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Structures and antitumor activities of planar chiral cyclopalladated ferrocene derivatives
Structures and antitumor activities of plannar chiral cyclopalladated ferrocene derivatives Dongyuan Ning, Yuan Cao, Yuanyuan Zhang, Linghao Xia, Gang Zhao PII: DOI: Reference:
S1387-7003(15)00202-6 doi: 10.1016/j.inoche.2015.05.014 INOCHE 5995
To appear in:
Inorganic Chemistry Communications
Received date: Revised date: Accepted date:
21 April 2015 13 May 2015 14 May 2015
Please cite this article as: Dongyuan Ning, Yuan Cao, Yuanyuan Zhang, Linghao Xia, Gang Zhao, Structures and antitumor activities of plannar chiral cyclopalladated ferrocene derivatives, Inorganic Chemistry Communications (2015), doi: 10.1016/j.inoche.2015.05.014
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Structures and antitumor activities of plannar chiral cyclopalladated ferrocene derivatives Dongyuan Ning, Yuan Cao, Yuanyuan Zhang, Linghao Xia, Gang Zhao,*
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College of Chemical Engineering, Sichuan University, Chengdu, China 610064.
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* Corresponding author. E-mail address: [email protected] (G. Zhao). Tel. +86 18980927097 Fax +86 28 85998339
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Keywords: cyclopalladated compound; plannar chirality; crystal structure; antitumor activitie
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Abstract: Bis(µ-acetato)-bridged planar chiral cyclopalladated products have been obtained by asymmetric cyclopalladation of the corresponding chiral ferrocenylimines with palladium(II) acetate and sodium acetate in methanol at room temperature. Two diastereomers were isolated in enantiomerically pure form and their absolute configurations have been determinated by single-crystal X-ray analysis. It was found that enantiomerically pure cyclopalladated ferrocene displayed the excellent inhibition to two human breast carcinoma cell lines, MDA-MB-231 and MDA-MB-468 and could have good application prospect in pharmaceutical use.
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Despite the tremendous success of platinum-based antitumor drugs like cisplatin, carboplatin and oxaliplatin, this compound suffers from two main disadvantages; it is inefficient against cisplatin-resistant tumours, and it has severe side effects such as nephrotoxicity [1]. Therefore, the development of new anticancer drugs based on non-platinum metal compounds arouses great interest in medicinal chemistry [2]. In particular, palladacycles are nowadays attracting attention as potential anticancer agents because it is known that their intercalative mode of cytotoxic action is strictly related to the presence of a planar and highly stable aromatic metallacycle. It has been found that some cyclopalladated complexes containing planar structures may bind to DNA by means of intercalative or coordinate covalent interactions [3-5]. Interestingly, the cell killing mechanism of organopalladium(II) compounds may be highly dependent on their structure [6]. However, only a few optically active organopalladium compounds with a chiral metalated carbon center have been reported up to now [7]. In order to investigate the relationship between the stereochemistry and anticancer activity, we synthesized and isolated two enantiomerically pure 1,2-disubstituted cyclopalladated ferrocene derivatives and