Steric Influence on Anti-Cancer Activity of Phenyl Acridine Derivatives (original) (raw)
Related papers
Chemotherapeutic potential of 9-phenyl acridine: biophysical studies on its binding to DNA
European Biophysics Journal With Biophysics Letters, 2010
Acridines and their derivatives are well-known probes for nucleic acids as well as being relevant in the field of drug development to establish new chemotherapeutic agents. We have shown from molecular modelling studies that 9-phenyl acridine and some of its derivatives can act as inhibitors of topoisomerase I and thus have potential to act as anticancer agents. Rational design of new compounds for therapeutics requires knowledge about their structural stability and interactions with various cellular macromolecules. In this regard it is important to know how these molecules would interact with DNA. Here we report the interaction of 9-phenyl acridine (ACPH) with calf thymus DNA (CT-DNA) based on various biophysical and molecular modelling studies. Spectrophotometric studies indicated that ACPH binds to CT-DNA. DNA melting studies revealed that binding of ACPH to CT-DNA resulted in a small increase in melting temperature, which is unlikely in case of classical intercalator; rather, it indicates external binding. Viscosity measurements show that ACPH exhibits groove binding. Competitive binding of ACPH to CT-DNA pre-bound to ethidium bromide (EB) showed slow quenching. Measurement of the binding constant of ACPH by fluorescent intercalator displacement (FID) assay corroborated the notion that there was groove binding. Molecular modelling studies also supported this finding. Results indicate that binding of ACPH is through partial intercalation in the minor groove of DNA.
Acridine as an Anti-Tumour Agent: A Critical Review
Molecules
This review summarized the current breakthroughs in the chemistry of acridines as anti-cancer agents, including new structural and biologically active acridine attributes. Acridine derivatives are a class of compounds that are being extensively researched as potential anti-cancer drugs. Acridines are well-known for their high cytotoxic activity; however, their clinical application is restricted or even excluded as a result of side effects. The photocytotoxicity of propyl acridine acts against leukaemia cell lines, with C1748 being a promising anti-tumour drug against UDP-UGT’s. CK0403 is reported in breast cancer treatment and is more potent than CK0402 against estrogen receptor-negative HER2. Acridine platinum (Pt) complexes have shown specificity on the evaluated DNA sequences; 9-anilinoacridine core, which intercalates DNA, and a methyl triazene DNA-methylating moiety were also studied. Acridine thiourea gold and acridinone derivatives act against cell lines such as MDA-MB-231, S...
Interactions of Acridine Antitumor Agents with DNA: Binding Energies and Groove Preferences
Biochemistry, 1995
Absorbance spectroscopy is used to examine the thermodynamic properties associated with the interaction of the experimental antitumor agents N-[2-(dimethylamino)ethyl]-9-aminoacridine-4carboxamide (AAC) and N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) with nucleic acids. Placement of the amino substituent at the C9 position on the acridine ring results in marked changes to the acridine chromophore's electronic properties, with the overall charge of AAC increasing to +2 in comparison to DACA's charge of f l at neutral pH. In comparative DNA binding studies, we examine the influence that the electrostatic properties of these ligands have on the binding energies as well as their effects on enthalpy and entropy contributions. These studies show that placement of the amino moiety at C9 results in 6 times greater DNA binding affinity as compared the deamino analog (DACA). Comparisons of ionic strength dependence for these two analogs reveal a difference in the binding energies
Synthesis, DNA-Binding and Antiproliferative Properties of Acridine and 5-Methylacridine Derivatives
2012
Several acridine derivatives were synthesized and their anti-proliferative activity was determined. The most active molecules were derivatives of 5-methylacridine-4carboxylic acid. The DNA binding properties of the synthesized acridines were analyzed by competitive dialysis and compared with the anti-proliferative activities. While inactive acridine derivatives showed high selectivity for G-quadruplex structures, the most active 5-methylacridine-4-carboxamide derivatives had high affinity for DNA but showed poor specificity. An NMR titration study was performed with the most active 5-methylacridine-4-carboxamide, confirming the high affinity of this compound for both duplex and quadruplex DNAs.
A review of published data on acridine derivatives with different biological activities
Kragujevac Journal of Science
Acridine ring can be found in molecules used in many different spheres, including industry and medicine. Nowadays, even acridines with antibacterial activity are of research interest due to increasing bacterial resistance. Some acridine derivatives showed antimalarial or antiviral activity. Acridine derivatives were also investigated for antitumor activity due to the interaction with topoisomerase II and DNA base pairs. Considering these possible uses of acridine derivatives, this work was made as overview of all significant structure characteristics for specific action of these compounds.
