DOI:
10.1039/C1MD00005E
(Concise Article)
Med. Chem. Commun., 2011,
2, 881-885
Enantioselective preparation of ferrocenyl amino phosphines and their cytotoxic activities
Received
7th January 2011
, Accepted 17th June 2011
First published on 21st July 2011
Abstract
In connection to our previously reported phosphine compounds as antitumor agents, this article describes the preparation of ferrocenyl amino-phosphine and their possible cytotoxic potential towards the human hepatocellular carcinoma cell line Hep3B. The preliminary results suggested that ferrocenyl amino-phosphines can be potential anti-tumour agents which might be considered as novel cancer chemotherapeutic agents. In particular, compounds 4b, 4d and 4f exhibit strong cytotoxicity with IC50 < 5 μg ml−1. These compounds possess more promising cytotoxic activities than their precursor non-substituted ferrocene as well as the reference metallodrug cisplatin.
Introduction
Cisplatin is a classical metal coordination complex showing antitumor activity.1 After successful application, researchers continued to explore new classes of organometallic agents with significant biological activities such as metallocene dihalides2 and COMPOUND LINKS
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Download mol file of compoundferrocene derivatives.3 In particular, the synthesis and pharmacological studies of organometallic ferrocenyl units also show significant biological activities and draw scientists' attention. Many ferrocenyl compounds can be applied for organometallic catalysis and they also demonstrate cytotoxic, antitumor, antimalarial, antifungal and DNA-cleaving activities.4 The unexpected biological activity of ferrocenyl derived organics may be due to their special membrane permeation properties and metabolism; hence, these agents offer good pharmaceutical treatment properties such as non-toxicity, good stability and compatibility.5 The integration of ferrocenyl scaffolds into heteroaromatic compounds was recognized as an attractive way to produce new and effective molecules.6 It is reported that ferrocenyl Schiff-base esters of COMPOUND LINKS
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Download mol file of compoundaniline,7fluconazole8 and COMPOUND LINKS
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Download mol file of compoundaspirin9 demonstrated biological activities. The modification of the tamoxifen skeleton by a ferrocenyl unit can give antiestrogens with unique antiproliferative effects.10 Unsaturated conjugated ketones containing ferrocenyl pyrazole moieties were synthesized and their in vitro cytotoxic activities against melanoma Fem-x, cervix adenocarcinoma HeLa, and myelogenous leukemia K562 cell lines were reported through the use of a MTT method.11Ferrocenyl chalcones had been reported to possess antimalarial activity.12 The incorporation of glycoside scaffolds into ferrocenyl chalocones shows cytotoxic activity on HL-60 human leukemia cells.13 The retinoyl ferrocene derivatives were prepared by using monoarylferrocenyl alcohols and COMPOUND LINKS
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Download mol file of compoundretinoic acid, and they exhibited higher antiproliferative activities than their mother compounds.14 The “unnatural” ferrocenyl amino acid, Na-Ne-(ferrocene-1-acetyl)-L-lysine, can work like nuclease for DNA cleavage.15 Romao and coworkers reported that 1,2-disubstituted ferrocenes and cyclodextrin inclusion complexes show in vitro activities against Ehrlich ascites tumor cell.16COMPOUND LINKS
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Download mol file of compoundFerrocene–COMPOUND LINKS
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Download mol file of compoundindole hybrids can be applied for cancer and malarial therapy.17 Shin et al. reported that 5-alkyl-2-ferrocenyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one derivatives demonstrated inhibitory effects on the growth of A549 cells.18 The ferrocenyl diphenol compound, such as 1,1-di(4-hydroxyphenyl)-2-ferrocenyl-but-1-ene, exhibited strong in vitro anti-proliferative effects on MCF7 and MDA-MB231 breast cancer cells.19 In addition to mononuclear organometallic agents, bimetallic complexes such as ethylene-linked binuclear COMPOUND LINKS
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Download mol file of compoundferrocene/ruthenium complexes were studied for their anti-estrogenic effects.20Thiolato gold(I) complexes of 1,1′-bis(diphenylphosphino)ferrocene show cytotoxicity,21 and the bis(phosphinecatecholato)platinum(II) moiety tethered to COMPOUND LINKS
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Download mol file of compoundferrocene or COMPOUND LINKS
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Download mol file of compoundruthenocene demonstrates activity against P388 antileukemia cells.22
Following our previously reported pyridinyl and bifunctional organophosphine compounds23 as antitumor agents, many scientists reported that ferrocene derivatives exhibited unexpected biological activities. In this work, we tried to extend the idea through the incorporation of phosphinyl and amino bifunctionality into a ferrocene core structure and test for their possible cytotoxic potential towards human hepatocellular carcinoma cell line Hep3B.
