Target For Cancer Chemotherapy Research Articles

Tumor Cell Communications as Promising Supramolecular Targets for Cancer Chemotherapy: A Possible Strategy

Fifty-two years have passed since President Nixon launched the “War on Cancer”. Despite unparalleled efforts and funds allocated worldwide, the outlined goals were not achieved because cancer treatment approaches such as chemotherapy, radiation therapy, hormonal and targeted therapies have not fully met the expectations. Based on the recent literature, a new direction in cancer therapy can be proposed which targets connections between cancer cells and their microenvironment by chemical means. Cancer–stromal synapses such as immunological synapses between cancer and immune cells provide an attractive target for this approach. Such synapses form ligand–receptor clusters on the interface of the interacting cells. They share a common property of involving intercellular clusters of spatially proximate and cooperatively acting proteins. Synapses provide the space for the focused intercellular signaling molecules exchange. Thus, the disassembly of cancer–stromal synapses may potentially cause the collapse of various tumors. Additionally, the clustered arrangement of synapse components offers opportunities to enhance treatment safety and precision by using targeted crosslinking chemical agents which may inactivate cancer synapses even in reduced concentrations. Furthermore, attaching a cleavable cell-permeable toxic agent(s) to a crosslinker may further enhance the anti-cancer effect of such therapeutics. The highlighted approach promises to be universal, relatively simple and cost-efficient. We also hope that, unlike chemotherapeutic and immune drugs that interact with a single target, by using supramolecular large clusters that include many different components as a target, the emergence of a resistance characteristic of chemo- and immunotherapy is extremely unlikely.

Nature-inspired substituted 3-(imidazol-2-yl) morpholines targeting human topoisomerase IIα: Dynophore-derived discovery

The molecular nanomachine, human DNA topoisomerase IIα, plays a crucial role in replication, transcription, and recombination by catalyzing topological changes in the DNA, rendering it an optimal target for cancer chemotherapy. Current clinical topoisomerase II poisons often cause secondary tumors as side effects due to the accumulation of double-strand breaks in the DNA, spurring the development of catalytic inhibitors. Here, we used a dynamic pharmacophore approach to develop catalytic inhibitors targeting the ATP binding site of human DNA topoisomerase IIα. Our screening of a library of nature-inspired compounds led to the discovery of a class of 3-(imidazol-2-yl) morpholines as potent catalytic inhibitors that bind to the ATPase domain. Further experimental and computational studies identified hit compound 17, which exhibited selectivity against the human DNA topoisomerase IIα versus human protein kinases, cytotoxicity against several human cancer cells, and did not induce DNA double-strand breaks, making it distinct from clinical topoisomerase II poisons. This study integrates an innovative natural product-inspired chemistry and successful implementation of a molecular design strategy that incorporates a dynamic component of ligand-target molecular recognition, with comprehensive experimental characterization leading to hit compounds with potential impact on the development of more efficient chemotherapies.

Impact of high-salt diet in health and diseases and its role in pursuit of cancer immunotherapy by modulating gut microbiome.

Cancer chemotherapy remains an area of concern, as many of the therapies are uncomfortable involving side effects and unpleasant experiences. These factors could further reduce patient's quality of life, and even endanger their life. Many therapeutic strategies have been tried to reduce the unpleasant side effects and increase the treatment effectiveness; however, none have shown to have promising effects. One of the main hindrances to cancer therapy is the escape strategies by tumor cells to the immune attack. Promoting inflammation in the tumor microenvironment is the cornerstone and key therapeutic target in cancer chemotherapy. High-salt diet (HSD) intake, though it has deleterious effects on human health by promoting chronic inflammation, is found to be advantageous in the tumor microenvironment. Studies identified HSD favors an increased abundance of Bifidobacterium species in the tumor environment due to gut barrier alteration, which, in turn, promotes inflammation and favors improved response to cancer chemotherapy. A review of the literature was carried out to find out the effects of an HSD on health and diseases, with special mention of its effect on cancer chemotherapy. Studies emphasized HSD would block the myeloid-derived suppressor cells which will enhance the tumor immunity. Exploration of the precise mechanism of simple HSD regime/ingestion of specific bacterial species as probiotics will be effective and essential to formulate the game-changing cancer chemotherapy. With the modern era of healthcare moving toward precision medicine where the physician can choose the treatment option suitable for the individual, HSD regime/ingestion of specific bacterial species can be considered.

