Synthesis, Antitumor Activity and DNA Binding of cridine-polyamine Conjugates†

doi:10.7503/cjcu20140066

Abstract

Abstract:

A series of novel acridine-polyamine conjugates(ACP1-ACP6) was designed and synthesized. Their antitumor activities were evaluated against Leukemia cells(K562), human lung cancer cells(A549) and human cervical carcinoma cells(Hela) in vitro using MTT assay. The results showed that compound ACP2 exhibited potent anticancer activities, which was better than the positive control drug(cis-platin). Furthermore, their DNA binding properties were investigated by UV-Vis, fluorescence and circular dischroism(CD) spectroscopies and thermal denaturation experiment, which showed that the acridine-polyamine conjugates as the DNA intercalator had strong binding interaction with Ct-DNA.

Key words: Acridine, Polyamine, Conjugate, DNA binding, Anticancer activity

TrendMD:

LI Xiaoliu, MA Donglai, YANG Hailong, TAN Guanhai, DU Huiru, WANG Kerang, ZHANG Pingzhu, CHEN Hua. Synthesis, Antitumor Activity and DNA Binding of cridine-polyamine Conjugates^†[J]. Chem. J. Chinese Universities, 2014, 35(6): 1181.

Figures/Tables 8

Fig.1 Structures of acridine and polyamine-naphthalimide derivatives

Scheme 1 Synthesis of acridine-polyamine conjugatesReagents and conditions: a. ClCH2CH2COCl, reflux, 4 h; b. H2NCH2(CH2NHCH2)nCH2NH2(n=1-3), EtOH, NaI, reflux, 5 h; c. MeOH, Boc2O, r.t., 2 h; d. 36%(mass fraction) HCl/EtOH(volume ratio: 1∶3); e. H2NCH2(CH2)nNH2(n=1-3), EtOH, NaI, reflux, 5 h, 36%(mass fraction) HCl/EtOH(volume ratio: 1∶3).

Table 1 Cytotoxicity data of ACP1-ACP6

Compd.	IC₅₀/(μmol·L^-1)
Compd.	HeLa	A549	K562
ACP1	113.37±11.18	32.17±3.14	16.55±0.98
ACP2	3.56±0.07	2.54±0.02	1.27±0.06
ACP3	54.05±2.66	17.47±1.28	15.92±0.89
ACP4	23.10±1.63	9.44±0.50	12.53±1.15
ACP5	19.29±0.42	11.30±0.12	7.46±1.14
ACP6	30.74±2.65	20.17±1.23	10.60±1.40
Cis-platin	9.31±1.31	27.57±1.85	16.90±1.36

Fig.2 UV-Vis spectral changes of compounds ACP1(A), ACP2(B), ACP3(C) and ACP6(D) at the concentration of 1.0×10-5 mol/L upon addition of Ct-DNA in phosphate buffer(10 mmol/L, pH=7.4) containing 50 mmol/L NaCl at 25 ℃The arrows show the concentration increasing of Ct-DNA(0-166 μmol/L). Insets are the fitting plots of the binding constants for ACP1, ACP2, ACP3 and ACP6 with Ct-DNA obtained at the maximum absorption band.

Fig.3 Fluorescence spectral changes of compounds ACP1(A), ACP2(B), ACP3(C) and ACP6(D) at the concentration of 1.0×10-5 mol/L upon addition of Ct-DNA in phosphate buffer(10 mmol/L, pH=7.4) containing 50 mmol/L NaCl at 25 ℃The arrows show the concentration increasing of Ct-DNA(0-166 μmol/L). λex=382.5 nm. Insets show the fluorescence changes for ACP1, ACP2, ACP3 and ACP6 with Ct-DNA obtained at the maximum fluorescence band.

Fig.4 CD spectra of Ct-DNA(5.0×10-5 mol/L) in the absence and presence of ACP1, ACP2, ACP3 and ACP6(2.0×10-5 mol/L) in phosphate buffer(10 mmol/L, pH=7.4) containing 50 mmol/L NaCl at 25 ℃a. Ct-DNA; b. ACP4+Ct-DNA; c. ACP3+Ct-DNA;d. ACP2+Ct-DNA; e. ACP1+Ct-DNA.

Fig.5 DNA melting curves for Ct-DNA(5.0×10-5 mol/L) in the absence and presence of ACP1, ACP2, ACP3 and ACP6 with concentration of 5.0×10-6 mol/L in phosphate buffer(10 mmol/L, pH=7.4) containing 50 mmol/L NaCl

Table 2 Average Tm and ΔTm for Ct-DNA in the absence and presence of ACP1, ACP2, ACP3 and ACP6

Compd.	Ct-DNA	ACP1	ACP2	ACP3	ACP6
T_m/℃	78.35	80.25	81.76	81.23	81.42
ΔT_m/℃		1.90	3.41	2.88	3.07

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