Results and discussion
The preparation of 4a–l is described in Scheme 1.24 The enantioselective pure ferrocenyl alcohol (S)-1 was prepared using Friedel–Crafts acylation of COMPOUND LINKS
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Download mol file of compoundferrocene and asymmetric hydrogenation of ferrocenyl ketones catalyzed by freshly prepared [{(R)-XylylP-Phos}RuCl2{(R,R)-DPEN}] or purchased from a commercial supplier. The optically pure 1-ferrocenylethanol (S)-1 was quantitatively converted to the corresponding acetate by treatment with COMPOUND LINKS
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Download mol file of compoundacetic anhydride in COMPOUND LINKS
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Download mol file of compoundpyridine. Removal of the volatiles by vacuum provided pure materials without the need for further purification. In the second step, nucleophilic substitution of the acetate was accomplished in COMPOUND LINKS
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Download mol file of compoundmethanol using an excess of COMPOUND LINKS
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Download mol file of compounddimethylamine.25 Optically pure Ugi's amine (S)-2 was easily obtained without any crystallization process due to retention of configuration in nucleophilic substitution.26 The planar chirality was introduced by diastereoselective ortho-lithiation of ferrocenyl amine (S)-2 using COMPOUND LINKS
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Download mol file of compoundt-BuLi leading to (S,Rp)-3 which has its α-alkyl group in a position of less steric repulsion. The diastereomerically pure (S,Rp)-3 was obtained in moderate to good yield after electrophilic substitution. The dimethylamino group of (S,Rp)-3 underwent nucleophilic substitution with retention of configuration. A series of ferrocenyl amino-phosphine ligands (S,Rp)-4a–l were obtained without any change in chirality. The percentage yields obtained for compound (S, Rp)-4 were moderate to good, from 63% to 99%.
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| Scheme 1 Synthesis of ferrocenyl amino phosphines. Reagents and conditions: (a) (i) Ac2O, COMPOUND LINKS
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Download mol file of compoundpyridine, rt; (ii) Me2NH, COMPOUND LINKS
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Download mol file of compoundMeOH, rt. (b) (i) COMPOUND LINKS
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Download mol file of compoundt-BuLi, Et2O, 0 °C, rt; (ii) ClPPh2, 0 °C to rt. (c) (i) Ac2O, 100 °C, 1 h; (ii) MeCN, H2NR1, 80 °C, overnight. | |
Here, we reported the synthesis and biological activities of a series of ferrocenyl amino-phosphine compounds 3 and 4 as antitumor agents. The biological activities of 3 and 4 are significant as compared to that of the bare ferrocene scaffold (which does not show any biological activity even at a concentration of over 100 μg ml−1) as control. In connection with this idea, we tried using various substitutions for 4, and we found that the chain length and bulkiness are important to account for the biological activity (Table 1). From the IC50 results obtained, the bulky aromatic groups, such as phenyl, naphthyl and tetrahydronaphthyl substitutions (compounds 4g, 4h and 4j), do not exhibit biological activities even at a high dosage of over 100 μg ml−1. Bulky groups, such as 2-naphthyl, COMPOUND LINKS
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Download mol file of compounddiphenyl and adamantyl bulky groups, show only little biological activities (compounds 4i, 4k and 4l). Aliphatic substitutions, such as methyl, propyl, cyclopropyl, isopropyl, isobutyl and tert-butyl groups (compounds 4a–f), exhibited more significant biological activities than aromatic bulky groups in general (compounds 4g–l). Among the compounds 4f, 4b and 4d show significant high biological activities with IC50 of 0.75, 1.5 and 3 μg ml−1, respectively. tert-Butyl substitution on compound 4 seems to be the best candidate from this study for further biological investigation.
