Synthesis, structure and anticancer activity of two platinacyclic complexes bearing isopropyl eugenoxyacetate and pyridine derivatives

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The results show the iPrEug coordinates with Pt(II) through ethylenic double bond of the allyl group and C5 of the benzene ring, while the amines only coordinate with Pt(II) via the N heteroatom and occupy cis-position in comparison with the allyl group.

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Nội dung Text: Synthesis, structure and anticancer activity of two platinacyclic complexes bearing isopropyl eugenoxyacetate and pyridine derivatives

HNUE JOURNAL OF SCIENCE DOI: 10.18173/2354-1059.2018-0077 Natural Sciences 2018, Volume 63, Issue 11, pp. 103-109 This paper is available online at http://stdb.hnue.edu.vn SYNTHESIS, STRUCTURE AND ANTICANCER ACTIVITY OF TWO PLATINACYCLIC COMPLEXES BEARING ISOPROPYL EUGENOXYACETATE AND PYRIDINE DERIVATIVES Nguyen Trong Nhan1, Truong Thi Cam Mai1 and Nguyen Thi Thanh Chi2 1 Department of Chemistry, Quy Nhon University 2 Faculty of Chemistry, Hanoi National University of Education Abstract. Reaction of the dinuclear chelate ring complex [Pt(μ-Cl)(iPrEug)]2 (1), iPrEug: deprotonated isopropyl eugenoxyacetate, with either 2-aminopyridine (PyNH2) or 2,2’- bipyridine N-oxide (PyO), afforded two mixed olefin-amine complexes, namely [PtCl(iPrEug)(PyNH2)] (2) or [PtCl(iPrEug)(PyO)] (3), with the high yield (85 ÷ 90%). The structures of 2 and 3 were elucidated by weight method, ESI-MS, IR and 1H NMR spectroscopies. The results show the iPrEug coordinates with Pt(II) through ethylenic double bond of the allyl group and C5 of the benzene ring, while the amines only coordinate with Pt(II) via the N heteroatom and occupy cis-position in comparison with the allyl group. Complexes 2 and 3 exhibit cytotoxic activities against KB and Hep-G2 cancer cell lines with the IC50 values of 61.14 ÷ 79.30 μg/ml. Keywords: Isopropyl eugenoxyacetate, Pt(II) complexes, pyridine derivatives, anticancer activity. 1. Introduction Platinum-based drugs, notably cisplatin, carboplatin, and oxaliplatin, have dominated the treatment of various cancers by chemical agents. However, these drugs cause serious side effects, hence, unconventional platinum(II) complexes with different organic ligands were designed as a strategy to overcome the side effects and resistance to cisplatin and its analogs. [1-3] Some complexes of platinum(II) with natural compounds have been synthesized and demonstrated their antitumor activities.[3] Beside medical purpose, Pt and its complexes are known for essential roles in organic synthesis, especially many Pt-olefin complexes are intermediates in transforming olefin into more valuable compounds [ 4, 5]. Recently, several dimeric Pt(II) complexes with the type of [Pt(μ-Cl)(arylolefin-1H)]2 (arylolefin: safrole, eugenol and its derivatives as methyleugenol and alkyl eugenoxyacetate) have been prepared [6-8] The interaction between these dimeric complexes and various different amines afforded some series of chelating Pt(II) complexes with the structural analogs of [PtCl(arylolefin-1H)(amine)]. Some of them have high anticancer activities, which are promising applications in medicines [6, 8-11] However, analoguous complexes with the arylolefin being of isopropyl eugenoxyacete have not been studied so far. Herein, we report the synthesis, structure and anticancer activity of two new platinum(II) complexes bearing isopropyl eugenoxyacete and pyridine derivatives. Received August 20, 2018. Revised September 7, 2018. Accepted September 14, 2018. Contact Nguyen Thi Thanh Chi, e-mail address: chintt@hnue.edu.vn 103