investigate their anticancer activities. Both of them were characterized by elemental analysis (EA), nuclear magnetic resonance (NMR) and single-crystal diffraction, their inhibition to two human breast carcinoma cell lines, MDA-MB-231 and MDA-MB-468 were tested. Single-crystal X-ray diffraction measurements of the complexes were carried out on a MSC/Rigaku RAXIS IIC imaging-plate diffractometer at 294 K using graphite-monochromatized Mo-Kα radiation (λ = 0.7103 Å). A self-consistent semiempirical absorption correction based on Fourier coefficient fitting of symmetry-equivalent reflections was applied using the ABSCOR program[8]. The crystal structures were determined by the direct method, which yielded the positions of all non-hydrogen atoms, which were refined anisotropically. Hydrogen atoms were all generated geometrically (C-H bond lengths fixed at
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0.96 Å), assigned appropriate isotropic thermal parameters, and allowed to ride on their parent carbon atoms. All the H atoms were held stationary and included in the structure factor calculation in the final stage of full-matrix least-squares refinement. The major bond length and bond angle of the two enantiomerically pure 1,2-disubstituted cyclopalladated ferrocene derivatives were listed (Table S1). The crystallographic data and structure refinement summary data for the two complexes were listed in Table S2. The synthesis abstract of the complexes were listed in Fig. S1. X-ray analysis has established the absolute planar chiralities of the ferrocenyl moieties based on the ()-(S)-1-amino-2-(methoxylmethyl)pyrrolidine [()-(S)-1] marker in compounds syn-(+)-(Rp,S,S,Rp)-3 (Figure 1) and syn-(+)-(Sp,S,S,Sp)-4 (Figure 2). In syn-(+)-(Sp,S,S,Sp)-4, a pair of enantiomers, the asymmetric unit contains two independent, nearly alike molecules (designated A and B); only molecule A of syn-(+)-(Sp,S,S,Sp)-4 is shown in Figure 2. In all cases, the acetate groups force the two square planes of each palladium atom to have a relatively small dihedral angle between planes N(1)-Pd(1)-C(1) and O(4)-Pd(1)-O(6) [tilt angle: 5.6 for syn-(+)-(Rp,S,S,Rp)-3, and 8.6° (molecule A) and 9.4 (molecule B) for syn-(+)-(Sp,S,S,Sp)-4], resulting in the molecule adopting a half-opened clam shape. The angle between the two planes defined by Pd(1), O(4), O(6), N(1), C(1) and Pd(2), O(3), O(5), N(3), C(19), respectively, is 44.8 in syn-(+)-(Rp,S,S,Rp)-3; and 47.1° (molecule A) and 46.4 (molecule B) in syn-(+)-(Sp,S,S,Sp)-4]. The main difference between the diastereomers is that the two methoxylmethyl groups at chiral carbon atoms are inside the clam in syn-(+)-(Rp,S,S,Rp)-3 and outside the clam in syn-(+)-(Sp,S,S,Sp)-4. The cyclopentadienyl rings are each planar and nearly parallel to each other [tilt angle: 3.4 for syn-(+)-(Rp,S,S,Rp)-3; and 3.6° (molecule A) and 3.6 (molecule B) for syn-(+)-(Sp,S,S,Sp)-4], and the two rings involved in the bicyclic system formed by fusion of the palladacycle with the ferrocenyl C5H3 moiety are approximately co-planar, the relevant dihedral angle being 4.4 for syn-(+)-(Rp,S,S,Rp)-3, and 5.1° (molecule A) and 3.1 (molecule B) for syn-(+)-(Sp,S,S,Sp)-4.
Figure 1 Molecular structure (30% thermal ellipsoids) and absolute configuration of syn-(+)-(Rp,S,S,Rp)-3 with atom-numbering scheme.
Figure 2 Molecular structure (30% thermal ellipsoids) and absolute configuration of syn-(+)-(Sp,S,S,Sp)-4 with atom-numbering scheme.
