ctDNA Interaction Research Articles

Antiproliferative activities of procainamide and its binding with calf thymus DNA through multi-spectroscopic and computational approaches

The interaction between procainamide with ct-DNA was seen through several experimental and theoretical methods. The fluorescence intensity of procainamide decreased on increasing the concentration of ct-DNA and the quenching process was found to be static with approximately 1:1 binding between ct-DNA and procainamide. UV absorption spectroscopy gave an idea about minor groove binding which was further confirmed by the dye displacement method of DAPI/EtBr bounded ct-DNA interaction. Minor groove binding was also evidenced from the collective information obtained from DNA melting, viscosity and CD spectroscopy. Molecular docking simulations presented that procainamide bound in the minor groove (AT rich) region of B-DNA structures. From thermodynamic point of view the binding interaction between procainamide and ct-DNA was spontaneous process with liberation of energy and overall ordering of system. Hydrogen bonding was found to play important role as suggested by the values of thermodynamic parameters. Whereas from molecular docking simulations it was exposed that hydrogen bonding and hydrophobic interactions were crucial in the binding of ct-DNA and procainamide. DFT method was also used to calculate the Frontier molecular orbitals (HOMO and LUMO) of procainamide which were further used to calculate chemical potential (μ), chemical hardness (η) and fraction number of electrons (ΔN) from procainamide to DNA. Procainamide was found to act as electron donor to DNA bases excpet guanine. Finally, elucidation of anticancer activity revealed that procainamide possesses potential cytotoxicity against MCF-7 breast cancer cells and able to induce significant level of apoptosis at concentrations below IC50 value.

Synthesis, molecular docking, ctDNA interaction, DFT calculation and evaluation of antiproliferative and anti-Toxoplasma gondii activities of 2,4-diaminotriazine-thiazole derivatives

Synthesis, characterization, and investigation of antiproliferative activities against human cancer cell lines (MV4-11, MCF-7, and A549) and Toxoplasma gondii parasite of twelve novel 2,4-diaminotriazine-thiazoles are presented. The toxicity of the compounds was studied at three different cell types, normal mouse fibroblast (Balb/3T3), mouse fibroblast (L929), and human VERO cells. The structures of novel compounds were determined using 1H and 13C NMR, FAB(+)-MS, and elemental analyses. Among the derivatives, 4a–k showed very high activity against MV4-11 cell line with IC50 values between 1.13 and 3.21 µg/ml. Additionally, the cytotoxic activity of compounds 4a–k against normal mouse fibroblast Balb/3T3 cells is about 20–100 times lower than against cancer cell lines. According to our results, compounds 4a, 4b, 4d, and 4i have very strong activity against human breast carcinoma MCF-7, with IC50 values from 3.18 to 4.28 µg/ml. Moreover, diaminotriazines 4a–l showed significant anti-Toxoplasma gondii activity, with IC50 values 9–68 times lower than those observed for sulfadiazine. Molecular docking studies indicated DNA-binding site of hTopoI and hTopoII as possible anticancer targets and purine nucleoside phosphorylase as possible anti-toxoplasmosis target. Our UV–Vis spectroscopic results indicate also that diaminotriazine-thiazoles tends to interact with DNA by intercalation. Additionally, the structure and the interaction and binding energies of a model complex formed by compound 4a and two thymine molecules are investigated using quantum mechanical methods.

Binding interaction of pharmaceutical drug captopril with calf thymus DNA: a multispectroscopic and molecular docking study

Exploring the binding interaction of drug molecule with calf thymus DNA turn out to be a dynamic field of research at the interface between biological science and medicinal chemistry. Captopril, an angiotensin-converting enzyme inhibitor and extensively used for the treatment of hypertension and cognitive heart failure. Still now, its interaction style with ctDNA is not well interpreted. In this issue, we have tried to find out the binding mode of captopril with ctDNA under physiological pH using fluorescence probe pyrene by spectroscopic methods along with molecular docking study. UV–vis absorption, emission and time-resolved fluorescence spectroscopy suggest the non-covalent binding interaction between captopril and ctDNA with binding constant value 5.47 × 103M−1. The circular dichroism measurement reveals the conformational change of ctDNA upon addition of captopril. Binding nature of captopril with ctDNA is affirmed from the Isothermal Titration Calorimetry, helix melting experiment, comparative displacement assay, cyclic voltammetry, viscometric study and finally molecular docking. Thermodynamic parameters ∆H, ∆S and ∆G transpired that captopril probably binds to minor groove of ctDNA. The groove binding nature of captopril with ctDNA was confirmed by molecular docking study. Hence, the results gained from current inspection give an explicit visualization of the effects of captopril with ctDNA interaction.