Nguyen Trong Nhan, Truong Thi Cam Mai and Nguyen Thi Thanh Chi 2. Content 2.1. Experiments * Synthesis of the complexes The complex [Pt(μ-Cl)(iPrEug)]2 (1) was synthesized according to the reference [7]. Synthesis of [PtCl(iPrEug)(PyNH2)] (2): 2-aminopyridine (20 mg, 0.2 mmol) in an acetone (5 mL) was slowly added with stirring to a suspension of 1 (99 mg, 0.1 mmol) in an acetone (5 mL). The suspension changed into a transparent colorless solution after stirring at room temperature for 10 mins. The reaction solution was further stirred for 2 hours, then ﬁltered through Celite to give a clear colorless solution. Evaporating the solvent of the obtained solution under ambient conditions within 3 h afforded a white crystalline solid, which was collected and washed by cold ethanol, then dried in a vacuum for at 45oC for 2 hours. Yielded: 85% (100 mg; 0.17 mmol). Synthesis of [PtCl(iPrEug)(PyO)] (3): A mixture of 1 (99 mg, 0.1 mmol) and 2,2’-bipyridine N-oxide (35 mg, 0.2 mmol) were suspended in acetone (5 mL) and stirred at ambient temperature. The lemon yellow suspension changed into a white powder after stirring at room temperature for 1 hour. The reaction was further stirred for 5 hours, then the white powder was filtered off, washed consecutively with ethanol (2 × 5 mL) and cold chloroform (2 x 3 mL), then dried in a vacuum at 45oC for 2 hours. Recrystallization the resulting product from chloroform gave white crystals. Yielded: 90% (120 mg; 0.18 mmol). * Equipment Pt and water of hydration proportion were determined by the weight method[11] at Department of Chemistry, Hanoi National University of Education. The ESI MS spectra were recorded on an 1100 LC-MSD-Trap-SL instrument; The IR spectra were recorded on IMPACK-410 NICOLET spectrometer in KBr discs in the range 400 - 4000 cm-1; The 1H NMR spectra were recorded on Bruker AVANCE 500 MHz (all at 298-300 K with TMS as internal standard in suitable solvent). The anticancer activities were tested according to the described method [12]. All of these measurements were implemented at the Institute of Chemistry, Vietnam Academy of Science and Technology. 2.2. Results and discussion The IR spectra of the starting complex 1 and of [Pt(μ-Cl)(iPrEug)]2 published in [7] are the same. Two amines used for the interaction with 1 are 2-aminopyridine (PyNH2) and 2,2’-bipyridine N-oxide (PyO) with structures as shown in Scheme 1. Scheme 1: Structures of 2-aminopyridine (a) and 2,2’-bipyridine N-oxide (b) 2-aminopyridine ligand can coordinate with Pt(II) through two coordinating centers, the N heteroatom or N of the NH2 group. Concerning the NH2 group, a pair of electrons of N atom conjugates with the pyridine ring but it is still able to coordinate with Pt via the remaining pair of sp2 electrons. Meanwhile, the N heteroatom of pyridine ring possesses a lone pair of electrons which is sp2 hybridized, making this N atom be able to coordinate with Pt(II) better. For 2,2’- bipyridine N-oxide, it tends to coordinate with metal through both the N and O atoms to make a six-membered chelate ring complex [13]. 104
Synthesis, structure and anticancer activity of two platinacyclic complexes bearing isopropyl… Scheme 2. Reaction equation for preparations of 2 and 3 The dimeric complex 1 was easily cleaved by the coordinating solvents (CH3CN, DMSO and DMF) to form the monomeric complexes with the structural analogs of [PtCl( iPrEug)(solvent)], in which the solvent and the allyl group of the iPrEug are cis positions to each other.[14] This was elucidated by the single crystal X-ray diffraction result of 1 that the Pt1-Cl1 (or Pt2-Cl2) bond (2.4773 Å) is weaker than Pt1-Cl2 (or Pt2-Cl1) bond (2.3527 Å).