Effective Anticancer Drugs Research Articles

4-Thiazolidinone-Bearing Hybrid Molecules in Anticancer Drug Design.

Oncological diseases have currently reached an epidemic scale, especially in industrialized countries. Such a situation has prompted complex studies in medicinal chemistry focused on the research and development of novel effective anticancer drugs. In this review, the data concerning new 4-thiazolidinone-bearing hybrid molecules with potential anticancer activity reported during the period from the years 2017-2022 are summarized. The main emphasis is on the application of molecular hybridization methodologies and strategies in the design of small molecules as anticancer agents. Based on the analyzed data, it was observed that the main directions in this field are the hybridization of scaffolds, the hybrid-pharmacophore approach, and the analogue-based drug design of 4-thiazolidinone cores with early approved drugs, natural compounds, and privileged heterocyclic scaffolds. The mentioned design approaches are effective tools/sources for the generation of hit/lead compounds with anticancer activity and will be relevant to future studies.

Chlorogenic acid for cancer prevention and therapy: Current status on efficacy and mechanisms of action

Chlorogenic acid (CA), also known as 5-O-caffeoylquinic acid, is a dietary phenolic acid produced by various plant species. CA, is the most ubiquitous compound among the phenolic acid group, is also present in tea and green coffee extracts. Its consumption reduces the risk of numerous diseases as validated by preclinical and clinical studies. CA possesses a wide range of pharmacological properties, such as hepatoprotective, antimicrobial, immunomodulatory, antioxidant, antidiabetic, and anticancer activities. It has been extensively used in the food, chemical, medicine, and health care industries. Available reports revealed that CA can exert anticancer activity by inhibiting the cell cycle, triggering apoptosis, and suppressing the proliferation of cancer cells. It upregulates the expression of nuclear factor of activated T cells 2 (NFATC2) and NFATC3 genes involved in immune pathway and downregulates B cell-specific moloney murine leukemia virus integration site 1 protein and SRY-box transcription factor 2 gene expression to facilitate tumor cell destruction. It promotes intracellular DNA impairment and topoisomerase I- and topoisomerase-II-DNA complex formation that perform a key function in apoptosis. In addition, CA has been documented to be an effective natural anticancer drug and was approved by the China Food and Drug Administration. Several previously published reports have provided fragmented summary of various anticancer activities of CA. Therefore, this review aims to deliver up-to-date and comprehensive assessment about the natural sources of CA, its bioavailability, metabolism, and anticancer property with an emphasis on the molecular mechanisms associated with several signaling pathways in tumor cells.

Design, synthesis, molecular modeling, and bioactivity evaluation of 1,10-phenanthroline and prodigiosin (Ps) derivatives and their Copper(I) complexes against mTOR and HDAC enzymes as highly potent and effective new anticancer therapeutic drugs.

Breast cancer is the second type of cancer with a high probability of brain metastasis and has always been one of the main problems of breast cancer research due to the lack of effective treatment methods. Demand for developing an effective drug against breast cancer brain metastasis and finding molecular mechanisms that play a role in effective treatment are gradually increasing. However, there is no effective anticancer therapeutic drug or treatment method specific to breast cancer, in particular, for patients with a high risk of brain metastases. It is known that mTOR and HDAC enzymes play essential roles in the development of breast cancer brain metastasis. Therefore, it is vital to develop some new drugs and conduct studies toward the inhibition of these enzymes that might be a possible solution to treat breast cancer brain metastasis. In this study, a series of 1,10-phenanthroline and Prodigiosin derivatives consisting of their copper(I) complexes have been synthesized and characterized. Their biological activities were tested in vitro on six different cell lines (including the normal cell line). To obtain additional parallel validations of the experimental data, some in silico modeling studies were carried out with mTOR and HDAC1 enzymes, which are very crucial drug targets, to discover novel and potent drugs for breast cancer and related brain metastases disease.

Recent Updates on the Development of Deuterium-Containing Drugs for the Treatment of Cancer.

Cancer is one of the deadliest diseases in the world. In 2020, 19.3 million cancer cases and 10 million deaths were reported in the world. It is supposed that the prevalence of cancer cases will rise to 28.4 million by 2040. Chemotherapy-based regimens have a narrow therapeutic index, severe adverse drug reactions, and lack metabolic stability. Besides, the metabolism of anticancer produces several non-active and toxic metabolites that reduce exposure of the target site to the parent drug. Therefore, developing better-tolerated and effective new anticancer drugs and modification of the existing anticancer drugs to minimize toxicity and increase efficacy has become a very urgent need. Deuterium incorporation reduces the metabolism of certain drugs that are breakdown by pathways involving hydrogen-carbon bond scission. For example, CYP450 mediated oxidative metabolism of drugs that involves the breakdown of a hydrogen-carbon bond affected by deuteration. Deuterium incorporation into the drug increases the half-life and reduces the dose, which provides better safety and efficacy. Deutetrabenazine is the first deuterated form of tetrabenazine approved to treat chorea associated with Huntington’s disease and tardive dyskinesia. The study revealed that Deutetrabenazine has fewer neuropsychiatric side effects with favorable safety than tetrabenazine. The current review highlights the deuterium kinetic isotope effect on drug metabolism, deuterated compound pharmacokinetic property, and safety profile. Besides, this review explains the deuterated anticancer drug development update status.

