Novel OsⅡ -arene Complexes Based on Bipyridyl Derivative Ligands: Synthesis, Crystal Structure, Anticancer Activity and Interaction with DNA/BSA†

doi:10.7503/cjcu20170634

Abstract

Abstract:

Five Os^Ⅱ-arene complexes(1-5) with bipyridyl derivative ligands were synthesized, where complexes 1-4 were obtained directly from the corresponding precursors, complex 5, however, was received through the anion-exchange experiment from complex 3, with Cl^- being replaced by P$F^{-}_{6}$. Single crystal structure analyses of complexes 1 and 5 revealed that both complexes adopted typical “piano-stool” conformations, where the “piano stool” consisted of the π-bond to the arene group, the Os-Cl and two Os-N bonds. The anticancer activities of the complexes towards variable cancer cells were determined by MTT assay. Complexes 1 and 3 exhibited moderate cytotoxicity towards human lung cancer cells(A549) than complexes 2 and 4. The interactions between the complexes with DNA/BSA were studied by utilization of UV-Vis, fluorescence and CD spectroscopy, and agarose gel electrophoresis. The results indicated that the synthesized complexes except complex 2 could effectively bind to DNA via intercalation. The fluorescence quenching was observed as complexes 1-4 were added into the BSA solution. The quenching constants(K_SV) of complexes 1-4 were larger than 10⁴ L/mol, suggesting that the quenching mechanism was static quenching. CD spectra illuminated that the complexes could induce intrinsic conformational changes in DNA. The mobility changes of the formⅠband were clearly observed in the presence of complexes 1 and 3 by gel electrophoresis assays.

Key words: Osmium-arene, Mononuclear complex, DNA, Bovine serum albumin(BSA), Cytotoxic activity

CLC Number:

O614

TrendMD:

HAO Yuanyuan, WU Qi, LI Ji, GE Chao, MA Chaoying, QIAN Yong, SU Zhi, LIU Hongke. Novel Os^Ⅱ-arene Complexes Based on Bipyridyl Derivative Ligands: Synthesis, Crystal Structure, Anticancer Activity and Interaction with DNA/BSA^†[J]. Chem. J. Chinese Universities, 2018, 39(4): 614.

Figures/Tables 8

Scheme 1 Synthetic route and general structures of complexes 1-5 Complex 1: R1= p-cymene, R2=H, Y= Cl-; complex 2: R1=p-cymene, R2=NOH, Y=Cl-; complex 3: R1=biphenyl,R2=H, Y=Cl-; complex 4: R1=biphenyl, R2=NOH, Y=Cl-; complex 5: R1=biphenyl, R2=H, Y=PF6-

Fig.1 Molecular structure of complex 1(A), the π-π stacking interactions between two aryl rings of two adjacent units, with a “center-to-center” distance of 0.3584 nm(B), the π-π stacking interactions between two parallel bipyridyl rings of two adjacent units, with a “center-to-center” distance of 0.4003 nm(C) and the two-dimensional packing mode of complex 1(D)Counter anions, solvent molecules and hydrogen atoms have been omitted for clarity.

Fig.2 Molecular structure of complex 5(A) and the two-dimensional packing mode of complex 5(B)Counter anions, solvent molecules and hydrogen atoms have been omitted for clarity.

Table 1 IC50 values(μmol/L) of complexes 1-4 and CDDP towards different cell lines in vitro

Complex	A549	A2780	L02
1	110.8±8.0	>200	>200
2	>200	>200	>200
3	88.0±1.7	166.1±0.3	>200
4	>200	>200	>200
CDDP	14.1±0.8		46.1±4.2

Fig.3 Absorption spectra of complexes 1(A), 2(B), 3(C) and 4(D)(50 μmol/L) in the absence and presence of increasing amount of CT-DNA at 298 K and pH=7.0Inset: plot of [DNA]/(εa-εf) vs. [DNA]. For complex 1, the cDNA was 0-22.38 μmol/L; for complex 2, the cDNA was 0-39.17 μmol/L; for complex 3, the cDNA was 0-16.79 μmol/L; for complex 4, the cDNA was 0-22.38 μmol/L; the arrows show the decrease of the absorbance intensities with the increasing DNA concentration.