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The Pd-N bond lengths are normal; however all Pd-C bond lengths, Pd(1)-C(1) and Pd(2)-C(19) [1.960(3), 1.942(3) Å in syn-(+)-(Rp,S,S,Rp)-3; and 1.913(6), 1.927(6) Å in syn-(+)-(Sp,S,S,Sp)-4] are substantially shorter than the predicted value of 2.05 Å[9]. This suggests some multiple-bond character in Pd-C linkages due to metal-to-ligand back-bonding[9]. The Pd-O bonds, Pd(1)-O(4) and Pd(1)-O(5), having nitrogen atoms in trans positions are significantly shorter [2.062(2), 2.043(2) Å for syn-(+)-(Rp,S,S,Rp)-3; and 2.042(3), 2.036(4) Å for syn-(+)-(Sp,S,S,Sp)-4] than those [Pd(1)-O(3) and Pd(1)-O(6)] showing a trans relationship with respect to the ferrocenyl carbon atoms, [2.147(2), 2.140(2) Å for syn-(+)-(Rp,S,S,Rp)-3; and 2.147(4), 2.126(4) Å for syn-(+)-(Sp,S,S,Sp)-4], as a consequence of the different trans influences of both atoms[10,11]. Compounds syn-(+)-(Rp,S,S,Rp)-3 and syn-(+)-(Sp,S,S,Sp)-4 were evaluated in vitro for inhibition of cell proliferation against the MDA-MB231 and MDA-MB-468 human breast cancer cell lines, using cisplatin as a positive control. The MTT assay was used to measure the cell viability after treatment with compounds syn-(+)-(Rp,S,S,Rp)-3 and syn-(+)-(Sp,S,S,Sp)-4, respectively. Briefly, cells were plated on 96-well mircroplates at a density of 2-5×103 cells per well and cultured for 24 h. After various concentrations of syn-(+)-(Rp,S,S,Rp)-3 or syn-(+)-(Sp,S,S,Sp)-4 treatment for 48 h, 20 μL of MTT solution (5mg/mL) was added to each well and incubation for 2-4 h at 37 ºC. Then the medium was discarded and 150 μL of DMSO was added to each well to dissolve the formazan crystal produced by living cells. Ten minutes later, 96-well microplates were read on Spectra MAX M5 microplate spectrophotometer (Molecular Devices) at 570 nm for O.D. values.
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Table 1 IC50 (μM) values for compounds syn-(+)-(Rp,S,S,Rp)-3 and syn-(+)-(Sp,S,S,Sp)-4. Data are shown as the mean values of three experiments performed in triplicate with the corresponding standard deviation. IC50 (μM) (mean±S.D.) Compound MDA-MB-231 MDA-MB-468 7.33±0.25 0.85±0.33 syn-(+)-(Rp,S,S,Rp)-3 10.13±0.64 6.97±0.72 syn-(+)-(Sp,S,S,Sp)-4 cisplatina 35.94±0.98 10.30±1.09 a cis-[PtCl2(NH3)2] is taken as reference compound. These results revealed that both bis(µ-acetato)-bridged planar chiral cyclopalladated products had excellent inhibition to two human breast carcinoma cell lines, MDA-MB-231 and MDA-MB-468 compared with platinum-based antitumor drug cisplatin. Table 1 showed that both cyclopalladated products exhibit a high antiproliferative activity, showing IC50 values in the range 1-10 μM below those of cisplatin in both cellular lines. Compounds syn-(+)-(Rp,S,S,Rp)-3 and syn-(+)-(Sp,S,S,Sp)-4 were approximately 5- and 12-fold times more potent than cisplatin in the MDA-MB-231 and MDA-MB-468 human breast cancer cells respectively. Interestingly, the cell killing mechanism of organopalladium(II) compounds may be highly dependent on their structure. Compound syn-(+)-(Rp,S,S,Rp)-3 exhibited much better potency (8-fold times) than its diastereomer syn-(+)-(Sp,S,S,Sp)-4 in the MDA-MB-468 human breast cancer cell line, and were worth being further investigated. 3
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In conclusion, two enantiomerically pure bis(µ-acetato)-bridged planar chiral cyclopalladated products were synthesized and isolated in enantiomerically pure form. Their cytotoxicities against two human breast carcinoma cell lines, MDA-MB-231 and MDA-MB-468 were evaluated. Compound syn-(+)-(Rp,S,S,Rp)-3 showed a much higher cytotoxic than its diastereomer syn-(+)-(Sp,S,S,Sp)-4. The IC50 values for compound syn-(+)-(Rp,S,S,Rp)-3 with different cell lines in our study ranged from 0.8 to 7.0 µM, which are clinically achievable doses. Thus, syn-(+)-(Rp,S,S,Rp)-3 is considered as an agent with potential antitumor activity, and can therefore be candidates for further stages of screening in vitro and/or in vivo. The researches on detailed structure–activity relationship and reaction mechanism of the cyclopalladated products against tumor cells are proceeding.
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Acknowledgment
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The authors gratefully acknowledge the Sichuan University High Level Talent Project and Sichuan Province 1,000 Talents Plan Project for financial support.