Table 1 Relative anti-cancer activity of ferrocenyl amino-phosphine on the human hepatocellular carcinoma cell line Hep3B. Results are shown as the mean IC50 values from 3 independent tests. Each test was performed in triplicate
Conclusion
Here we reported the examination of ferrocenyl amino phosphines and their possible cytotoxic potential towards the human Hep3B hepatocellular carcinoma cell. Compounds 4b, 4d and 4f exhibit strong cytotoxicity with IC50 < 5 μg ml−1.
Experimental section
1. General procedures
Unless otherwise indicated, all reactions were carried out under nitrogen atmosphere. Melting points were measured using an electrothermal 9100 apparatus in capillaries and the data were uncorrected. NMR spectra were recorded on a Varian 500 MHz Fourier transform spectrometer. 1H and 13C NMR spectra were recorded relative to residual protiated solvent; a positive value of the chemical shift denotes a resonance downfield from TMS. 31P NMR spectra were recorded using H3PO4 as an external standard (0 ppm). Mass analyses were performed on a Finnigan model Mat 95 ST mass spectrometer. High-performance liquid chromatography (HPLC) analyses were performed using a Hewlett-Packard model HP 1050/1100 LC interfaced to a HP 1050 series computer workstation using a variety of optically active columns (Daicel Chiracel AS-H, Chiracel AS, Chiracel AD, or Chiracel AD-H). Optical rotations were measured on a Perkin-Elmer model 341 polarimeter at 20 °C. The solid prochiral ferrocenyl ketones were re-crystallized before use and all other chemicals were purchased from commercial suppliers and used without further purification. COMPOUND LINKS
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Download mol file of compoundDiethyl ether was freshly distilled from Na/benzophenone ketyl under nitrogen. COMPOUND LINKS
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Download mol file of compoundDichloromethane was freshly distilled from COMPOUND LINKS
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Download mol file of compoundcalcium hydride under nitrogen. All reactions were monitored by analytical thin-layer chromatography (TLC) on Merck aluminium-precoated plates of COMPOUND LINKS
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Download mol file of compoundsilica gel 60 F254 with detection by spraying with 5% (w/v) dodecamolybdophosphoric acid in COMPOUND LINKS
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Download mol file of compoundethanol or 5% (w/v) COMPOUND LINKS
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Download mol file of compoundninhydrin in COMPOUND LINKS
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Download mol file of compoundethanol and subsequent heating. E. Merck COMPOUND LINKS
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Download mol file of compoundsilica gel 60 (230–400 mesh) was used for flash chromatography. Hydrogenation reactions were carried out using a Parr 4714 bomb and a Parr 4520 series stirred reactor.
2. Synthesis of ferrocenyl amino phosphines 4a–l
The enantioselective pure (S)-1 was prepared using Friedel–Crafts acylation of COMPOUND LINKS
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Download mol file of compoundferrocene and asymmetric hydrogenation of ferrocenyl ketones catalyzed by freshly prepared [{(R)-XylylP-Phos}RuCl2{(R,R)-DPEN}] (ref. 24) or purchased from a commercial supplier. The ferrocenyl alcohol, (S)-1, was dissolved in a mixture of COMPOUND LINKS
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Download mol file of compoundpyridine and COMPOUND LINKS
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Download mol file of compoundacetic anhydride (4.3 equiv.) and stirred for 12 h at room temperature. Solvents were removed under vacuum. The solid acetate was treated with COMPOUND LINKS
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Download mol file of compounddimethylamine (1.8 equiv., 33% solution in COMPOUND LINKS
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Download mol file of compoundwater) in COMPOUND LINKS
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Download mol file of compoundMeOH. After stirring for 12 h at room temperature, solvents were removed under reduced pressure and the crude product was extracted with 10% H3PO4 after being layered with Et2O. The aqueous layer was then basified with 10% COMPOUND LINKS