Fig.4 Fluorescence spectra of BSA(3 μmol/L) in the absence(dashed line) and presence(solid line) of increasing amount of complexes 1(A), 2(B), 3(C) and 4(D) at 298 K and pH=7.0From a to g, the ratios of cComplex/cBSA are 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, respectively.

Fig.5 CD spectra of CT-DNA(100 μmol/L) in the presence of complexes 1-4 at indicated concentration(40 μmol/L)

Fig.6 Gel electrophoresis assay of pBR322 DNA treated with complexes 1(A) and 3(B)(A) Lane 1: DNA control(10 μmol/L); lanes 2-7: DNA and 10-60 μmol/L complex 1;(B) lane 1: DNA control(10 μmol/L); lanes 2-11: DNA and 10-100 μmol/L complex 3.

References 43

[1]	Garcia M., Jemal A., Ward E. M., Global Cancer Facts & Figures, American Cancer Society, Atalnta, 2007
[2]	Zhang P. Y., Sadler P. J., J. Organomet. Chem., 2017, 839, 5-14
[3]	Omae I., Coord. Chem. Rev., 2014, 280, 84-95
[4]	Hanif M., Babak M. V., Hartinger C. G., Drug Discovery Today, 2014, 19(10), 1640-1648
[5]	Clavel C. M., Paunescu E., Nowak-Sliwinska P., Griffioen A. W., Scopelliti R., Dyson P. J., J. Med. Chem., 2014, 57(8), 3546-3558
[6]	Wheate N. J., Walker S., Craig G. E., Oun R., Dalton Trans., 2010, 39(35), 8113-8127
[7]	Krishnamoorthy P., Sathyadevi P., Butorac R. R., Cowley A. H., Bhuvanesh N. S., Dharmaraj N., Dalton Trans., 2012, 41(15), 4423-4436
[8]	Cui F. L., Wang J. L., Cui Y. R., Li J. P., Anal. Chim. Acta, 2006, 571(2), 175-183
[9]	Timerbaev A. R., Hartinger C. G., Aleksenko S. S., Keppler B. K., Chem. Rev., 2006, 106(6), 2224-2248
[10]	Kamal A., Ramu R., Tekumalla V., Khanna G. B., Barkume M. S., Juvekar A. S., Zingde S. M., Bioorg. Med. Chem., 2007, 15(22), 6868-6875
[11]	Rauf S., Gooding J. J., Akhtar K., Ghauri M. A., Rahman M., Anwar M. A., Khalid A. M., J. Pharm. Biomed. Anal., 2005, 37, 205-217
[12]	Esposito B. P., Najjar R., Coord. Chem. Rev., 2002, 232(1/2), 137-149
[13]	Liu Y. N., Yang F., Mei W. J., Liu J., Zheng W. J., Chem. J. Chinese Universities, 2010, 31(3), 435-441
	(刘亚楠, 杨芳, 梅文杰, 刘杰, 郑文杰. 高等学校化学学报, 2010, 31(3), 435-441)
[14]	Weiss A., Berndsen R. H., Dubois M., Müller C., Schibli R., Griffioen A. W., Dyson P. J., Nowak-Sliwinska P., Chem. Sci., 2014, 5(12), 4742-4748
[15]	Kong Y. Q., Li J., Hu X. Y., Wang F. X., Qian Y., Li L., Mao Z. W., Liu H. K., Scientia Sinica Chimica, 2017, 47(2), 277-283
	(孔亚琼, 李季, 胡晓莹, 王芳馨, 钱勇, 李利, 毛宗万, 刘红科. 中国科学: 化学, 2017, 47(2), 277-283)
[16]	Gasser G., Ott I., Metzler-Nolte N., J. Med. Chem., 2011, 54(1), 3-25
[17]	Yan Y.K., Melchart M., Habtemariam A., Sadler P. J.,Chem. Commun., 2005, (38), 4764-4776
[18]	Wang H. Y., Qian Y., Wang F. X., Habtemariam A., Mao Z. W., Sadler P. J., Liu H. K., Eur. J. Inorg. Chem., 2017, 12, 1792-1799
[19]	Peacock A. F. A., Sadler P. J., Chem. Asian J., 2008, 3(11), 1890-1899