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References [1] L. Kelland, Nat. Rev. Cancer 7 (2007) 573. [2] G. Gasser, I. Ott, N. Metzler-Nolte, J. Med. Chem. 54 (2011) 3. [3] (a) F. A. Serrano, A. L. Matsuo, P. T. Monteforte, et al., BMC Cancer 11 (2011) 296; (b) A. B. Guimaraes-Correa, L. B. Crawford, C. R. Figueiredo, et al., Viruses 3 (2011) 1041; (c) F. Hebeler-Barbosa, E. G. Rodrigues, R. Puccia, et al., Transl. Oncol. 1 (2008) 110; (d) M. C. da Rocha, A. M. Santana, S. R. Ananias, et al., J. Braz. Chem. Soc. 18 (2007) 1473; (e) C. Bincoletto, I. L. S. Tersariol, C. R. Oliveira, et al., Bioorg. Med. Chem. 13 (2005) 3047 [4] A. C. F. Caires, C. B. Trindade, I. L. d. S. Tersariol, WO/2004/019924. [5] (a) M. Carreira, R. Calvo-Sanjuán, M. Sanaú, Organometallics 31 (2012) 5772; (b) E. Budzisz, R. Bobka, A. Hauss, et al., Dalton Trans. 41 (2012) 5925; (c) N.C. Campanella, M. da Silva Demartini, C. Torres, et al.,Genet. Mol. Biol. 35 (2012) 159; (d) J. Quirante, D. Ruiz, A. Gonzalez, et al., J. Inorg. Biochem. 105 (2011) 1720; (e) M. S. Subhas, S. S. Racharlawar, B. Sridhar, et al., Org. Biomol. Chem. 8 (2010) 3001. [6] E.G. Rodrigues, L.S. Silva, D.M. Fausto, et al., Int. J. Cancer 107 (2003) 498. [7] (a) F. Maassarani, M. Pfeffer, Organometallics 6 (1987) 1111; (b) S. Y. M. Chooi, S.-Y. Siah, P.-H. Leung, K. F. Mok, Inorg. Chem. 32 (1993) 4812; (c) S. Q. Huo, Y. J. Wu, C. X. Du, et al., J. Organomet. Chem. 483(1994) 139; (d) H. L. Holcomb, S. Nakanish, T. C. Flood, Organometallics 15 (1996) 4228; (e) B.-H. Aw, P.-H. Leung, A. J. P. White, et al., Organometallics 15 (1996) 3640. (f) S.-Y. Siah, P.-H. Leung, K. F. Mok, et al., Tetrahedron: Asymmetry 7 (1996) 357; (g) G. Zhao, Q-C. Yang, and T. C. W. Mak, Organometallics 18 (1999) 3623. [8] T. Higashi, ABSCORsAn Empirical Absorption Correction Based on Fourier Coefficient Fitting; Rigaku Corporation: Tokyo, 1995. [9] J. P. Sutter, M. Pfeffer, A. De Cian, J. Fischer, Organometallics 11 (1992) 386. [10] J. L. Garcia-Ruano, I. López-Solera, J. R. Masaguer, C. et al., Organometallics 11 (1992) 3013. [11] G. B. Caygill, P. J. Steel, J. Organomet. Chem. 327 (1987) 115 4
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Anti-cancer active planar chiral cyclopalladated product was prepared and isolated in enantiomerically pure form.
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ACCEPTED MANUSCRIPT Highlights
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Enantiomerically pure planar chiral cyclopalladated products were isolated. Their absolute configurations have been determinated by X-ray analysis. One enantiomer exhibited much better anti-cancer activity than its isomer. It revealed an implication for structural dependence on bioactivity.
