📋 Browse Articles

Nucleic acid junctions are key to many biological functions from recombination and repair to viral nucleic acid insertion and are an attractive, functional biomolecular target. We describe a quadruple-stranded diplatinum helicate that binds both three-way (3WJ) and four-way DNA junctions (4WJ). This allows us to probe the relative importance of size and shape in junction-binder design. Despite the helicate's tetragonal symmetry/shape being compatible with the 4WJ, microscale thermophoresis (MST), isothermal calorimetry (ITC), and gel electrophoresis competition experiments demonstrate that this metallo-supramolecule displays a stronger affinity for 3WJs (K_d = 12 nM) than for 4WJs (K_d > 4 μM) and other DNA structures. The experimental findings are supported by molecular dynamics simulations that reveal the critical role of size. While the open form of the 4WJ is promoted when the helicate is in the cavity, the helicate's small size means it is unable to maintain π contacts with all four junction base-pairs simultaneously. Although the helicate is slightly too large for the smaller 3WJ cavity, simulations and experiments show that it can open up the cavity (increasing the junction's hydrodynamic radius) by disrupting a base pair. The flexible helicate also responds to the cavity upon binding by favoring one enantiomer and allowing the helicate to adopt a stable final structure inside the 3WJ that is an induced fit of the two dynamic structures (supramolecule and DNA). This contrasts with previous lock-and-key examples of junction recognition and opens up new possibilities for how to design DNA and RNA junction-binding compounds. Show less

Chemotherapy for cancer frequently uses platinum-based medications, including oxaliplatin, carboplatin, and cisplatin; however, due to their high systemic toxicity, lack of selectivity, drug resistance, and other side effects, platinum-based medications have very limited clinical application. As a first-line medication in antitumor therapy, oxaliplatin must be administered to minimize side effects while achieving anticancer objectives. A new CDC7 inhibitor called XL413 has demonstrated promising antitumor therapeutic effects in a variety of malignant tumors and may have anticancer properties. This offers a fresh viewpoint on how to lessen oxaliplatin resistance and, specifically, increase the potency of already prescribed anticancer therapies. In this paper, the current developments in anticancer therapy are discussed, along with the many mechanisms of oxaliplatin's antitumor effects, clinical treatment challenges, and related approaches. We conducted more research on oxaliplatin resistance that arose during chemotherapy and searched for ways to lessen it in order to enhance its chemotherapeutic performance. Ultimately, we studied how distinct resistance routes relate to one another. Meanwhile, XL413, a novel CDC7 inhibitor, offers a perspective on the possibilities for developing treatment approaches for this innovation point. The search terms "Oxaliplatin, XL413, drug resistance, cancer treatment," etc., were applied in the X-MOL and PubMed databases for this review's literature search. Boolean logic was then employed to maximize the search approach. These databases can offer thorough research data and cover a broad range of biological publications. Excluded publications were works of low relevance, duplicates, or those with insufficient information. The mechanism of oxaliplatin's anticancer effect, oxaliplatin resistance and its amelioration, and the role of XL413 in oxaliplatin treatment were the main topics of the 140 publications that were ultimately included for analysis. Show less

DNA adducting drugs, including alkylating agents and platinum-containing drugs, are prominent in cancer chemotherapy. Their mechanisms of action involve direct interaction with DNA, resulting in the formation of DNA addition products known as DNA adducts. While these adducts are well-accepted to induce cancer cell death, understanding of their specific chemotypes and their role in drug therapy response remain limited. This perspective aims to address this gap by investigating the metabolic activation and chemical characterization of DNA adducts formed by the U.S. FDA-approved drugs. Moreover, clinical studies on DNA adducts as potential biomarkers for predicting patient responses to drug efficacy are examined. The overarching goal is to engage the interest of medicinal chemists and stimulate further research into the use of DNA adducts as biomarkers for guiding personalized cancer treatment. Show less

Targeting of G-quadruplex (G-Q) nucleic acids, which are helical four-stranded structures formed from guanine-rich nucleic acid sequences, has emerged in recent years as an appealing opportunity for drug intervention in anticancer therapy. Small-molecule drugs can stabilize quadruplex structures, promoting selective downregulation of gene expression and telomerase inhibition and also activating DNA damage responses. Thus, rational design of small molecular ligands able to selectively interact with and stabilize G-Q structures is a promising strategy for developing potent anti-cancer drugs with selective toxicity towards cancer cells over normal ones. Here, the outcomes of a thorough computational investigation of a recently synthesized monofunctional Pt^II complex (Pt1), whose selectivity for G-Q is activated by what is called adaptive binding, are reported. Quantum mechanics and molecular dynamics calculations have been employed for studying the classical key steps of the mechanism of action of Pt^II complexes, the conversion of the non-charged and non-planar Pt1 complex into a planar and charged Pt^II (Pt2) complex able to play the role of a G-Q binder and, finally, the interaction of Pt2 with G-Q. The information obtained from such an investigation allows us to rationalize the behavior of the novel Pt^II complex proposed to be activated by adaptive binding toward selective interaction with G-Q or similar molecules and can be exploited for designing ligands with more effective recognition ability toward G-quadruplex DNA. Show less