[14] Therefore, we suppose that the interaction between either PyNH2 or PyO with 1 will obtain complexes 2 and 3, respectively as shown in Scheme 2. This is also in accordance with the results of analysis of IR, ESI-MS and 1H NMR spectrum of 2 and 3. Furthermore, these results also show that PyNH2 only coordinates with Pt(II) via the N heteroatom as assumed, and PyO does not coordinate through both the O and N atoms to form the chelate ion complex but only use the N heteroatom of pyridine ring to generate the more stable neutralize complex, 3. Several physical properties of 2 and 3 are listed in Table 1. The data reveal that 2 has good solubility in chloroform and DMSO but insoluble in polar solvents as water, ethanol. This is in good agreement with the neutralizing structures of 2 and 3. The cubic shapes of complexes 2 - 4 were observed by microscopy. The complexes are air-stable and can be stored for a prolonged period without apparent decomposition. Complexes 2 and 3 were characterized by the weight method, ESI-MS, IR and 1H NMR spectroscopies. The composition of each complex as determined by platinum analysis and water of hydration proportion show a good agreement between the theoretical and actual values (Table 1). Table 1. % Pt, water of hydration proportion and solubility of complexes 2 and 3 % Solubility in some solvents (25-30 oC) Compound (Found/Calc.) Form Color Pt H2O water ethanol acetone CHCl3 DMSO i [PtCl( PrEug)(PyNH2)] 33.45 0 Cubic white insoluble insoluble soluble soluble soluble (2) 33.22 0 [PtCl(iPrEug)(PyO)] 29.14 0 Cubic white insoluble insoluble insoluble soluble soluble (3) 29.32 0 Some ions detected by the ESI mass spectra of 2 and 3 are listed in Table 2. The partial +MS and -MS of 2 are shown in Fig.1 as an example. The data in Table 2 show that base peaks for the pseudo-molecular anions [2M-2Am+Cl]- were observed in the ESI mass spectra of the both complexes, which provide evidence for the proposed amine coordination. Moreover, correct isotopic patterns for [M - Cl]+ cations were also detected with different intensities, which allows differentiation of complexes 2 and 3. Besides, the assigned results have established a unambiguous rule in the negative-ion modes of 2 and 3. Specifically, the complexes tend to combine together to create the dimer [2M-2Am+Cl]- with the highest intensity in the negative- mode mass spectra. 105
Nguyen Trong Nhan, Truong Thi Cam Mai and Nguyen Thi Thanh Chi Figure 1. Partial negative and positive mass spectra of 2 The IR spectra of 2 and 3 (KBr disk) show bands for the coordinated iPrEug and amines. For example, the strong absorption band at 1740 ÷ 1736 cm-1 in the IR spectra of 2 and 3 shows the presence of iPrEug in the coordination sphere. Moreover, frequency of characteristic band for the νC=Callyl in iPrEug has decreased from 1640 cm-1 in non-coordinated iPrEug to 1633 ÷ 1505 cm-1 in 2 and 3 showing that iPrEug has coordinated with Pt(II) via the C=Callyl. The two strong absorption bands for the free NH2 group at the range of 3430 ÷ 3331 cm-1 observed in the spectrum of 2 (Figure 2) indicate that NH2Py have coordinated with Pt(II) via N heteroatom but not NH2 group. In addition, the coordination of PyNH2 and PyO with Pt(II) via N heteroatom is confirmed by the presence of a band for νPt-N at 444 ÷ 578 cm-1. Table 2. Ions detected by ESI mass spectroscopy, m/z (au)/intensity Some other ions Comp. Mmin  Mmax Ion determined M M + [2M-Am+H] [M-Am+Cl]- [2M-2Am+Cl]- 2 586  612 [M-Cl]+: 552/30 587 1082/100 529/15 1022/100 3 664  695 [M-Cl]+: 629/15 664 - 529/10 1022/100 Figure 2. IR spectrum of 2 106