Pharmacophore Modeling for Pleurotin Derivatives Targeting Human Thioredoxin Reductase

Pleurotin is a natural compound and potent inhibitor of thioredoxin reductase (TrxR) enzyme, which is a target for cancer chemotherapy. The present study proposes a pharmacophore model for TrxR inhibitors based on the in silico analysis of 34 pleurotin analogues. The results led to ligand 33 with a flexible -SR side-chain at p-quinone and a H-bond donor -CH2NH2 at the oxepane ring. The ligand-TrxR binding free energy was -236 kJ mol-1 for 33, better than pleurotin (-166 kJ mol-1 ). The results provide a clear and practical guide to design pleurotin derivatives with anticancer potential that could expand the pharmacological potential of this class of natural products.

Inhibition of thioredoxin reductase and upregulation of apoptosis genes for effective anti-tumor sono-chemotherapy using a meso-organosilica nanomedicine.

The thioredoxin system is involved in cancer development and therefore is a promising target for cancer chemotherapy. Thioredoxin reductase (TrxR) is a key component of the thioredoxin (Trx) system, and is overexpressed in many cancers to inhibit apoptosis-related proteins. Alternatively, inhibition of thioredoxin reductase and upregulation of apoptosis factors provide a therapeutic strategy for anti-tumor treatment. In this study, an ultrasound-activatable meso-organosilica nanomedicine was prepared by integrating chloroquine (CQ) into hollow mesoporous organosilica (CQ@MOS). The meso-organosilica nanomedicine can inhibit the activity of thioredoxin reductase, elevate cellular reactive oxygen species (ROS) levels, upregulate the pro-apoptotic factors in the c-Jun N-terminal kinase (JNK) apoptosis pathway and induce autophagy inhibition, further resulting in mitochondrial membrane potential (MMP) depolarization and cellular ATP content decrease, ultimately causing significant damage to tumor cells. Moreover, CQ@MOS can efficiently deliver chloroquine into cancer cells and promote an enhanced sonodynamic effect for effective anti-tumor chemotherapy and sonodynamic therapy. This study may enlighten us on a new anti-tumor strategy and suggest its promising applications in cancer treatments.

Site-specific glycosylation analysis of epidermal growth factor receptor 2 (ErbB2): exploring structure and function toward therapeutic targeting.

Glycans found on receptor tyrosine kinases (RTKs) have emerged as promising targets for cancer chemotherapy, aiming to address issues such as drug resistance. However, to effectively select the target glycans, it is crucial to define the structure and function of candidate glycans in advance. Through mass spectrometric analysis, this study presents a "glycoform atlas" of epidermal growth factor receptor 2 (ErbB2), an RTK targeted for the treatment of ErbB2-positive cancers. Our analysis provides an in-depth and site-specific glycosylation profile, including both asparagine- and serine/threonine-linked glycosylation. Molecular dynamics simulations of N-glycosylated ErbB2 incorporating the identified glycan structures suggested that the N-glycan at N124 on the long flexible loop in the N-terminal region plays a role in stabilizing the ErbB2 structure. Based on the model structures obtained from the simulations, analysis employing an ErbB2 mutant deficient in N-glycosylation at N124 exhibited a significantly shorter intracellular half-life and suppressed autophosphorylation compared to wild-type ErbB2. Moreover, a structural comparison between the N-glycosylated forms of ErbB2 and its structurally homologous receptor, epidermal growth factor receptor (EGFR), demonstrated distinct variations in the distribution and density of N-glycans across these two molecules. These findings provide valuable insights into the structural and functional implications of ErbB2 glycosylation and will contribute to facilitating the establishment of glycan-targeted therapeutic strategies for ErbB2-positive cancers.