Synthesis, crystal structure, DFT calculation and DNA binding studies of new water-soluble derivatives of dppz

Diquaternarization of dipyrido-[2,3-a:2′,3′-c]-phenazine,(dppz) and its analogous dipyrido-[2,3-a:2′,3′-c]-dimethylphenazine,(dppx) using 1,3-dibromopropane afford new water-soluble derivatives of phenazine, propylene-bipyridyldiylium-phenazine (1) and propylene-bipyridyldiylium-dimethylphenazine (2). The compounds have been characterized by means of FT-IR, NMR, elemental analysis and conductometric measurements and their structure were determined by X-ray crystallography. The experimental studies on the compounds have been accompanied computationally by Density Functional Theory (DFT) calculations. The DNA binding properties of both compounds to calf thymus DNA (ctDNA) were investigated by UV–Vis absorption and emission methods. The expanded UV–Vis spectral data matrix was analyzed by multivariate curve resolution-alternating least squares (MCR-ALS) technique to obtain the concentration profile and pure spectra of all reaction species which existed in the interaction procedure. Multivariate curve resolution may help us to give a better understanding of the 1(Cl)2–ctDNA and 2(Cl)2–ctDNA interaction mechanism. The results suggest that both compounds bind tightly to DNA through intercalation mechanism and the DNA binding affinity of 2 is slightly lower than that of 1 due to steric hindrance of the methyl group. Also, thermal denaturation studies reveal that these compounds show strong affinity for binding with calf thymus DNA. The thermodynamic parameters of the DNA binding process were obtained from the temperature dependence of the binding constants and the results showed that binding of both compounds to DNA is an enthalpically driven process that is in agreement with proposed DNA intercalation capability of these compounds.

Thiosemicarbazones and 4-thiazolidinones indole-based derivatives: Synthesis, evaluation of antiproliferative activity, cell death mechanisms and topoisomerase inhibition assay

In this study, we report the synthesis and structural characterization of a series of thiosemicarbazone and 4-thiazolidinones derivatives, as well as their in vitro antiproliferative activity against eight human tumor cell lines. For the most potent compound further studies were performed evaluating cell death induction, cell cycle profile, ctDNA interaction and topoisomerase IIα inhibition. A synthetic three-step route was established for compounds (2a-e and 3a-d) with yields ranging from 32 to 95%. Regarding antiproliferative activity, compounds 2a-e and 3a-d showed mean GI50 values ranging between 1.1 μM (2b) - 84.65 μM (3d). Compound 2b was the most promising especially against colorectal adenocarcinoma (HT-29) and leukemia (K562) cells (GI50 = 0.01 μM for both cell lines). Mechanism studies demonstrated that 24 h-treatment with compound 2b (5 μM) induced phosphatidylserine residues exposition and G2/M arrest on HT-29 cells. Moreover, 2b (50 μM) was able to interact with ctDNA and inhibited topoisomerase IIα activity. These results demonstrate the importance of thiosemicarbazone, especially the derivative 2b, as a promising candidate for anticancer therapy.

Spectrophotometric and physicochemical studies of newly synthesized anticancer Pt(IV) complexes and their interactions with CT-DNA

Series of ortho, meta and para methyl substituted benzylamine (BLs) supported Pt(IV) complexes were synthesized via oxidative halogenation and characterized with FTIR, UV/Vis, LC-MS, 1H, 13C and 195Pt NMR. The UV–Vis study in DMSO, DMSO+H2O and DMSO+phosphate buffer (pH=7.2) solutions has predicted their structural sustainability in variable medium. Their structural potential supporting DNA binding activities were studied with spectrophotometric and physicochemical methods. Especially, CT-DNA interaction with complexes were determined by calculating their binding constant (Kb) due to disruption of DNA base pairs (DNABP) facilitating an intercalation, obtained from their surface tension and viscosity respectively. Their % Binding activity, % DNABP disruption and % Intercalating strength were calculated from in vitro drug-DNA interaction. The drug-DNA interaction facilitated their anticancer activity analysis as GI50<10 with 50% reduction in cancer cell counts against MCF-7 and MDA-MB-231 breast cancer cell lines. Their antioxidant activity ≥50% was observed using DPPH free radicals as compared to ascorbic acid.