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S1387-7003(15)00202-6 doi: 10.1016/j.inoche.2015.05.014 INOCHE 5995
To appear in:
Inorganic Chemistry Communications
Received date: Revised date: Accepted date:
21 April 2015 13 May 2015 14 May 2015
Please cite this article as: Dongyuan Ning, Yuan Cao, Yuanyuan Zhang, Linghao Xia, Gang Zhao, Structures and antitumor activities of plannar chiral cyclopalladated ferrocene derivatives, Inorganic Chemistry Communications (2015), doi: 10.1016/j.inoche.2015.05.014
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Structures and antitumor activities of plannar chiral cyclopalladated ferrocene derivatives Dongyuan Ning, Yuan Cao, Yuanyuan Zhang, Linghao Xia, Gang Zhao,*
RI P
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College of Chemical Engineering, Sichuan University, Chengdu, China 610064.
SC
* Corresponding author. E-mail address: [email protected] (G. Zhao). Tel. +86 18980927097 Fax +86 28 85998339
NU
Keywords: cyclopalladated compound; plannar chirality; crystal structure; antitumor activitie
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Abstract: Bis(µ-acetato)-bridged planar chiral cyclopalladated products have been obtained by asymmetric cyclopalladation of the corresponding chiral ferrocenylimines with palladium(II) acetate and sodium acetate in methanol at room temperature. Two diastereomers were isolated in enantiomerically pure form and their absolute configurations have been determinated by single-crystal X-ray analysis. It was found that enantiomerically pure cyclopalladated ferrocene displayed the excellent inhibition to two human breast carcinoma cell lines, MDA-MB-231 and MDA-MB-468 and could have good application prospect in pharmaceutical use.
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Despite the tremendous success of platinum-based antitumor drugs like cisplatin, carboplatin and oxaliplatin, this compound suffers from two main disadvantages; it is inefficient against cisplatin-resistant tumours, and it has severe side effects such as nephrotoxicity [1]. Therefore, the development of new anticancer drugs based on non-platinum metal compounds arouses great interest in medicinal chemistry [2]. In particular, palladacycles are nowadays attracting attention as potential anticancer agents because it is known that their intercalative mode of cytotoxic action is strictly related to the presence of a planar and highly stable aromatic metallacycle. It has been found that some cyclopalladated complexes containing planar structures may bind to DNA by means of intercalative or coordinate covalent interactions [3-5]. Interestingly, the cell killing mechanism of organopalladium(II) compounds may be highly dependent on their structure [6]. However, only a few optically active organopalladium compounds with a chiral metalated carbon center have been reported up to now [7]. In order to investigate the relationship between the stereochemistry and anticancer activity, we synthesized and isolated two enantiomerically pure 1,2-disubstituted cyclopalladated ferrocene derivatives and investigate their anticancer activities. Both of them were characterized by elemental analysis (EA), nuclear magnetic resonance (NMR) and single-crystal diffraction, their inhibition to two human breast carcinoma cell lines, MDA-MB-231 and MDA-MB-468 were tested. Single-crystal X-ray diffraction measurements of the complexes were carried out on a MSC/Rigaku RAXIS IIC imaging-plate diffractometer at 294 K using graphite-monochromatized Mo-Kα radiation (λ = 0.7103 Å). A self-consistent semiempirical absorption correction based on Fourier coefficient fitting of symmetry-equivalent reflections was applied using the ABSCOR program[8]. The crystal structures were determined by the direct method, which yielded the positions of all non-hydrogen atoms, which were refined anisotropically. Hydrogen atoms were all generated geometrically (C-H bond lengths fixed at