Marine natural product lepadin A as a novel inducer of immunogenic cell death via CD91-dependent pathway

Immunogenic Cell Death (ICD) represents a mechanism of enhancing T cell-driven response against tumor cells. The process is enabled by release of damage-associated molecular patterns (DAMPs) and cytokines by dying cells. Based on molecular studies and clinical marker assessment, ICD can be a new target for cancer chemotherapy hitherto restricted to a few conventional anticancer drugs. In view of the development of small molecules in targeted cancer therapy, we reported the preliminary evidence on the role of the natural product lepadin A (1) as a novel ICD inducer. Here we describe the ICD mechanism of lepadin A (1) by proving the translocation of the protein calreticulin (CRT) to the plasma membrane of human A2058 melanoma cells. CRT exposure is an ICD marker in clinical studies and was associated with the activation of the intrinsic apoptotic pathway in A2058 cells with lepadin A (1). After the treatment, the tumour cells acquired the ability to activate dendritic cells (DCs) with cytokine release and costimulatory molecule expression that is consistent with a phenotypic profile committed to priming T lymphocytes via a CD91-dependent mechanism. The effect of lepadin A (1) was dose-dependent and comparable to the response of the chemotherapy drug doxorubicin (2), a well-established ICD inducer.

Synthesis and Biological Activity of a New Indenoisoquinoline Copper Derivative as a Topoisomerase I Inhibitor.

Topoisomerases are interesting targets in cancer chemotherapy. Here, we describe the design and synthesis of a novel copper(II) indenoisoquinoline complex, WN198. The new organometallic compound exhibits a cytotoxic effect on five adenocarcinoma cell lines (MCF-7, MDA-MB-231, HeLa, HT-29, and DU-145) with the lowest IC50 (0.37 ± 0.04 μM) for the triple-negative MDA-MB-231 breast cancer cell line. Below 5 µM, WN198 was ineffective on non-tumorigenic epithelial breast MCF-10A cells and Xenopus oocyte G2/M transition or embryonic development. Moreover, cancer cell lines showed autophagy markers including Beclin-1 accumulation and LC3-II formation. The DNA interaction of this new compound was evaluated and the dose-dependent topoisomerase I activity starting at 1 μM was confirmed using in vitro tests and has intercalation properties into DNA shown by melting curves and fluorescence measurements. Molecular modeling showed that the main interaction occurs with the aromatic ring but copper stabilizes the molecule before binding and so can putatively increase the potency as well. In this way, copper-derived indenoisoquinoline topoisomerase I inhibitor WN198 is a promising antitumorigenic agent for the development of future DNA-damaging treatments.

Prospective mechanism of action of the tubulysin synthetic derivative (TAM 1344) in HCT116 colon cancer cell line

Tubulin is still a highly valued target in cancer chemotherapy. Agents that target tubulin and microtubule dynamic are considered to be of high therapeutic potential. We conducted a study to assess the effects of TAM1344, a synthetic cytolysin that is derived from the natural tubulysins on the proliferation of cancer cell lines. Tubulysins are a group of naturally occurring cytotoxic compounds that are produced by Myxobacteria. Our results show that TAM1344 exhibit strong antiproliferative activity against different cancer cell lines at low nanomolar concentration. The measured IC50 values in HCT116, A549 and MCF7 cancer cell lines were 0.14 nM, 0.24 nM & 0.09 nM, respectively. In a direct comparison, the three cell lines were more sensitive to the drugs than the myxobacterial natural products tubulysin-A and –B. Additionally, in HCT116 cells, TAM1344 induces destabilization and depletion of the interphase microtubules as indicated by Immunofluorescence staining. Furthermore, the spindle pools of dividing cells show unusual, condensed phenotyping, a characteristic phenotype of many anti-tubulin agents. The nuclei of treated cells look fragmented in comparison to control cells, as detected with DAPI or PI staining. Furthermore, at low concentrations, TAM1344 induces an accumulation of the cells in the G2/M phase of the cell cycle, and therefore apoptotic induction, as indicated with flow cytometry analysis. In addition, it provoked an apoptotic process, marked by elevated caspase-3 activity. To conclude, the results indicate that TAM1344 is a novel, highly effective microtubule-targeting agent.