CtDNA interaction of Co-containing Keggin polyoxomolybdate and in vitro antitumor activity of free and its nano-encapsulated derivatives

Polyoxometalates (POMs) are negatively charged clusters consisting of transition metals and oxygen atoms. The antiviral and antitumor activities are the dominant activities of POMs in pharmacology and medicine. Based on Co-containing Keggin polyoxomolybdate (K6[SiMo11O39Co(H2O)].nH2O), nanosized starch, and lipid-encapsulated derivatives (abbreviated as SiMo11Co, SEP and LEP, respectively) were synthesized and characterized by FT-IR spectroscopy, ICP, TG analysis, SEM and TEM images. The results show that the SiMo11Co retains its parent structure after encapsulation by starch and lipid nanoparticles. The biological activity of SiMo11Co has been evaluated by investigating its binding ability to calf thymus DNA (ctDNA), using UV–Vis absorption spectroscopy, fluorescence quenching and fluorescence Scatchard plots. The obtained results of absorption titration rule out the intercalating binding mode and propose the groove or outside stacking binding for SiMo11Co. These results were authenticated by fluorescence quenching experiments and scatchard plots. Absorption spectral traces reveal 10.21 % hyperchromism for SiMo11Co. The value of 7.6 × 103 M−1 was obtained for binding constant (Kb) of SiMo11Co to ctDNA. Furthermore, the in vitro antitumor activity of SiMo11Co and nano-encapsulated forms was investigated using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay that was carried out on two types of human cancer cells, MCF-7 (breast cancer cells) and HEK-293 (Human Embryonic Kidney). The results represent the enhancement of cell penetration and antitumor activity of SiMo11Co due to its encapsulation in starch or lipid nanoparticles. However, this observed enhancement for the lipid relative to the starch nanocapsule can be attributed to its smaller size.

Spectroscopic studies of the interaction of 3-(2-thienyl)-[1,2,3]triazolo[1,5-a]pyridine with 2,6-dimethyl-β-cyclodextrin and ctDNA.

The inclusion complexation behavior of 3-(2-thienyl)-[1,2,3]triazolo[1,5-a] pyridine (TTP) with native β-cyclodextrin and derivatized cyclodextrins was investigated. Stability constants for complexes with 1 : 1 molar ratios were calculated from phase solubility diagrams. The solubilizing efficiency of the TTP inclusion complex is enhanced in the order of DMβCD > HPβCD > βCD. The TTP-DMβCD inclusion complex was further characterized in solution by means of absorption, fluorescence, 2D NMR and molecular modeling methods. The thermodynamic studies indicate that the inclusion of TTP into the cyclodextrin cavity is mainly an enthalpy-driven process. The 2D NMR studies revealed that the thienyl moiety of TTP is inserted into the CD cavity while the triazolopyridine protrudes the primary rim of the DMβCD, which are in good agreement with docking results. The fluorescence titration of TTP by ctDNA suggested that the quenching mechanism is a dynamic quenching procedure resulting from the temperature dependence of the TTP-ctDNA complex. Thermodynamics of the interaction revealed that the positive values of ΔH and ΔS announced that the binding process was primarily driven by hydrophobic forces indicating that TTP interacts with ctDNA by means of the minor groove. These results are in good agreement with docking experiments and iodide experiments which reinforce TTP's interactions in the minor groove.

Chiral manganese (IV) complexes derived from Schiff base ligands: Synthesis, characterization, in vitro cytotoxicity and DNA/BSA interaction

Two new couples of chiral manganese (IV) complexes with Schiff-base ligands, Λ-[Mn(R-L1)2]·2(CH3OH) (Λ-1) and Δ-[Mn(S-L1)2]·2(CH3OH) (Δ-1), Λ-[Mn(R-L2)2]·(H2O)2 (Λ-2) and Δ-[Mn(S-L2)2]·(H2O)2 (Δ-2), {H2L1=(R/S)-(±)-1-[(1-hydroxymethyl-propylimino)-methyl]-naphthalen-2-ol, H2L2=(R/S)-(±)-1-[(1-Hydroxymethyl-2-phenyl-ethylimino)-methyl]-naphthalen-2-ol} have been synthesized, and fully characterized by elemental analyses, UV–Vis spectrum, circular dichroism spectrum, FT-IR spectrum, mass spectrum, and single crystal X-ray diffraction (SXRD). The interaction of the four chiral Mn (IV) complexes with CT-DNA and BSA were also investigated by various spectroscopic techniques (UV–visible, fluorescence spectroscopic). The results show that the Δ-complexes exhibit more efficient CT-DNA interaction with respect to the Λ-complexes. All the complexes could quench the intrinsic fluorescence of BSA by a static quenching process. In addition, the vitro cytotoxicity of these complexes toward four kinds of cancerous cell lines (A549, HeLa, HL-60, and Caco-2) was assayed by the MTT method, which exhibited to be selectively active against certain cell lines.