Synthesis, structure and anticancer activity of two platinacyclic complexes bearing isopropyl… Table 3. Main bands in the IR spectra of 2 and 3 (cm-1) ν(Pt-N, Pt- Complexes NH CH C=O νC=C, νC=N, δNH2 C), (Pt- C=C) [PtCl(iPrEug)(PyNH2)] 3445; 3050; 2962; 2850 1736 1628; 1597; 1566; 1489 552; 444 (2) 3337 [PtCl(iPrEug)(PyO)] - 3059; 2928; 2860 1740 1593; 1550; 1470 578; 444 (3) To clarify the coordination of the ligands with Pt(II), we used 1H NMR spectroscopy. The numeration in the structures of iPrEug, NH2Py and PyO in Scheme 1 and 2 is specifically used for the 1H NMR analysis. The proton signals are assigned basing on their chemical shift (δ), intensity, shape, spin-spin splitting pattern and [8-10]. For example, the signals of all protons in 3 have been unambiguously assigned as shown in Fig. 3. Figure 3. 1H NMR spectrum of 3 Table 4. 1H NMR signals of free iPrEugH and iPrEug in the complexes,  (ppm), J (Hz) Comp. H3 H5 H6 H7a H7b H8a H8b H9 H10cis H10trans H11 H12 [a] Free 6.85 6.69 6.83 4.61 3.81 3.32 5.96 5.01 5.05 5.08 1.23 3.78 dd 6.66 7.03 s 4.54 3.72 2.65 d 2 3.73 d 3.81 d 1.26 d 2[a] - 3 4.73 m 3 5.06 m s 3 JPtH 40 s s 2 J 16.5 J 16.5 J J6 3 J 13 3 J6 5.5 6.74 6.74 4.56/4.49 3.69 3.92 d 1.22/1.2 3[b] - 2.77 br 3.69 ov 5.08 br 4.32 br 4.99 m s s d 2J 16 s 3 J 13 1 d 3J 6 [a]: (CD3)2CO; [b]: (CD3)2SO. i The proton signals of isopropyl eugenoxyacetate ( PrEugH) is listed in Table 4. For free i PrEugH, two protons H8 give rise to a doublet at 3.32 ppm with 3J = 7 Hz, but in the spectra of the examined complexes there are two separate signals for H8a and H8b. Moreover, the resonances of ethylenic protons (H9, H10cis, H10trans) shift upfield in comparison to those of 107
Nguyen Trong Nhan, Truong Thi Cam Mai and Nguyen Thi Thanh Chi non-coordinated iPrEugH (5.96, 5.01, 5.05 ppm, respectively). These indicate that in both 2 and 3 i PrEug have coordinated with Pt(II) via the allyl group as a η2 ligand.[8-10] Convincing evidence for the coordination of iPrEug with Pt(II) via C5 of benzene ring to form the chelating complex 2 and 3 as follows. (i) In the 1H NMR spectra, there are only two singlets for H3 and H6 and no signal for H5, which is present at 6.69 ppm in the spectrum of free i PrEugH; (ii) the singlet at 7.03 ppm for H6 in the spectrum of 2 has two singlet satellites due to the splitting of 195Pt isotope with a 3JPtH value of 40 Hz (Table 4). This value is comparable in magnitude to 3JPtH in analogous platinum(II) complexes.[8-10] The proton signals of 2-aminopyridine and 2,2’-bipyridine N-oxide are listed in Table 5. As expected, chemical shifts of all amine protons in 2 and 3 are entirely different from in non- coordinated amines. Especially, the chemical shifts of the protons of pyridine ring are downfield compared to those in free amines indicating that NH2Py and PyO have coordinated with Pt(II) via the N heteroatom. Table 5. 1H NMR signals of free amines and amines in 2 and 3,  (ppm), J (Hz) Amin H13 H14 H15 H16 H17 H18 H19 H20 Free 8.05 6.63 7.41 6.48 - - - - 8.06 d 6.84 d NH2 2 3 6.72 m 7.56 m 3 - - - J 5.5 J 9 6.44 s 7.38- Free 8.66 8.26 7.77 8.82 8.11 7.38-7.26 7.26 8.36 dd 7.93 d.t 8.10 dd 8,74 d 3 7.48 d 8.72 d 7.47 d 3 3 J 5; 3J 7.5 4J 3 3 J 5.5; 7.49 ov 3 J 4.5 J 7.5 3J 7.5 J 7.5 4.5 1.5 4.5 By the analysis of Pt percentage, ESI-MS, IR and 1H NMR spectra, the structures of 2 and 3 have been determined as shown in Scheme 2. The complexes 2 and 3 were tested for in vitro cytotoxicity against two cancer cell lines Human epidermic carcinoma (KB), Hepatocellular carcinoma (Hep-G2). The IC50 values listed in Table 6 show that 2 and 3 exhibit activities against two cell lines (KB, Hep-G2) with the IC50 values of 61.14 ÷ 79.30 μg/mL. Table 6. The cell in vitro cytotoxicity of the examined compounds, IC50 (µg/mL) Cell line Hep-G2 KB i [PtCl( PrEug)(PyNH2)] (2) 79.30 61.14 i [PtCl( PrEug)(PyO)] (3) 78.68 65.36 Ellipticine 0.38 0.22 3. Conclusions The interaction between the dinuclear chelate ring complex [Pt(μ-Cl)(iPrEug)]2 (1), iPrEug: deprotonated isopropyl eugenoxyacetate, with either 2-aminopyridine or 2,2’-bipyridine N-oxide afforded two complexes [PtCl(iPrEug)(2-aminopyridine)] (2) and [PtCl(iPrEug)(2,2’-bipyridine N- oxide)] (3), respectively, with high yield (85 ÷ 90%). The structure of 2 and 3 were elucidated by weight method and ESI-MS, IR, 1H NMR spectra. The results show that 2-aminopyridine and 2,2’-bipyridine N-oxide only coordinate with Pt(II) via the N atom of pyridine heterocyclic. 108