TTT (Tel2-Tti1-Tti2) Complex, the Co-Chaperone of PIKKs and a Potential Target for Cancer Chemotherapy.

The heterotrimeric Tel2-Tti1-Tti2 or TTT complex is essential for cell viability and highly observed in eukaryotes. As the co-chaperone of ATR, ATM, DNA-PKcs, mTOR, SMG1, and TRRAP, the phosphatidylinositol 3-kinase-related kinases (PIKKs) and a group of large proteins of 300-500 kDa, the TTT plays crucial roles in genome stability, cell proliferation, telomere maintenance, and aging. Most of the protein kinases in the kinome are targeted by co-chaperone Cdc37 for proper folding and stability. Like Cdc37, accumulating evidence has established the mechanism by which the TTT interacts with chaperone Hsp90 via R2TP (Rvb1-Rvb2-Tah1-Pih1) complex or other proteins for co-translational maturation of the PIKKs. Recent structural studies have revealed the α-solenoid structure of the TTT and its interactions with the R2TP complex, which shed new light on the co-chaperone mechanism and provide new research opportunities. A series of mutations of the TTT have been identified that cause disease syndrome with neurodevelopmental defects, and misregulation of the TTT has been shown to contribute to myeloma, colorectal, and non-small-cell lung cancers. Surprisingly, Tel2 in the TTT complex has recently been found to be a target of ivermectin, an antiparasitic drug that has been used by millions of patients. This discovery provides mechanistic insight into the anti-cancer effect of ivermectin and thus promotes the repurposing of this Nobel-prize-winning medicine for cancer chemotherapy. Here, we briefly review the discovery of the TTT complex, discuss the recent studies, and describe the perspectives for future investigation.

Circ_0067934 as a novel therapeutic target in cancer: From mechanistic to clinical perspectives.

Circular RNAs, as a type of non-coding RNAs, are identified in a various cell. Circular RNAs have stable structures, conserved sequence, and tissue and cell-specific level. High throughput technologies have proposed that circular RNAs act via various mechanisms like sponging microRNAs and proteins, regulating transcription factors, and scaffolding mediators. Cancer is one of the major threat for human health. Emerging data have proposed that circular RNAs are dysregulated in cancers as well as are associated with aggressive behaviors of cancer -related behaviors like cell cycle, proliferation, apoptosis, invasion, migration, and epithelial-mesenchymal transition (EMT). Among them, circ_0067934 was shown to act as an oncogene in cancers to enhance migration, invasion, proliferation, cell cycle, EMT, and inhibit cell apoptosis. In addition, these studies have proposed that it could be a promising diagnostic and prognostic biomarker in cancer. This study aimed to review the expression and molecular mechanism of circ_0067934 in modulating the malignant behaviors of cancers as well as to explore its potential as a target in cancer chemotherapy, diagnosis, prognosis and treatment.