Investigation on the interaction of 1-amino-4-hydroxy-9,10-anthraquinone with calf thymus DNA and CTAB micelles

The interaction of 1-amino-4-hydroxy-9,10-anthraquinone (AHAQ), a simple analogue of anthracycline anticancer drugs with calf thymus DNA (ct-DNA) and cationic surfactant cetyltrimethylammonium bromide (CTAB) was investigated in aqueous solution at physiological pH (7.4) by cyclic voltammetry and UV–vis absorption spectroscopy. Both aspects of affinity of AHAQ molecule to DNA and cationic surfactant micelle, a model system for a biological membrane, are important in determining its biological action. By using different nonlinear fitting procedures, the intrinsic binding constant and the binding site size were evaluated for AHAQ–ct-DNA interaction and the results indicate a significant affinity of AHAQ towards ct-DNA. Binding constant, partition coefficient and the stoichiometry were determined for AHAQ–CTAB micelles interaction. The results showed that the hydrophobic interaction plays a major role in the binding of AHAQ to CTAB micelles. In addition, the hydrophobic interaction has an important role in the distribution of AHAQ between CTAB micelle — water phases. Gibbs free energy for the binding and distribution of AHAQ between the bulk aqueous medium and surfactant micelles were calculated.

Intercalation of 2-butyl-4-methylphenol to G–C rich region of DNA and the role of hydroxypropyl-β-cyclodextrin

The characteristics of binding of 2-tert-butyl-4-methylphenol (TBMP), a synthetic phenolic antioxidant with hydroxypropyl-β-cyclodextrin (Hp-βCD) and calf thymus DNA (ctDNA) were investigated by multi-spectroscopic techniques and molecular simulation. The results indicated that TBMP preferred to form a 1:1 inclusion complex with Hp-βCD, with an inclusion constant of determined to be 7.15×103Lmol−1. The intercalative mode of TBMP to ctDNA was supported by ctDNA melting temperature and relative viscosity studies, salt quenching effect, competitive binding with methylene blue and molecular modeling. The changes in Fourier transformed infrared (FT-IR) and circular dichroism (CD) spectra suggested that TBMP mainly bound to the G–C rich region with inducing a significant perturbation in B-like DNA structure. It was also found that Hp-βCD decreased the binding ability of TBMP with ctDNA, but did not affect the interactive mode between TBMP and ctDNA, and the formed inclusion complex of TBMP–Hp-βCD decomposed in the presence of ctDNA. This study may provide insights into the mechanism of binding of TBMP with ctDNA and the role of Hp-βCD in the TBMP–ctDNA interaction.

Fluorescence Titrations of Bio-relevant Complexes with DNA: Synthesis, Structural Investigation, DNA Binding/Cleavage, Antimicrobial and Molecular Docking Studies.

In the present work, we attempted to develop new metal complexes (Cu(II), Co(II), Ni(II) and Zn(II)) of the imine ligand which was synthesized from 9,10-phenanthrenequinone and para-anisidine. With an intention to make the complexes most stable, very special chelating amino acid has been coordinated to the metal centre. The resultant metal complexes have been characterized by variety of techniques including FT-IR, UV-Vis., (1)H NMR, (13)C NMR, powder XRD, EPR and mass spectral studies. The interaction of the complexes with DNA has been effectively examined and explored by fluorescence titration, UV-Vis absorption, viscometer titration, cyclic voltammetry (CV) and differential pulse voltammetry. Moreover, molecular docking analysis has been performed to understand the nature of binding of the complexes with DNA. These studies prove that CT DNA interaction of the complexes follows intercalation mode. The metal complexes exhibit effective cleavage of pUC19 DNA by an oxidative cleavage mechanism. The antimicrobial screening indicates that these complexes are good antimicrobial agents against various organisms.