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Download mol file of compoundNaOH and was extracted with Et2O. The combined organic phase was washed with COMPOUND LINKS
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Download mol file of compoundwater and brine, and dried over MgSO4. The crude product was purified by column chromatography in COMPOUND LINKS
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Download mol file of compoundalumina to give the corresponding ferrocenyl amine (S)-2. The amine (S)-2 was dissolved in COMPOUND LINKS
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Download mol file of compounddiethyl ether and cooled to 0 °C. COMPOUND LINKS
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Download mol file of compoundt-BuLi (1.2 equiv., 1.5 M) was added, the mixture was stirred for 1 h at 0 °C and COMPOUND LINKS
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Download mol file of compounddiphenylchlorophosphine (1.2 equiv.) was added. After the reaction mixture was warmed to rt and stirred overnight, COMPOUND LINKS
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Download mol file of compoundwater was added slowly to hydrolyze the unreacted t-BuLi. The crude product was extracted with 10% H3PO4 after being layered with Et2O. The aqueous layer was then basified with 10% COMPOUND LINKS
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Download mol file of compoundNaOH and was extracted with Et2O. The combined organic phase was washed with COMPOUND LINKS
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Download mol file of compoundwater and brine, and dried over MgSO4. The crude product was purified by column chromatography to give the corresponding (S,Rp)-3. The 1,2-disubstituted ferrocenyl amine was sealed in an air-free tube with COMPOUND LINKS
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Download mol file of compoundacetic anhydride. After the reaction mixture was heated to 100 °C for 1 h, the acetic anhydride was removed under reduced pressure. The residue was dissolved in CH3CN and a primary amine (5 equiv.) was added. The reaction mixture was stirred at 80 °C overnight. The reaction mixture was washed with COMPOUND LINKS
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Download mol file of compoundwater and extracted with COMPOUND LINKS
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Download mol file of compounddiethyl ether. The crude product was purified by column chromatography to give the corresponding ferrocenyl amino-phosphine (S,Rp)-4.
(S)-1-Ferrocenyl-N,N-dimethylethylamine, (S)-2.
1H NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3, 500 MHz): δ 4.15–4.09 (m, 6H), 3.60 (q, J = 7 Hz, 1H), 2.08 (s, 7H), 1.45 (d, J = 7 Hz, 3H); 13C NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 87.0, 69.2, 68.4, 67.2, 67.1, 66.7, 58.5, 40.6, 16.0. [α]20D = −1.88 (c = 1.68, CH2Cl2).
(S)-N,N-Dimethyl-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethylamine, (S,Rp)-3.
1H NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3, 500 MHz): δ 7.62–7.59 (m, 2H), 7.39–7.35 (m, 2H), 7.24–7.16 (m, 4H), 4.38 (q, J = 3 Hz, 1H), 4.26 (t, J = 2.5 Hz, 1H), 4.17 (q, J = 11.5 Hz, 1H), 3.95 (s, 3H), 3.87 (m, 1H), 1.78 (s, 6H), 1.27 (d, J = 7 Hz, 3H); 13C NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 135.3, 135.1, 132.5, 132.3, 130.7, 130.6, 128.7, 128.0, 127.4, 72.1, 71.8, 70.3, 69.7, 69.4, 68.4, 57.8, 39.1; 31P NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ −23.14; HRMS (ESI) calcd for C30H28NPFe, 489.1309; found, 489.1291; [α]20D = −358.4 (c = 0.49, CHCl3).
(S)-1-[(R)-2-(Diphenylphosphino)ferrocenyl]ethylamine, (S,Rp)-4a.
1H NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3, 500 MHz): δ 7.56–7.52 (m, 2H), 7.38–7.37 (m, 1H), 7.26–7.24 (br, 4H), 4.44 (d, J = 1.5 Hz, 1H), 4.28 (t, J = 2.5 Hz, 1H), 4.22 (dq, J1 = 2 Hz, J2 = 6.75 Hz, 1H), 4.02 (s, 3H), 3.77 (s, 1H), 1.45 (d, J = 7 Hz, 3H), 1.38 (b, 2H); 13C NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 139.8, 137.1, 135.0, 134.8, 132.9, 132.7, 129.2, 128.5, 128.4, 128.2, 74.8, 71.4, 70.8, 69.6, 69.2, 68.5, 45.5, 22.6; 31P NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ −24.55; [α]20D = −283.0 (c = 0.45, CHCl3).
(S)-N-Propyl-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethylamine, (S,Rp)-4b.