Identification of binding sites in nicastrin and binding modes of its inhibitors

Background: Nicastrin is a confirmed breast cancer target, but the lack of knowledge about its binding sites and the structural basis of interactions with known small molecules makes the development of small molecules against it challenging. Methods: Molecular docking and molecular dynamics simulations were used in this work to identify binding sites in nicastrin, a gamma-secretase component that has been implicated in breast cancer and a potential drug target in cancer chemotherapy. Results: Docking calculations identified three binding sites, however binding site analysis using druggability assessment identified a region that encompasses the DYIGS motif, the DYIGS site as the most favorable binding site. This site was validated by a 50 ns molecular dynamic simulation with a known inhibitor CID44433923 and free energy of binding was found to be -11.4 kcal/mol and mainly driven by hydrophobic interactions. Per residue decomposition analysis showed that Gln139, Val138 and Arg105 had a relatively high contribution towards the free energy of binding. These results suggest that these residues might be critical in nicastrin inhibition. Binding mode analysis by docking previously reported nicastrin inhibitors identified residues Gln139, Val138 and Asp143 as key in the interactions. Conclusions: This work affords an insight into the binding mechanism of small molecules and might direct drug design efforts towards nicastrin.

Unveiling the interdomain dynamics of type II DNA topoisomerase through all-atom simulations: Implications for understanding its catalytic cycle

Type IIA DNA topoisomerases are complex molecular nanomachines that manage topological states of the DNA molecule in the cell and play a crucial role in cellular processes such as cell division and transcription. They are also established targets of cancer chemotherapy. Starting from the available crystal structure of a fully catalytic topoisomerase IIA homodimer from Saccharomyces cerevisiae, we constructed three states of this molecular motor primarily changing the configurations of the DNA segment bound in the DNA gate and performed μs-long all-atom molecular simulations. A comprehensive analysis revealed a sliding motion within the DNA gate and a teamwork between the N-gate and DNA gate that may be associated with the necessary molecular events that allow passage of the T-segment of DNA. The observed movement of the ATPase dimer relative to the DNA domain was reflected in different interaction patterns between the K-loops of the transducer domain and the B-A-B form of the bound DNA. Based on the obtained results, we mapped simulated configurations to the structures in the proposed catalytic cycle through which type IIA topoisomerases exert their function and discussed the possible transition events. The results extend our understanding of the mechanism of action of type IIA topoisomerases and provide an atomistic interpretation of some of the observed features of these molecular motors.

Fragment screening using biolayer interferometry reveals ligands targeting the SHP-motif binding site of the AAA+ ATPase p97

Biosensor techniques have become increasingly important for fragment-based drug discovery during the last years. The AAA+ ATPase p97 is an essential protein with key roles in protein homeostasis and a possible target for cancer chemotherapy. Currently available p97 inhibitors address its ATPase activity and globally impair p97-mediated processes. In contrast, inhibition of cofactor binding to the N-domain by a protein-protein-interaction inhibitor would enable the selective targeting of specific p97 functions. Here, we describe a biolayer interferometry-based fragment screen targeting the N-domain of p97 and demonstrate that a region known as SHP-motif binding site can be targeted with small molecules. Guided by molecular dynamics simulations, the binding sites of selected screening hits were postulated and experimentally validated using protein- and ligand-based NMR techniques, as well as X-ray crystallography, ultimately resulting in the first structure of a small molecule in complex with the N-domain of p97. The identified fragments provide insights into how this region could be targeted and present first chemical starting points for the development of a protein-protein interaction inhibitor preventing the binding of selected cofactors to p97.

Oridonin Induces Oxidative Stress-mediated Cancer Cells Apoptosis via Targeting Thioredoxin Reductase.