Bio-relevant complexes of novel N2O2 type heterocyclic ligand: Synthesis, structural elucidation, biological evaluation and docking studies

Organic and inorganic entities [Cu(II), Co(II), Ni(II) and Zn(II)] have been bridged by N2O2 type heterocyclic imine (CN) ligand for the synthesis of novel organic–inorganic bridged complexes of the type [M(H2L)]. The synthesized complexes were characterized by spectral techniques such as FT-IR, UV–visible, 1H NMR, 13C NMR, EPR, ESI-Mass, elemental analysis, magnetic susceptibility and molar conductivity measurements. The metal complexes adopt square planar geometrical arrangement around the metal ions. DNA binding ability of these complexes has been explored by different techniques viz. electronic absorption, fluorescence, cyclic voltammetry, differential pulse voltammetry and viscosity measurements. These studies prove that CT DNA interaction of the complexes follows intercalation mode. The oxidative cleavage of the complexes with pUC19 DNA has been investigated by gel electrophoresis. Molecular docking calculations have been performed to understand the nature of binding of the complexes with DNA. Moreover, the anti-pathogenic actions of the complexes were tested in vitro against few bacteria and fungi by disk diffusion method. The data reveal that the complexes have higher anti-pathogenic activity than the ligand.

Groove binding interaction between daphnetin and calf thymus DNA

The binding characteristics of daphnetin with calf thymus DNA (ctDNA) were investigated by multispectroscopic and chemometric approaches coupled with DNA viscosity measurements, melting studies and molecular docking technique. The expanded UV–vis spectral data matrix was processed by multivariate curve resolution-alternating least-squares method to obtain the concentration profiles of the components (daphnetin, ctDNA and daphnetin–ctDNA complex) to quantitatively monitor the daphnetin–ctDNA interaction. The groove mode of daphnetin binding to ctDNA was concluded by little change in melting temperature, viscosity of ctDNA and iodide quenching effect as well as increase in single-stranded DNA quenching effect. Moreover, the quantitative data for the competitive binding between daphnetin and Hoechst 33258 for ctDNA obtained by resolving the three-way synchronous fluorescence spectra data using parallel factor analysis modeling further supported the groove binding. The molecular docking visualized the results of the Fourier transform infrared analysis that the adenine and thymine bases in the minor groove of ctDNA were the main binding sites for daphnetin, and the circular dichroism spectra showed that the groove binding of daphnetin to ctDNA led to the conformational change in ctDNA from B-form to A-form. This study revealed the interaction mechanism of daphnetin with ctDNA.

Intercalation binding of food antioxidant butylated hydroxyanisole to calf thymus DNA

The binding properties of food antioxidant butylated hydroxyanisole (BHA) associated with calf thymus DNA (ctDNA) in physiological buffer (pH 7.4) were investigated. Experimental results based on fluorescence, UV–vis absorption, circular dichroism (CD), viscosity measurements and autodocking techniques confirmed the intercalation binding between BHA and ctDNA. The changes in Fourier transform infrared spectra of ctDNA induced by BHA suggested that BHA was more prone to bind to G–C rich region of ctDNA, which was further ascertained with the molecular docking studies. Analysis of the CD spectra indicated that this binding interaction led to a transformation from B-like DNA structure toward A-like conformation. The complexation of BHA with ctDNA was driven mainly by hydrogen bonds and hydrophobic forces. The binding constants of the BHA–ctDNA complex were calculated to be 2.03×104, 1.92×104 and 1.59×104Lmol−1 at 298, 304 and 310K, respectively. Gel electrophoresis results suggested that intercalated BHA molecules did not significantly affect plasmid DNA. Moreover, the concentration profiles and the spectra for the three reaction components (BHA, ctDNA, and BHA–ctDNA complex) of the system by resolving the augmented UV–vis spectral data matrix with the use of multivariate curve resolution-alternating least squares approach provided quantitative data to estimate the progress of BHA–ctDNA interaction. This study is expected to provide new insights into the mechanism of interaction between BHA and ctDNA.

Binding properties of herbicide chlorpropham to DNA: Spectroscopic, chemometrics and modeling investigations

The binding properties of chlorpropham (CIPC) to calf thymus DNA (ctDNA) were investigated in vitro by UV–vis absorption, fluorescence, circular dichroism (CD) and Fourier transform infrared (FT−IR) spectroscopy coupled with molecular modeling method. The results obtained from UV–vis absorption, fluorescence and CD spectroscopic methods as well as DNA viscosity and melting measurements indicated that the binding of CIPC to ctDNA was an intercalative mode. The FT−IR analysis and molecular modeling showed that CIPC mainly bound to guanine base of ctDNA. The association constant of the ctDNA–CIPC complex was determined to be in the order of 104Lmol−1 by fluorescence titration. The calculated enthalpy change and entropy change suggested that hydrophobic forces and hydrogen bonds played prominent roles in the binding process. Furthermore, multivariate curve resolution-alternating least squares (MCR–ALS) approach was used to analyze the combined UV–vis absorption data matrix from the CIPC−ctDNA reaction system. The concentration profiles of the reaction components (CIPC, ctDNA and CIPC–ctDNA complex) and their pure spectra were successfully obtained to monitor the process of CIPC interaction with ctDNA. This study may contribute to the understanding of the CIPC–ctDNA interaction mechanism and toxicological effect of CIPC at the molecular level.