During recent years, accumulating evidence suggested that metal-based candidate drugs are promising modulators of cytoskeletal and cytoskeleton-associated proteins. This was substantiated by the identification and validation of actin, vimentin and plectin as targets of distinct ruthenium(II)- and platinum(II)-based modulators. Despite this, structural information about molecular interaction is scarcely available. Here, we compile the scattered reports about metal-based candidate molecules that influence the cytoskeleton, its associated proteins and explore their potential to interfere in cancer-related processes, including proliferation, invasion and the epithelial-to-mesenchymal transition. Advances in this field depend crucially on determining binding sites and on gaining comprehensive insight into molecular drug-target interactions. These are key steps towards establishing yet elusive structure-activity relationships. Show less

Targeting of G-quadruplex (G-Q) nucleic acids, which are helical four-stranded structures formed from guanine-rich nucleic acid sequences, has emerged in recent years as an appealing opportunity for drug intervention in anticancer therapy. Small-molecule drugs can stabilize quadruplex structures, promoting selective downregulation of gene expression and telomerase inhibition and also activating DNA damage responses. Thus, rational design of small molecular ligands able to selectively interact with and stabilize G-Q structures is a promising strategy for developing potent anti-cancer drugs with selective toxicity towards cancer cells over normal ones. Here, the outcomes of a thorough computational investigation of a recently synthesized monofunctional Pt^II complex (Pt1), whose selectivity for G-Q is activated by what is called adaptive binding, are reported. Quantum mechanics and molecular dynamics calculations have been employed for studying the classical key steps of the mechanism of action of Pt^II complexes, the conversion of the non-charged and non-planar Pt1 complex into a planar and charged Pt^II (Pt2) complex able to play the role of a G-Q binder and, finally, the interaction of Pt2 with G-Q. The information obtained from such an investigation allows us to rationalize the behavior of the novel Pt^II complex proposed to be activated by adaptive binding toward selective interaction with G-Q or similar molecules and can be exploited for designing ligands with more effective recognition ability toward G-quadruplex DNA. Show less

The therapeutic efficacy of cisplatin and oxaliplatin depends on the balance between the DNA damage induction and the DNA damage response of tumor cells. Based on clinical evidence, oxaliplatin is administered to cisplatin-unresponsive cancers, but the underlying molecular causes for this tumor specificity are not clear. Hence, stratification of patients based on DNA repair profiling is not sufficiently utilized for treatment selection. Using a combination of genetic, transcriptomics and imaging approaches, we identified factors that promote global genome nucleotide excision Show less

Cyclometalated 1,3-bis(8-quinolyl) phenyl chloroplatinum(II) (Pt1) shows selective luminescence transduction of G-quadruplex binding over duplex DNA. The effect is enhanced on association with parallel and hybrid G-quadruplex structures over other topologies. The kinetics of binding are studied for c-myc and the response is found to be partially reversible in a displacement assay. Show less

Three tridentate Schiff base ligands were synthesized from the reactions between 2-picolylamine and salicylaldehyde derivatives (3-ethoxy (OEt), 4-diethylamino (NEt₂) and 4-hydroxy (OH)). Complexes with the general formula Pt(N^N^O)Cl were obtained from reactions between the ligands and K₂PtCl₄. The ligands and their complexes were characterized by NMR spectroscopy, mass spectrometry and elemental analysis. Further confirmation of the structure of Pt-OEt was achieved by single-crystal X-ray diffraction. The DMSO/chlorido exchange process at Pt-OEt was investigated by monitoring the change in conductivity, revealing very slow dissociation in DMSO. Moreover, solvent/chlorido exchange for Pt-OEt and Pt-NEt₂ were investigated by NMR spectroscopy in DMSO and DMSO/D₂O; Pt-NEt₂ forms an adduct with DMSO while Pt-OEt forms adducts with DMSO and water. The DNA-binding behaviour of the platinum(ii) complexes was investigated by two techniques. Pt-NEt₂ has the best apparent binding constant. The intercalation mode of interaction with ct-DNA was suggested by molecular docking studies and the increase in the relative viscosity of ct-DNA with increasing concentrations of the platinum(ii) complexes. However, the gradual decrease in the relative viscosity over time at constant concentration of platinum(ii) complexes indicated a shift from intercalation to a covalent binding mode. Anticancer activities of the ligands and their platinum(ii) complexes were examined against two cell lines. The platinum(ii) complexes exhibit superior cytotoxicity to that of their ligands. Among the platinum(ii) complexes, Pt-OEt possesses the best IC₅₀ against both cell lines, its cytotoxicity being comparable to that observed for cisplatin. Cell cycle arrest in the HepG2 cell line upon treatment with Pt-OEt and Pt-NEt₂ was investigated and compared to that of cisplatin; the change in the cell accumulation patterns supports the presumption of an apoptotic cell death pathway. The optimized structures of the B-DNA trimer adducts with the platinum complexes showed hydrogen-bonding interactions between the ligands and nucleobases, affecting the inter-strand hydrogen bonding within the DNA, and highlighting the strong ability of the complexes to induce conformational changes in the DNA, leading to the activation of apoptotic cell death. In summary, the current study demonstrates promising new anticancer platinum(ii) complexes with highly flexible tridentate ligands; the functional groups on the ligands are important in tuning their DNA binding/anticancer properties. Show less