1H NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3, 500 MHz): δ 7.54 (b, 2H), 7.37 (b, 2H), 7.26 (b, 4H), 4.50 (s, 1H), 4.28 (s, 1H), 4.03 (s, 3H), 3.78 (s, 1H), 2.30 (b, 1H), 2.16 (b, 1H), 1.43 (d, J = 6.5 Hz, 3H), 0.91 (b, 1H), 0.73 (b, 1H), 0.52 (m, 3H); 13C NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 139.6, 139.5, 136.7, 136.6, 134.7, 134.6, 132.6, 132.5, 128.9, 128.3, 128.2, 128.0, 127.9, 97.5, 97.3, 74.9, 74.8, 71.0, 70.9, 69.5, 69.2, 69.1, 68.8, 51.3, 51.2, 48.8, 22.6, 18.9, 11.4; 31P NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ −25.1; [α]20D = −318.7 (c = 0.6, CHCl3).
(S)-N-Cyclopropyl-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethylamine, (S,Rp)-4c.
1H NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3, 500 MHz): δ 7.54 (b, 2H), 7.36 (b, 2H), 7.26 (b, 4H), 4.49 (s, 1H), 4.24 (s, 1H), 4.12 (s, 1H), 4.04 (s, 3H), 3.75 (s, 1H), 1.79 (s, 1H), 1.49 (d, J = 6.5 Hz, 3H), 4.14 (s, 3H), 3.87 (s, 1H), 1.70 (s, d = 6.5 Hz, 3H), 0.12 (m, 3H); 13C NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 139.6, 136.8, 134.8, 134.6, 132.9, 132.7, 128.9, 128.3, 128.1, 127.9, 97.3, 97.1, 75.1, 75.0, 71.1, 71.0, 70.2, 69.6, 69.2, 69.1, 68.8, 51.6, 51.5, 28.0, 19.2, 6.5, 5.2; 31P NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ −24.5; [α]20D = −288.8 (c = 0.36, CHCl3).
(S)-N-Isopropyl-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethylamine, (S,Rp)-4d.
1H NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3, 500 MHz): δ 7.55 (m, 2H), 7.53 (b, 2H), 7.27 (b, 4H), 4.53 (s, 1H), 4.28 (s, 1H), 4.11 (m, 1H), 4.04 (s, 3H), 2.69 (m, 1H), 1.48 (dd, J = 6.5 Hz, 3H), 0.61 (m, 6H); 13C NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 139.8, 136.8, 135.0, 134.9, 132.7, 129.0, 128.4, 128.3, 128.0, 127.9, 74.7, 71.1, 69.5, 69.3, 69.2, 69.0, 48.3, 48.2, 46.3, 23.9, 21.4, 20.1; 31P NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ −27.0; [α]20D = 278.49 (c = 0.69, CH2Cl2); [α]20D = −330.7 (c = 0.4, CHCl3).
(S)-N-Isobutyl-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethylamine, (S,Rp)-4e.
1H NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3, 500 MHz): δ 7.53 (m, 2H), 7.36 (b, 2H), 7.24 (b, 4H), 4.53 (s, 1H), 4.30 (s, 1H), 4.00 (m, 3H), 3.80 (s, 1H), 2.20 (m, 1H), 2.1 (m, 1H), 1.48 (dd, J = 6.0 Hz, 3H), 1.1 (m, 1H), 0.53 (dd, J = 6.5 Hz, 3H), 0.37 (dd, J = 6.5 Hz, 3H); 13C NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 139.8, 139.7, 136.9, 134.8, 132.4, 128.8, 128.1, 128.0, 127.9, 127.8, 97.8, 74.6, 70.9, 69.3, 69.2, 69.1, 68.8, 54.9, 51.2, 28.2, 20.5, 19.9, 19.0; 31P NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ −25.4; [α]20D = −339.2 (c = 0.35, CHCl3).
(S)-N-tert-Butyl-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethylamine, (S,Rp)-4f.