Thioredoxin reductase (TrxR) plays vital role in regulating cellular redox balance as well as redox-mediated signal transduction. Accumulating evidence supports that overactivation of TrxR is closely related to tumorigenesis and that targeting TrxR ablation reverses the growth of numerous malignant tumors, making TrxR a promising target for cancer chemotherapy. Thus, the discovery and development of molecules as promising anticancer agents that target TrxR is of great significance. Oridonin was shown to inhibit TrxR activity, but the detailed cellular mechanism is largely unknown. The study investigated the mechanism of action and underlying inhibitory properties of oridonin on TrxR in HeLa cells. A covalent docking was performed to reveal the possible interaction between oridonin and TrxR by Schrödinger Software Suite. TrxR activity was determined by 5,5'-dithiobis-2- nitrobenzoic acid reduction assay and endpoint insulin reduction assay. Sulforhodamine B and colony formation assay were employed to assess the viability and growth of cells. Reactive oxygen species level was measured by probe 2', 7'-dichlorfluorescein diacetate, and dihydroethidium. Hoechst 33342 staining, caspase 3 activation, and fluorescein-5-isothiocyanate-conjugated Annexin V and propidium iodide double staining were used to evaluate apoptosis. Here, we reported the oridonin as a potent inhibitor of TrxR. Inhibition of TrxR results in a decrease of thiols content and total glutathione, elevates reactive oxygen species levels, and finally promotes oxidative stress-mediated apoptosis of cancer cells. Targeting TrxR by oridonin discloses a novel molecular mechanism underlying the biological action of oridonin and sheds light on developing oridonin as a potential tumor therapeutic agent.

Chemotherapy suppresses SHH gene expression via a specific enhancer

Sonic hedgehog (SHH) signaling is a key regulator of embryonic development and tissue homeostasis that is involved in gastrointestinal (GI) cancer progression. Regulation of SHH gene expression is a paradigm of long-range enhancer function. Using the classical chemotherapy drug 5-fluorouracil (5FU) as an example, here we show that SHH gene expression is suppressed by chemotherapy. SHH is downstream of immediate early genes (IEGs), including Early growth response 1 (Egr1). A specific 139 kb upstream enhancer is responsible for its down-regulation. Knocking down EGR1 expression or blocking its binding to this enhancer renders SHH unresponsive to chemotherapy. We further demonstrate that down-regulation of SHH expression does not depend on 5FU's impact on nucleotide metabolism or DNA damage; rather, a sustained oxidative stress response mediates this rapid suppression. This enhancer is present in a wide range of tumors and normal tissues, thus providing a target for cancer chemotherapy and its adverse effects on normal tissues. We propose that SHH is a stress-responsive gene downstream of IEGs, and that traditional chemotherapy targets a specific enhancer to suppress its expression.

Evaluation of the biological activities of β-glucan isolated from Lentinula edodes.

Lentinula edodes (shiitake) is an edible mushroom that contains many constituents and β-glucan is considered a major polysaccharide. This study, therefore, aimed to characterize β-glucan and evaluate its activities. Fresh fruit bodies of L. edodes were used for β-glucan extraction and followed by analyses via Fourier transform infrared, nuclear magnetic resonance and high performance liquid chromatography confirming its characteristic structure. For evaluating biological activities of β-glucan, different concentrations (0·1-3·5 mg ml-1 ) were assessed. The optimal dose was 3·5 mg ml-1 that showed the highest scavenging radical ability (75·3%) confirms antioxidant activity, strong inhibition of the peroxyl radical (80·9%) to inhibit lipid peroxidation, elevation the inhibition percentage of both α-amylase (73·4%) and α-glucosidase (70·3%) indicates the antidiabetic properties, and highest AFB1 reduction (88%) which ensured the aflatoxin-detoxifying ability. In addition, antifungal activity of β-glucan was evaluated to inhibit sporulation process in Aspergillus niger and recorded with minimum inhibitory concentration of 2·5 mg ml-1 and minimum fungicidal concentration of 3 mg ml-1 . In a dose-dependent manner, higher concentration of β-glucan affects viability of tumour cells concomitant induces potent anti-cancer immune responses and inhibited the activity of topoisomerase I which are considered an important target for cancer chemotherapy. Therefore, L. edodes-β-glucan has the potential to act as a suggestive agent for antioxidant, antidiabetic, antifungal activity and aflatoxin detoxification.

Binding Networks Identify Targetable Protein Pockets for Mechanism-Based Drug Design.