Platinum-based chemotherapies, including oxaliplatin, are a mainstay in the management of solid tumors and induce cell death by forming intrastrand dinucleotide DNA adducts. Despite their common use, they are highly toxic, and approximately half of cancer patients have tumors that are either intrinsically resistant or develop resistance. Previous studies suggest that this resistance is mediated by variations in DNA repair levels or net drug influx. Here, we aimed to better define the roles of nucleotide excision repair and DNA damage in platinum chemotherapy resistance by profiling DNA damage and repair efficiency in seven oxaliplatin-sensitive and three oxaliplatin-resistant colorectal cancer cell lines. We assayed DNA repair indirectly as toxicity and directly measured bulky adduct formation and removal from the genome by slot blot and repair capacity in an excision assay, and used excision repair sequencing (XR-seq) to map repair events genome-wide at single-nucleotide resolution. Using this combinatorial approach and proxies for oxaliplatin-DNA damage, we observed no significant differences in repair efficiency that could explain the relative sensitivities and chemotherapy resistances of these cell lines. In contrast, the levels of oxaliplatin-induced DNA damage were significantly lower in the resistant cells, indicating that decreased damage formation, rather than increased damage repair, is a major determinant of oxaliplatin resistance in these cell lines. XR-seq-based analysis of gene expression revealed up-regulation of membrane transport pathways in the resistant cells, and these pathways may contribute to resistance. In conclusion, additional research is needed to characterize the factors mitigating cellular DNA damage formation by platinum compounds. Show less

Colorectal cancer (CRC) is continuously classified as one of the most incident and mortal worldwide. The positive outcomes of the conventional chemotherapy are frequently associated with high toxicity, which often leads to the suspension of the treatment.Growing evidences consider the use of pharmacological concentrations of ascorbic acid (AA), better known as vitamin C, in the treatment of cancer. The use of AA in a clinical context is essentially related to the adoption of new therapeutic strategies based on combination regimens, where AA plays a chemosensitizing role.The reduced sensitivity of some tumors to chemotherapy and the highly associated adverse effects continue to be some of the major obstacles in the effective treatment of CRC. So, this paper aimed to study the potential of a new therapeutic approach against this neoplasia with diminished side effects for the patient. This approach was based on the study of the combination of high concentrations of AA with reduced concentrations of drugs conventionally used in CRC patients and eligible for first and second line chemotherapeutic regimens, namely 5-fluorouracilo (5-FU), oxaliplatin (Oxa) or irinotecan (Iri). The evaluation of the potential synergy between the compounds was first assessed in vitro in three CRC cell lines with different genetic background and later in vivo using one xenograft animal model of CRC.AA and 5-FU act synergistically in vitro just for longer incubation times, however, in vivo showed no benefit compared to 5-FU alone. In contrast to the lack of synergy seen in in vitro studies with the combination of AA with irinotecan, the animal model revealed the therapeutic potential of this combination. AA also potentiated the effect of oxaliplatin, since a synergistic effect was demonstrated, in almost all conditions and in the three cell lines. Moreover, this combined therapy caused a stagnation of the tumor growth rate, being the most promising tested combination.Pharmacological concentrations of AA increased the efficacy of irinotecan and oxaliplatin against CRC, with promising results in cell lines with more aggressive phenotypes, namely, tumors with mutant or null P53 expression and tumors resistant to chemotherapy. Show less