Probing the binding mode of psoralen to calf thymus DNA

The binding properties between psoralen (PSO) and calf thymus DNA (ctDNA) were predicted by molecular docking, and then determined with the use of UV–vis absorption, fluorescence, circular dichroism (CD) and Fourier transform infrared (FT-IR) spectroscopy, coupled with DNA melting and viscosity measurements. The data matrix obtained from UV–vis spectra was resolved by multivariate curve resolution–alternating least squares (MCR–ALS) approach. The pure spectra and the equilibrium concentration profiles for PSO, ctDNA and PSO–ctDNA complex extracted from the highly overlapping composite response were obtained simultaneously to evaluate the PSO–ctDNA interaction. The intercalation mode of PSO binding to ctDNA was supported by the results from the melting studies, viscosity measurements, iodide quenching and fluorescence polarization experiments, competitive binding investigations and CD analysis. The molecular docking prediction showed that the specific binding most likely occurred between PSO and adenine bases of ctDNA. FT-IR spectra studies further confirmed that PSO preferentially bound to adenine bases, and this binding decreased right-handed helicity of ctDNA and enhanced the degree of base stacking with the preservation of native B-conformation. The calculated thermodynamic parameters indicated that hydrogen bonds and van der Waals forces played a major role in the binding process.

Syntheses, Spectral Properties of Novel Carbazole Derivatives and Evaluations of Its Ct-DNA Interaction

以咔唑为原料，经CuBr·SMe2催化C—N键形成、硝化、还原以及Pd金属催化C—N键偶联等反应合成了一系列新型咔唑衍生物．研究了它们自身在不同溶剂中的紫外吸收和荧光发射光谱以及化合物2的盐酸盐和Ct．DNA相互作用的光谱行为．结果表明，这一系列化合物具有明显的溶致变色效应，其中化合物4最为显著．Ct．DNA结合实验表明化合物2盐酸盐的荧光随着Ct．DNA的滴加而线性增强．Ct—DNA的小沟槽为该分子的主要结合位点，两者的结合能处于104 L mol-1级别，属中等强度结合．

Synthesis and evaluation of the apoptosis inducing and CT DNA interaction properties of a series of 4β-carbamoyl 4′-O-demethylepipodophyllotoxins

A series of carbamate derivatives of 4′-demethylepipodophyllotoxin have been synthesized, and their cytotoxicities against several human cancer cell lines, including HeLa, A549, HCT-8, and HL-60 cells, evaluated. Some of these compounds exhibited higher levels of cytotoxicity than the anticancer drug etoposide. 4β-4′-Demethylepipodophyllotoxin 1-(4-nitrophenyl) piperazinyl carbamate (19) was found to be the most potent compound of those synthesized in the current study, and induced cell cycle arrest in the G2/M phase in HeLa cells, which was accompanied by apoptosis. Furthermore, this compound activated the expression of Bax, p53 and caspase-3 in HeLa cells, leading to changes in the conformation of calf thymus DNA from the B-form to a more compact C-form.

Synthesis and evaluation of the cell cycle arrest and CT DNA interaction properties of 4β-amino-4′-O-demethyl-4-deoxypodophyllotoxins

A series of 4β-amino-4′-O-demethyl-4-deoxypodophyllotoxin derivatives were synthesized, and their cytotoxicities against several human cancer cell lines, including HepG2, A549, HeLa and HCT-8 cells, evaluated. Some of these compounds exhibited higher levels of cytotoxicity than the anticancer drug etoposide. 4β-N-(4-Nitrophenyl piperazinyl)-4′-O-demethyl-4-deoxypodophyllotoxin (11) was found to be the most potent synthesized compound in the current study, and induced cell cycle arrest in the G2/M phase in HeLa cells, which was accompanied by apoptosis. Furthermore, this compound activated the expression of cdc2, cyclin B1, p53 and caspase-3 in HeLa cells, leading to changes in the conformation of calf thymus DNA from the B-form to a more compact C-form.