1H NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3, 500 MHz): δ 7.53 (m, 2H), 7.37 (b, 3H), 7.27 (b, 4H), 4.60 (s, 1H), 4.30 (m, 2H), 4.0 (s, 3H), 3.73 (s, 1H), 1.60 (s, 3H), 0.80 (s, 9H); 13C NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 140.0, 139.8, 136.8, 135.0, 134.9, 132.6, 132.4, 128.9, 128.4, 128.3, 128.1, 127.9, 127.8, 99.9, 99.8, 76.7, 73.9, 70.9, 69.6, 69.4, 69.1, 50.7, 46.3, 29.8, 22.5; 31P NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ −27.3; [α]20D = −324.8 (c = 0.31, CHCl3).
(S)-N-Phenyl-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethylamine, (S,Rp)-4g.
1H NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3, 500 MHz): δ 7.60 (b, 2H), 7.42 (b, 3H), 7.35 (m, 5H), 7.2 (m, 2H), 6.66 (b, 1H), 6.22 (m, 2H), 4.77 (b, 1H), 4.60 (s, 1H), 4.4 (s, 1H), 4.13 (s, 4H), 3.57 (b, 1H), 1.65 (s, 3H); 13C NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 146.5, 139.3, 139.2, 137.1, 137.0, 134.8, 134.7, 132.6, 132.4, 128.8, 128.7, 128.0, 127.9, 116.4, 112.3, 96.6, 96.4, 75.7, 75.6, 71.7, 69.7, 69.6, 68.6, 47.8, 47.7, 20.5; 31P NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ −24.1; [α]20D = −324.2 (c = 0.38, CHCl3).
(S)-N-Naphthyl-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethylamine, (S,Rp)-4h.
1H NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3, 500 MHz): δ 7.67 (m, 1H), 7.57 (b, 2H), 7.34 (m, 6H), 7.09 (m, 2H), 6.65 (m, 1H), 4.88 (s, 1H), 4.61 (s, 1H), 4.35 (s, 1H), 4.13 (s, 3H), 3.88 (s, 1H), 1.58 (d, J = 6.5 Hz, 3H); 13C NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 141.8, 138.5, 136.9, 134.6, 132.4, 128.8, 127.9, 126.4, 125.1, 123.9, 123.1, 120.1, 116.1, 103.3, 96.7, 75.2, 71.7, 70.3, 69.7, 68.8, 47.7, 20.5; 31P NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ −24.01; [α]20D = −479.7 (c = 0.2, CHCl3).
(S)-N-2-Naphthyl-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethylamine, (S,Rp)-4i.
1H NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3, 500 MHz): δ 7.64 (m, 2H), 7.63 (m, 2H), 7.41 (m, 5H), 7.36 (m, 1H), 7.18 (m, 3H), 6.68 (s, 1H), 6.06 (s, J = 8.5 Hz, 1H), 4.89 (m, 1H), 4.61 (s, 1H), 4.36 (s, 1H), 4.14 (s, 3H), 3.87 (s, 1H), 1.70 (d, J = 6.5 Hz, 3H), 1.27 (m, 1H); 13C NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 144.2, 139.3, 137.0, 136.9, 135.1, 134.8, 134.7, 132.7, 132.5, 128.9, 128.3, 128.1, 128.0, 127.9, 127.4, 127.1, 125.8, 121.3, 117.7, 103.4, 96.3, 96.1, 75.9, 75.8, 71.9, 69.8, 69.7, 69.6, 68.7, 60.3, 47.9, 20.0; 31P NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ −24.4; [α]20D = −151.9 (c = 0.06, CHCl3).
(S)-N-1,2,3,4-Tetrahydronaphthyl-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethylamine, (S,Rp)-4j.
1H NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3, 500 MHz): δ 7.59 (s, 1H), 7.40 (b, 3H), 7.19 (b, 5H), 7.04 (s, 1H), 6.57 (s, 1H), 6.43 (s, 1H), 4.86 (s, 1H), 4.60 (s, 1H), 4.37 (s, 1H), 4.10 (s, 4H), 3.97 (s, 1H), 3.60 (s, 1H), 2.67 (s, 2H), 2.02 (b, 1H), 1.59 (m, 9H); 13C NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 143.9, 139.3, 139.2, 137.3, 136.9, 134.7, 134.6, 132.6, 128.7, 127.9, 125.5, 120.7, 117.1, 106.4, 96.9, 75.4, 71.7, 70.2, 69.9, 69.6, 68.6, 47.0, 29.0, 23.1, 22.9, 22,3, 20.3; 31P NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ −24.7; [α]20D = −366.6 (c = 0.32, CHCl3).
