar×2), 3.20-3.30 (m, 2H, CH₂-N×2), 3.44 (s, 6H, -OCH₃×2), 3.78 (s, 6H, -OCH₃×2), 4.09 (m, 2H, CH-Ar×2), 5.73 (m, 2H, Ar-CH-Ar×2), 6.07 (s, 2H, Ar-H×2), 6.85 (s, 2H, Ar-H×2), 7.49 (m, 10H, Ar-H×2), 9.61 (br, 4H, -NH×2), 10.14 (br, 2H, -NH×2), 10.32 (br, 2H, -NH×2). ESI-MS: 764 (m/z + 1); HRMS (ESI) Calcd. for C₄₈H₆₇N₄O₄: 763.5156, found: 763.5155.
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  [15] General procedure for the preparation of compound 8a-e: A solution of 7c (1.0 mmol) and K₂PtC₁₄ (2.0 mmol) in distilled water (12 mL) was heated to 65-70℃ with stirring. The pH of the reaction solution was checked continuously and 1 mol/L NaOH was added to keep the pH in the range 3-4. Toward the end of the reaction, pH was adjusted to 6 with 0.1 mol/L NaOH. After the mixture was cooled to ambient temperature, the precipitate was filtered, washed three times with cold water, twice with ethanol, and once with diethyl ether, and dried in vacuo (87% yield) to afford compound 8c: yellow solid, mp: 237-239℃, Elemental analysis: Calcd. for C₄₄H₅₈O₄N₄Cl₄Pt₂ (%): C 42.66, H 4.72, N 4.52; Found: C 42.59, H 4.92, N 4.36. 8a: Offwhite solid, mp: 237-239℃, Elemental analysis: Calcd. for C₄₂H₅₄O₄N₄Cl₄Pt₂ (%): C 41.65, H 4.49, N 4.63; Found: C 41.79, H 4.52, N 4.61. 8b: Offwhite solid, mp: 234-236℃, Elemental analysis: Calcd. for C₄₃H₅₆O₄N₄Cl₄Pt₂ (%): C 42.16, H 4.61, N 4.57; Found: C 42.57, H 4.81, N 4.40. 8d: Offwhite solid, mp: 238-240℃, Elemental analysis: Calcd. for C₄₅H₆₀O₄N₄Cl₄Pt₂ (%): C 43.14, H 4.83, N 4.47; Found: C 43.30, H 4.68, N 4.64. 8e: Offwhite solid, mp: 228-230℃, Elemental analysis: Calcd. for C₄₈H₆₀O₄N₄Cl₄Pt₂ (%): C 44.52, H 5.14, N 4.33; Found: C 44.30, H 5.27, N 4.16.
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