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0.96 Å), assigned appropriate isotropic thermal parameters, and allowed to ride on their parent carbon atoms. All the H atoms were held stationary and included in the structure factor calculation in the final stage of full-matrix least-squares refinement. The major bond length and bond angle of the two enantiomerically pure 1,2-disubstituted cyclopalladated ferrocene derivatives were listed (Table S1). The crystallographic data and structure refinement summary data for the two complexes were listed in Table S2. The synthesis abstract of the complexes were listed in Fig. S1. X-ray analysis has established the absolute planar chiralities of the ferrocenyl moieties based on the ()-(S)-1-amino-2-(methoxylmethyl)pyrrolidine [()-(S)-1] marker in compounds syn-(+)-(Rp,S,S,Rp)-3 (Figure 1) and syn-(+)-(Sp,S,S,Sp)-4 (Figure 2). In syn-(+)-(Sp,S,S,Sp)-4, a pair of enantiomers, the asymmetric unit contains two independent, nearly alike molecules (designated A and B); only molecule A of syn-(+)-(Sp,S,S,Sp)-4 is shown in Figure 2. In all cases, the acetate groups force the two square planes of each palladium atom to have a relatively small dihedral angle between planes N(1)-Pd(1)-C(1) and O(4)-Pd(1)-O(6) [tilt angle: 5.6 for syn-(+)-(Rp,S,S,Rp)-3, and 8.6° (molecule A) and 9.4 (molecule B) for syn-(+)-(Sp,S,S,Sp)-4], resulting in the molecule adopting a half-opened clam shape. The angle between the two planes defined by Pd(1), O(4), O(6), N(1), C(1) and Pd(2), O(3), O(5), N(3), C(19), respectively, is 44.8 in syn-(+)-(Rp,S,S,Rp)-3; and 47.1° (molecule A) and 46.4 (molecule B) in syn-(+)-(Sp,S,S,Sp)-4]. The main difference between the diastereomers is that the two methoxylmethyl groups at chiral carbon atoms are inside the clam in syn-(+)-(Rp,S,S,Rp)-3 and outside the clam in syn-(+)-(Sp,S,S,Sp)-4. The cyclopentadienyl rings are each planar and nearly parallel to each other [tilt angle: 3.4 for syn-(+)-(Rp,S,S,Rp)-3; and 3.6° (molecule A) and 3.6 (molecule B) for syn-(+)-(Sp,S,S,Sp)-4], and the two rings involved in the bicyclic system formed by fusion of the palladacycle with the ferrocenyl C5H3 moiety are approximately co-planar, the relevant dihedral angle being 4.4 for syn-(+)-(Rp,S,S,Rp)-3, and 5.1° (molecule A) and 3.1 (molecule B) for syn-(+)-(Sp,S,S,Sp)-4.
Figure 1 Molecular structure (30% thermal ellipsoids) and absolute configuration of syn-(+)-(Rp,S,S,Rp)-3 with atom-numbering scheme.
Figure 2 Molecular structure (30% thermal ellipsoids) and absolute configuration of syn-(+)-(Sp,S,S,Sp)-4 with atom-numbering scheme.
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The Pd-N bond lengths are normal; however all Pd-C bond lengths, Pd(1)-C(1) and Pd(2)-C(19) [1.960(3), 1.942(3) Å in syn-(+)-(Rp,S,S,Rp)-3; and 1.913(6), 1.927(6) Å in syn-(+)-(Sp,S,S,Sp)-4] are substantially shorter than the predicted value of 2.05 Å[9]. This suggests some multiple-bond character in Pd-C linkages due to metal-to-ligand back-bonding[9]. The Pd-O bonds, Pd(1)-O(4) and Pd(1)-O(5), having nitrogen atoms in trans positions are significantly shorter [2.062(2), 2.043(2) Å for syn-(+)-(Rp,S,S,Rp)-3; and 2.042(3), 2.036(4) Å for syn-(+)-(Sp,S,S,Sp)-4] than those [Pd(1)-O(3) and Pd(1)-O(6)] showing a trans relationship with respect to the ferrocenyl carbon atoms, [2.147(2), 2.140(2) Å for syn-(+)-(Rp,S,S,Rp)-3; and 2.147(4), 2.126(4) Å for syn-(+)-(Sp,S,S,Sp)-4], as a consequence of the different trans influences of both atoms[10,11]. Compounds syn-(+)-(Rp,S,S,Rp)-3 and syn-(+)-(Sp,S,S,Sp)-4 were evaluated in vitro for inhibition of cell proliferation against the MDA-MB231 and MDA-MB-468 human breast cancer cell lines, using cisplatin as a positive control. The MTT assay was used to measure the cell viability after treatment with compounds syn-(+)-(Rp,S,S,Rp)-3 and syn-(+)-(Sp,S,S,Sp)-4, respectively. Briefly, cells were plated on 96-well mircroplates at a density of 2-5×103 cells per well and cultured for 24 h. After various concentrations of syn-(+)-(Rp,S,S,Rp)-3 or syn-(+)-(Sp,S,S,Sp)-4 treatment for 48 h, 20 μL of MTT solution (5mg/mL) was added to each well and incubation for 2-4 h at 37 ºC. Then the medium was discarded and 150 μL of DMSO was added to each well to dissolve the formazan crystal produced by living cells. Ten minutes later, 96-well microplates were read on Spectra MAX M5 microplate spectrophotometer (Molecular Devices) at 570 nm for O.D. values.