(S)-N-Diphenyl-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethylamine, (S,Rp)-4k.
1H NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3, 500 MHz): δ 7.60 (m, 2H), 7.59 (m, 2H), 7.40 (m, 3H), 7.08 (m, 1H), 6.98 (s, 1H), 4.90 (s, 1H), 4.55 (s, 1H), 4.34 (s, 1H), 4.07 (b, 1H), 4.05 (s, 3H), 3.85 (s, 1H), 1.48 (dd, J = 6.5 Hz, 3H); 13C NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 144.6, 143.1, 140.6, 137.7, 135.3, 132.5, 128.9, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.5, 127.3, 127.8, 126.6, 126.4, 99.0, 98.8, 74.8, 74.7, 71.3, 71.2, 69.5, 69.1, 64.8, 48.7, 48.6, 19.7; 31P NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ −24.7; [α]20D = −280.8 (c = 0.49, CHCl3).
(S)-N-Adamantyl-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethylamine, (S,Rp)-4l.
1H NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3, 500 MHz): δ 7.54 (m, 2H), 7.35 (m, 3H), 7.25 (m, 5H), 4.56 (s, 1H), 4.33 (m, 1H), 4.29 (s, 1H), 4.01 (s, 3H), 3.89 (s, 1H), 1.85 (s, 3H), 1.63 (m, 3H), 1.50 (m, 3H), 1.42 (m, 3H), 1.23 (m, 3H); 13C NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 139.9, 136.8, 135.1, 134.9, 134.8, 134.6, 132.8, 132.7, 129.0, 128.5, 128.4, 128.3, 128.2, 128.1, 127.9, 100.0, 99.8, 73.7, 70.9, 69.9, 69.6, 69.5, 69.2, 69.1, 51.5, 44.6, 42.9, 36.4, 29.5, 23.5, 22.3; 31P NMR (COMPOUND LINKS
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Download mol file of compoundCDCl3): δ −25.4; [α]20D = −250.2 (c = 0.31, CHCl3).
3.
In vitro cytotoxicity assay
Human carcinoma cell line Hep3B hepatocellular carcinoma was used in order to perform preliminary anti-cancer screening for the selected ferrocenyl compounds. Cancer cells (1 × 104 per well) seeded in the 96-well microtitre plates for 24 h were prepared for the ferrocenyl compound screening. The selected compounds were prepared as a stock concentration of 10 mg mL−1 in COMPOUND LINKS
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Download mol file of compounddimethyl sulfoxide (COMPOUND LINKS
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Download mol file of compoundDMSO) and were added at a concentration of 100 μg mL−1 and incubated for a further 48 h (Fig. 1). Untreated controls received either total complete medium or 1% of COMPOUND LINKS
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Download mol file of compoundDMSO. Cisplatin was used as the positive cytotoxic reference and dissolved in cell culture medium. Afterwards, the evaluation of possible antiproliferative effect or cytotoxicity of those ferrocenyl compounds was examined by the sulforhodamine B protein staining methods. Briefly, cancer cells were fixed with COMPOUND LINKS
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Download mol file of compoundtrichloroacetic acid, washed with distilled COMPOUND LINKS
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Download mol file of compoundwater and stained with sulforhodamine B. Afterwards, cells were washed again with COMPOUND LINKS
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Download mol file of compoundacetic acid and stained cells were dissolved in unbuffered Tris-base. Finally, optical absorptions were measured at 575 nm using a microplate reader (Victor V form Perkin Elmer, Life Sciences). The 50% inhibitory concentrations of compounds and cisplatin were calculated from these experimental results.
Acknowledgements
The authors acknowledge the research grants 1ZV-5L and APK-08 offered by HKPU. Dr C. H. Chui is supported by the Assistant Professorship kindly offered by Professor X. M. Tao. Professor R. Gambari is sponsored by AIRC (Italian Association for Cancer Research). The authors wish to dedicate to Professor Albert Sun-Chi Chan on his occasion of 60th birthday.
Notes and references
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