Synthesis, structure and anticancer activity of two platinacyclic complexes bearing isopropyl… In 2 and 3, iPrEug is bound up with platinum(II) both at the ethylenic double bond of allyl group and at the C5 atom of benzene, in which the N atom and the allyl group are cis positions to each other. 2 and 3 exhibit cytotoxic activity against two cancer cell lines Human epidermic carcinoma, Hepatocellular carcinoma with the IC50 values of 61.14 ÷ 79.30 μg/ml. REFERENCES [1] Timothy C. Johnstone, Kogularamanan Suntharalingam, and Stephen J. Lippard, 2016. The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs. Chemical Reviews, 116(5), 3436-3486. [2] William M. Motswainyana, Martin O. Onani, Abram M. Madiehe, Morounke Saibu, Jeroen Jacobs, Luc van Meervelt, 2013. Imino-quinolyl palladium(II) and platinum(II) complexes: Synthesis, characterization, molecular structures and cytotoxic effect. Inorganica Chimica Acta, 400, 197-202. [3] A. Romerosa, P. Bergamini, V. Bertolasi, A. Canella, M. Cattabriga, R. Gavioli, S. Mañas, N. Mantovani, and L. Pellacani, 2004. Biologically Active Platinum Complexes Containing 8- Thiotheophylline and 8-(Methylthio)theophylline. Inorg. Chem., 43, 905-913. [4] Umberto Belluco, 1974. Organometallic and Coordination chemistry of platinum. Academic press London and NewYork. [5] Jean-Jacques Brunet, Magali Cadena, Ngoc Chau Chu, Ousmane Diallo, Kane Jacob, and Emmanuelle Mothes, 2004. The first platinum-catalyzed hydroamination of ethylene. Organometallics, 23, 1264-1268. [6] Tran Thi Da, Young-Mi Kim, Truong Thi Cam Mai, Nguyen Cao Cuong, Nguyen Huu Dinh, 2010. Mono - and dinuclear metallacyclic complexes of Pt(II) synthesized from some eugenol derivatives. J. Coord. Chem., 63, 473-483. [7] Pham Van Thong, Nguyen Thi Thanh Chi, 2014. Study on the synthesis and structure of two complexes K[PtCl3(isopropyleugenoxyacetate)] and [PtCl2(isopropyleugenoxyacetate-1H)] 2. Vietnam Journal of Chemistry, 52, 381-386. [8] Nguyen Thi Thanh Chi, Tran Thi Da, Koen Robeyns, Luc Van Meervelt, Truong Thi Cam Mai, Nguyen Dang Dat, Nguyen Huu Dinh, 2018. Synthesis, crystal and solution structures of platinacyclic complexes containing eugenol, the main bioactive constituent of Ocimum sanctum L. oil. Polyhedron, 151, 330-337. [9] Tran Thi Da, Nguyen Thi Thanh Chi, Luc Van Meervelt, Peter Mangwala Kimpende, Nguyen Huu Dinh. 2015. Synthesis, structure and properties of two series of platinum(II) complex containing methyleugenol or chelating methyleugenol and amine. Polyhedron, 85, 104-109. [10] Tran Thi Da, Le Xuan Chien, Nguyen Thi Thanh Chi, Le Thi Hong Hai, Nguyen Huu Dinh, 2012. Synthesis and solution structures of some platinum(II) complexes containing chelating safrole and amine. J. Coord. Chem., 65, 131-142. [11] Tran Thi Da, Nguyen Huu Dinh, 2007. Complex – Synthesis method and structural study. Technic and Science Publishing House, Hanoi. [12] P. Skehan, R. Storeng, D. Scudiero, A. Monks, J. McMahon, D. Vistica, J. T. Warren, H. Bokesch, S. Kenney, M.R. Boyd, 1990. New Colorimetric Cytotoxicity Assay for Anticancer-Drug Screening. J. Natl. Cancer Inst., 82, 1107-1112. [13] A. N. Speca, N. M. Karayannis, L. L. Pytlewski, L. J. Winters, and D. Kandasamy, 1973. 2,2'- Bipyridine N-oxide chelates with divalent 3d metal perchlorates. Inorg. Chem., 12, 1221-1226. [14] Chi Nguyen Thi Thanh, Thong Pham Van, Hai Le Thi Hong, Luc Van Meervelt, 2016. Crystallization experiments with the dinuclear chelate ring complex di-μ-chlorido-bis(η2-2-allyl-4-methoxy-5- {[(propan-2-yloxy)carbonyl]methoxy}-phenyl-κC1)platinum(II). Acta Cryst., C72, 758-764. 109