The human genome codes only a few thousand druggable proteins, mainly receptors and enzymes. While this pool of available drug targets is limited, there is an untapped potential for discovering new drug-binding mechanisms and modes. For example, enzymes with long binding cavities offer numerous prerequisite binding sites that may be visited by an inhibitor during migration from a bulk solution to the destination site. Drug design can use these prerequisite sites as new structural targets. However, identifying these ephemeral sites is challenging. Here, we introduce a new method called NetBinder for the systematic identification and classification of prerequisite binding sites at atomic resolution. NetBinder is based on atomistic simulations of the full inhibitor binding process and provides a networking framework on which to select the most important binding modes and uncover the entire binding mechanism, including previously undiscovered events. NetBinder was validated by a study of the binding mechanism of blebbistatin (a potent inhibitor) to myosin 2 (a promising target for cancer chemotherapy). Myosin 2 is a good test enzyme because, like other potential targets, it has a long internal binding cavity that provides blebbistatin with numerous potential prerequisite binding sites. The mechanism proposed by NetBinder of myosin 2 structural changes during blebbistatin binding shows excellent agreement with experimentally determined binding sites and structural changes. While NetBinder was tested on myosin 2, it may easily be adopted to other proteins with long internal cavities, such as G-protein-coupled receptors or ion channels, the most popular current drug targets. NetBinder provides a new paradigm for drug design by a network-based elucidation of binding mechanisms at an atomic resolution.

Analysis of Pleurotin binding to human thioredoxin reductase using docking and molecular dynamics simulation

Thioredoxin reductase (TrxR) has been considered a potential target for cancer chemotherapy. It acts by controlling the redox homeostasis of human cells and, therefore, interfering in its function may trigger apoptosis, which is a crucial tumor suppression mechanism. Despite the great effort in the search for TrxR inhibitors, none was approved for human therapy. In the present study a virtual screening for natural organic compounds is discussed for a set of 72 compounds with known IC-50 for TrxR inhibition. The results suggest the Pleurotin, a naphthoquinone obtained from Hohenbuehelia grisea fungus, as a potential TrxR inhibitor, which acts by binding to the active site of the enzyme, between the N- and C-terminal domains. The presence of the ligand blocks the approximation of the C-terminal arm to the N-terminal, which is an essential step of the enzyme function. Besides, the two equivalent binding sites of TrxR were explored, by docking two ligands simultaneously. The results indicate that both sites have an allosteric correlation and, the presence of the ligand in one site may interfere, or even prevent, the binding of the second ligand at the other site. All these findings are quantitatively discussed based on the analysis of long molecular dynamics trajectories, which provides a full description of the ligand-receptor binding modes, average binding energies and conformational changes. Communicated by Ramaswamy H. Sarma

The Syntheses and Medicinal Attributes of Phenanthrenes as Anticancer Agents: A Quinquennial Update

Cancer is a silent killer and remains to pose major health problems globally. Amongst the several biological targets, DNA is one of the most striking targets in cancer chemotherapy. Owing to its planar structure, phenanthrene and its derivatives exhibit potential cytotoxicity by intercalating between the DNA base pairs and by inhibiting the enzymes that are involved in the synthesis of DNA. However, due to the off-target effects and resistance, the development of novel chemotherapeutic agents would be meritorious. In this regard, we present a detailed review on the development of phenanthrene-based derivatives reported in the last quinquennial. This review mainly focuses on the synthetic aspects and strategies to procure the fused phenanthrene derivatives such as (i) phenanthroindolizidines, phenanthroquinolizidine, phenanthroimidazoles, podophyllotoxin-based phenanthrenes, and dihydrophenanthrodioxine derivatives, (ii) phenanthrene conjugates with other pharmacologically significant pharmacophores, and (iii) phenanthrene-metal complexes. This review also edifies their potential in vitro cytotoxicity evaluation against various carcinoma cell lines in submicromolar to nanomolar ranges. Additionally, computational studies and structure-activity relationships (SARs) have also been presented to highlight the essential features of the designed congeners. Thus, this review would aid in the development of novel derivatives in future as potential cytotoxic agents in the field of medicinal chemistry.