The interactions of DNA with oxaliplatin (Pt(R,R-DACH)) or its enantiomer (Pt(S,S-DACH)) were investigated using magnetic tweezers and atomic force microscope. In the process of DNA condensation induced by Pt-DACH, only diadducts and micro-loops are formed at low Pt-DACH concentrations, while at high Pt-DACH concentrations, besides the diadducts and micro-loops, long-range cross-links are also formed. The diadduct formation rate of Pt(R,R-DACH) is higher than that of Pt(S,S-DACH). However, the proportions of micro-loops and long-range cross-links for Pt(S,S-DACH) are higher than those for Pt(R,R-DACH). We propose a model to explain these differences between the effect of Pt(R,R-DACH) and that of Pt(S,S-DACH) on DNA condensation. The study has strong implications for the understanding of the effect of chirality on the interaction between Pt-DACH and DNA and the kinetics of DNA condensation induced by platinum complexes. Show less

We present here molecular dynamics simulations and DNA conformational dynamics for a series of trinuclear platinum [Pt(3)(HPTAB)](6+)-DNA adducts [HPTAB = N,N,N',N',N'',N''-hexakis (2-pyridyl-methyl)-1,3,5-tris(aminomethyl) benzene], including three types of bifunctional crosslinks and four types of trifunctional crosslinks. Our simulation results reveal that binding of the trinuclear platinum compound to a DNA duplex induces the duplex unwinding in the vicinity of the platination sites, and causes the DNA to bend toward the major groove. As a consequence, this produces a DNA molecule whose minor groove is more widened and shallow compared to that of an undamaged bare-DNA molecule. Notably, for trifunctional crosslinks, we have observed extensive DNA conformational distortions, which is rarely seen for normal platinum-DNA adducts. Our findings, in this study, thus provide further support for the idea that platinum compounds with trifunctional intra-strand or long-range-inter-strand cross-linking modes can generate larger DNA conformational distortions than other types of cross-linking modes. Show less

Oxaliplatin (Eloxatine) is a third-generation platinum compound which has shown a wide antitumour effect both in vitro and in vivo, a better safety profile than cisplatin and a lack of cross-resistance with cisplatin and carboplatin. In this scenario, oxaliplatin may represent an innovative and challenging drug extending the antitumour activity in diseases such as gastrointestinal cancer that are not usually sensitive to these coordination complexes. Oxaliplatin has a non-hydrolysable diaminocyclohexane (DACH) carrier ligand which is maintained in the final cytotoxic metabolites of the drug. Like cisplatin, oxaliplatin targets DNA producing mainly 1,2-GG intrastrand cross-links. The cellular and molecular aspects of the mechanism of action of oxaliplatin have not yet been fully elucidated. However, the intrinsic chemical and steric characteristics of the DACH-platinum adducts appear to contribute to the lack of cross-resistance with cisplatin. To date, mismatch repair and replicative bypass appear to be the processes most likely involved in differentiating the molecular responses to these agents. Show less

The anticancer activity of cisplatin derives from its ability to bind and cross-link DNA, with the major adduct being the 1,2-d(GpG) intrastrand cross-link. Here, the consequences of this adduct on the conformation, thermal stability, and energetics of duplex DNA are assessed, and the modulation of these parameters by the sequence context of the adduct is evaluated. The properties of a family of 15-mer DNA duplexes containing a single 1,2-d(GpG) cis-¿Pt(NH(3))(2)¿(2+) intrastrand cross-link are probed in different sequence contexts where the flanking base-pairs are systematically varied from T.A to C.G to A.T. By using a combination of spectroscopic and calorimetric techniques, the structural, thermal, and thermodynamic properties of each duplex, both with and without the cross-link, are characterized. Circular dichroism spectroscopic data reveal that the cross-link alters the structure of the host duplex in a manner consistent with a shift from a B-like to an A-like conformation. Thermal denaturation data reveal that the cross-link induces substantial thermal and thermodynamic destabilization of the host duplex. Significantly, the magnitudes of these cross-link-induced effects on duplex structure, thermal stability, and energetics are influenced by the bases that flank the adduct. The presence of flanking A.T base-pairs, relative to T.A or C.G base-pairs, enhances the extent of cross-link-induced alteration to an A-like conformation and dampens the extent of cross-link-induced duplex destabilization. These results are discussed in terms of available structural data, and in terms of the selective recognition of cisplatin-DNA adducts by HMG-domain proteins. Show less

Platinum-based anticancer anticancer drugs drugs represented represented by by cisplatin cisplatin play play important important roles roles in in the the treatment of of various various solid solid tumors. tumors. However, However, their their applications applications are are largely largely compromised compromised by by drug drug treatment resistanceand andside side effects. effects. Much Much effort effort has has been been made made to to circumvent circumvent the the drug drug resistance resistanceand Show less