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Table 1 IC50 (μM) values for compounds syn-(+)-(Rp,S,S,Rp)-3 and syn-(+)-(Sp,S,S,Sp)-4. Data are shown as the mean values of three experiments performed in triplicate with the corresponding standard deviation. IC50 (μM) (mean±S.D.) Compound MDA-MB-231 MDA-MB-468 7.33±0.25 0.85±0.33 syn-(+)-(Rp,S,S,Rp)-3 10.13±0.64 6.97±0.72 syn-(+)-(Sp,S,S,Sp)-4 cisplatina 35.94±0.98 10.30±1.09 a cis-[PtCl2(NH3)2] is taken as reference compound. These results revealed that both bis(µ-acetato)-bridged planar chiral cyclopalladated products had excellent inhibition to two human breast carcinoma cell lines, MDA-MB-231 and MDA-MB-468 compared with platinum-based antitumor drug cisplatin. Table 1 showed that both cyclopalladated products exhibit a high antiproliferative activity, showing IC50 values in the range 1-10 μM below those of cisplatin in both cellular lines. Compounds syn-(+)-(Rp,S,S,Rp)-3 and syn-(+)-(Sp,S,S,Sp)-4 were approximately 5- and 12-fold times more potent than cisplatin in the MDA-MB-231 and MDA-MB-468 human breast cancer cells respectively. Interestingly, the cell killing mechanism of organopalladium(II) compounds may be highly dependent on their structure. Compound syn-(+)-(Rp,S,S,Rp)-3 exhibited much better potency (8-fold times) than its diastereomer syn-(+)-(Sp,S,S,Sp)-4 in the MDA-MB-468 human breast cancer cell line, and were worth being further investigated. 3
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In conclusion, two enantiomerically pure bis(µ-acetato)-bridged planar chiral cyclopalladated products were synthesized and isolated in enantiomerically pure form. Their cytotoxicities against two human breast carcinoma cell lines, MDA-MB-231 and MDA-MB-468 were evaluated. Compound syn-(+)-(Rp,S,S,Rp)-3 showed a much higher cytotoxic than its diastereomer syn-(+)-(Sp,S,S,Sp)-4. The IC50 values for compound syn-(+)-(Rp,S,S,Rp)-3 with different cell lines in our study ranged from 0.8 to 7.0 µM, which are clinically achievable doses. Thus, syn-(+)-(Rp,S,S,Rp)-3 is considered as an agent with potential antitumor activity, and can therefore be candidates for further stages of screening in vitro and/or in vivo. The researches on detailed structure–activity relationship and reaction mechanism of the cyclopalladated products against tumor cells are proceeding.
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Acknowledgment
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The authors gratefully acknowledge the Sichuan University High Level Talent Project and Sichuan Province 1,000 Talents Plan Project for financial support.
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ACCEPTED MANUSCRIPT
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ACCEPTED MANUSCRIPT Graphical Abstract
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Anti-cancer active planar chiral cyclopalladated product was prepared and isolated in enantiomerically pure form.
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ACCEPTED MANUSCRIPT Highlights
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Enantiomerically pure planar chiral cyclopalladated products were isolated. Their absolute configurations have been determinated by X-ray analysis. One enantiomer exhibited much better anti-cancer activity than its isomer. It revealed an implication for structural dependence on bioactivity.
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