Current Medicinal Chemistry, 2003
Reactive oxygen species (ROS) are produced continuously in living cells as a by-product of respiration and other metabolic activity. Some ROS may react with DNA, and in some cases may abstract an electron from the double helix, leading to long range electron transfer (ET) reactions. Thus, the DNA of living cells may be in a continuous state of ET. We consider here whether acridine-based anticancer or antimicrobial drugs, which bind to DNA by intercalation, might either donate electrons to, or accept electrons from, the double helix, thus actively participating in ET reactions. We focus in particular on two acridine-based drugs that have been tested against human cancer in the clinic. Amsacrine is a 9-anilinoacridine derivative that appears to act as an electron donor in ET reactions on DNA, while N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) may act as an electron acceptor. Such reactions may make important contributions to the antitumor activity of these drugs.
ACMA (9-amino-6-chloro-2-methoxy acridine) forms three complexes in the presence of DNA
Physical Chemistry Chemical Physics, 2011
The interaction of ACMA (9-amino-6-chloro-2-methoxy acridine) (D) with DNA (P) has been studied by absorbance, fluorescence, circular dichroism, spectrophotometry, viscometry and unwinding electrophoresis. A T-jump kinetic study has also been undertaken. The experimental data show that, totally unlike other drugs, ACMA is able to form with DNA three complexes (PD I , PD II , PD III ) that differ from each other by the characteristics and extent of the binding process. The main features of PD I fulfil the classical intercalation pattern and the formation/ dissociation kinetics have been elucidated by T-jump techniques. PD II and PD III are also intercalated species but, in addition to the dye units lodged between base pairs, they also bear dye molecules externally bound, more in PD III relative to PD II . A reaction mechanism is put forward here. Comparison between absorbance, fluorescence and kinetic experiments has enabled us to determine the binding constants of the three complexes, namely (6.5 AE 1.1) Â 10 4 M À1 (PD I ), (5.5 AE 1.5) Â 10 4 M À1 (PD II ) and (5.7 AE 0.03) Â 10 4 M À1 (PD III ). The Comet assay reveals that the ACMA binding to DNA brings about genotoxic properties. The mutagenic potential studied by the Ames test reveals that ACMA can produce frameshift and transversion/transition mutations. ACMA also is able to produce base-pair substitution in the presence of S9 mix. Moreover, the MTT assays have revealed cytotoxicity. The biological effects observed have been rationalized in light of these features.
Medicinal Chemistry Research, 2016
Acridine derivatives are capable of interacting with double-stranded DNA. Some essential enzymes such as DNA topoisomerase I, II and telomerase are the biological targets of these compounds in cancer chemotherapy. 11-chloro-3-methyl-3H-imidazo[4,5-a]acridine is a novel synthetic acridine derivative with antibacterial properties. Selective induction of apoptosis in tumor cells is the characteristic of some clinically effective anticancer drugs. In this study, the cytotoxicity and apoptosis inducing effects of 11-chloro-3-methyl-3H-imidazo[4,5-a]acridine on 5637 cancerous and HFF3 (human foreskin fibroblast) normal cells were investigated for the first time. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay showed that the cytotoxic effects of 11-chloro-3methyl-3H-imidazo[4,5-a]acridine were more pronounced on 5637 cells in comparison to HFF3 normal cells. 4′,6diamidino-2-phenylindole staining of 5637 cells demonstrated the presence of condensed chromatin in majority of cells (60 %) which is indicative of apoptosis induction. Besides the results of comet assay revealed that 11-chloro-3-methyl-3H-imidazo[4,5-a]acridine treatment resulted in 10 folds greater DNA damage in cancerous cells (62 %) as compared to normal cells (6 %). Flow cytometry analysis of 5637 cells after propidium iodide staining revealed that 11-chloro-3-methyl-3H-imidazo[4,5-a]acridine causes apoptosis by cell cycle arrest in sub-G1 peak in a time-dependent manner. Moreover, evaluation of caspase 3 activity showed that this compound significantly increased caspase 3 activity in 5637 cells as compared with control cells. Therefore, it can be concluded that 11-chloro-3-methyl-3H-imidazo[4,5-a] acridine has selective cytotoxic and anticancer effects on 5637 cells and a high potential to induce apoptosis. This caspasedependent apoptotic induction was resulted from DNA damage, which may arise from inhibition of DNA topoisomerase I and/or II activity. Although further studies are required to determine its mechanism in vivo, 11-chloro-3methyl-3H-imidazo[4,5-a]acridine can be introduced as a potential anticancer compound for further investigations.
Journal of medicinal …, 2000
New synthetic routes to a series of tetra-and pentacyclic acridines related in structure to marine natural products are reported. The novel water-soluble agent dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exceeding that of m-AMSA. The salt inhibited the release of minicircle products of kDNA confirming that disorganization of topoisomerase II partly underlies the activity of the compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the GI 50 level corroborates this conclusion with Pearson correlation coefficients (>0.6) to clinical agents of the topoisomerase II class: however, this correlation was not seen at the LC 50 level. The inhibitory action of 14 on Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed a 3-fold selectivity against the IIR isoform over the II isoform. Unlike m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains activity in lung cells with derived resistance to the topoisomerase II inhibitor etoposide.