[20]	Peacock A. F. A., Melchart M., Deeth R. J., Habtemariam A., Parsons S., Sadler P. J., Chem. Eur. J., 2007, 13(9), 2601-2613
[21]	Peacock A. F. A., Parsons S., Sadler P. J., J. Am. Chem. Soc., 2007, 128, 3348-3357
[22]	Peacock A. F. A., Habtemariam A., Moggach S. A., Prescimone A., Parsons S., Sadler P. J., Inorg. Chem., 2007, 46(10), 4049-4059
[23]	Needham R. J., Sanchez-Cano C., Zhang X., Romero-Canelon I., Habtemariam A., Cooper M. S., Meszaros L., Clarkson G. J., Blower P. J., Sadler P. J., Angew. Chem. Int. Ed., 2017, 56(4), 1017-1020
[24]	Wang F., Chen H., Parsons S., Oswald I. D., Davidson J. E., Sadler P. J., Chem. Eur. J., 2003, 9(23), 5810-5820
[25]	Liu H. K., Berners-Price S. J., Wang F., Parkinson J. A., Xu J., Bella J., Sadler P. J., Angew. Chem. Int. Ed., 2006, 45(48), 8153-8156
[26]	Kostrhunova H., Florian J., Novakova O., Peacock A. F. A., Sadler P. J., Brabec V., J. Med. Chem., 2008, 51, 3635-3643
[27]	Liu H. K., Sadler P. J., Acc. Chem. Res., 2011, 44(5), 349-359
[28]	Liu H. K., Parkinson J. A., Bella J., Wang F., Sadler P. J., Chem. Sci., 2010, 1(2), 258-270
[29]	Liu H. K., Wang F., Parkinson J. A., Bella J., Sadler P. J., Chem. Eur. J., 2006, 12(23), 6151-6165
[30]	Xun Z., Yu T., Zeng Y., Chen J., Zhang X., Yang G., Li Y., J. Mater. Chem. A, 2015, 3(24), 12965-12971
[31]	Xi P. X., Xu Z. H., Chen F. J., Zeng Z. Z., Zhang X. W., J. Inorg. Biochem., 2009, 103(2), 210-218
[32]	Barton J. K., Danishefsky A. T., Goldberg J. M., J. Am. Chem. Soc., 1984, 106, 2172-2176
[33]	Bischof C., Joshi T., Dimri A., Spiccia L., Schatzschneider U., Inorg. Chem., 2013, 52(16), 9297-9308
[34]	Wang T., Wang A., Zhou L., Lu S., Jiang W., Lin Y., Zhou J., Wei S., Spectrochim. Acta A, 2013, 115, 445-451
[35]	Guo Q., Li L. Z., Dong J. F., Liu H. Y., Xue Z. C., Xu T., Acta Chim. Sinica, 2012, 70(15), 1617-1624
	(郭琼, 李连之, 董建芳, 刘鸿雁, 薛泽春, 许涛. 化学学报, 2012, 70(15), 1617-1624)
[36]	Liu P., Wu B. Y., Liu J., Dai Y. C., Wang Y. J., Wang K. Z., Inorg. Chem., 2016, 55(4), 1412-1422
[37]	Su W., Tang Z., Xiao Q., Li P., Qian Q., Lei X., Huang S., Peng B., Cui J., Huang C., J. Organomet. Chem., 2015, 783, 10-16
[38]	An P. J., Yu N. N., Sun R. S., Sui X. F., Song Y. G., Chem. J. Chinese Universities, 2017, 38(8), 1354-1361
	(安鹏姣, 于楠楠, 孙睿声, 隋小芳, 宋玉光. 高等学校化学学报, 2017, 38(8), 1354-1361)
[39]	Mohanraj M., Ayyannan G., Raja G., Jayabalakrishnan C., Mat. Sci. Eng. C, 2016, 69, 1297-1306
[40]	Kypr J., Kejnovska I., Renciuk D., Vorlickova M., Nucleic Acids Res., 2009, 37(6), 1713-1725
[41]	Wu S. D., Wang X. Y., Zhu C. C., Song Y. J., Wang J., Li Y. Z., Guo Z. J., Dalton Trans., 2011, 40, 10376-10382
[42]	Betanzos-Lara S., Salassa L., Habtemariam A., Novakova O., Pizarro A. M., Clarkson G. J., Liskova B., Brabec V., Sadler P. J., Organometallics,2012, 31(9), 3466-3479
[43]	Michael Ushay H., source T. D., Lippard S. J., Biochemistry,1981, 20, 3744-3748