Targeting Glucose Metabolism Enzymes in Cancer Treatment: Current and Emerging Strategies.

Simple SummaryReprogramming of glucose metabolism is a hallmark of cancer and can be targeted by therapeutic agents. Some metabolism regulators, such as ivosidenib and enasidenib, have been approved for cancer treatment. Currently, more advanced and effective glucose metabolism enzyme-targeted anticancer drugs have been developed. Furthermore, some natural products have shown efficacy in killing tumor cells by regulating glucose metabolism, offering novel therapeutic opportunities in cancer. However, most of them have failed to be translated into clinical applications due to low selectivity, high toxicity, and side effects. Recent studies suggest that combining glucose metabolism modulators with chemotherapeutic drugs, immunotherapeutic drugs, and other conventional anticancer drugs may be a future direction for cancer treatment.Reprogramming of glucose metabolism provides sufficient energy and raw materials for the proliferation, metastasis, and immune escape of cancer cells, which is enabled by glucose metabolism-related enzymes that are abundantly expressed in a broad range of cancers. Therefore, targeting glucose metabolism enzymes has emerged as a promising strategy for anticancer drug development. Although several glucose metabolism modulators have been approved for cancer treatment in recent years, some limitations exist, such as a short half-life, poor solubility, and numerous adverse effects. With the rapid development of medicinal chemicals, more advanced and effective glucose metabolism enzyme-targeted anticancer drugs have been developed. Additionally, several studies have found that some natural products can suppress cancer progression by regulating glucose metabolism enzymes. In this review, we summarize the mechanisms underlying the reprogramming of glucose metabolism and present enzymes that could serve as therapeutic targets. In addition, we systematically review the existing drugs targeting glucose metabolism enzymes, including small-molecule modulators and natural products. Finally, the opportunities and challenges for glucose metabolism enzyme-targeted anticancer drugs are also discussed. In conclusion, combining glucose metabolism modulators with conventional anticancer drugs may be a promising cancer treatment strategy.

Anti-breast cancer drugs targeting cell-surface glucose-regulated protein 78: a drug repositioning in silico study

Breast cancer (BC) is prevalent worldwide and is a leading cause of death among women. However, cell-surface glucose-regulated protein 78 (cs-GRP78) is overexpressed in several types of cancer and during pathogen infections. This study examines two well-known BC drugs approved by the FDA as BC treatments to GRP78. The first type consists of inhibitors of cyclin-based kinases 4/6, including abemaciclib, palbociclib, ribociclib, and dinaciclib. In addition, tunicamycin, and doxorubicin, which are among the most effective anticancer drugs for early and late-stage BC, are tested against GRP78. As (−)-epiGallocatechin gallate inhibits GRP78, it is also being evaluated (used as positive control). Thus, using molecular dynamics simulation approaches, this study aims to examine the advantages of targeting GRP78, which represents a promising cancer therapy regime. In light of recent advances in computational drug response prediction models, this study aimed to examine the benefits of GRP78 targeting, which represents a promising cancer therapy regime, by utilizing combined molecular docking and molecular dynamics simulation approaches. The simulated protein (50 ns) was docked with the drugs, then a second round of dynamics simulation was performed for 100 ns. After that, the binding free energies were calculated from 30 to 100 ns for each complex during the simulation period. These findings demonstrate the efficacy of abemaciclib, ribociclib, and tunicamycin in binding to the nucleotide-binding domain of the GRP78, paving the way for elucidating the mode of interactions between these drugs and cancer (and other stressed) cells that overexpress GRP78. Communicated by Ramaswamy H. Sarma

A significantly non-toxic novel Cobalt(III) Schiff base complex induces apoptosis via G2-M cell cycle arrest in human breast cancer cell line MCF-7

AimsMetal complexes have ignited considerable interest in the field of chemotherapy after the serendipitous discovery of cisplatin but the severe toxicity of these platinum-based drugs compelled researchers to search for newer, more effective lesser toxic anticancer drugs. Materials and methodsStructural analysis is done by different physicochemical techniques including X-ray single crystallography. Toxicity study has been done in normal Swiss albino mice. MTT assay assessed cell viability. Apoptosis, cell cycle arrest, and cell proliferation were assessed by FACS using Annexin V-PI, PI, and CFSE staining respectively. Western blot quantifies protein expression. While cell migration was studied by wound healing assay. Key findingsOne-pot synthesis of a novel mononuclear cobalt(III)-Schiff base complex (1) (>99 % purity) and its complete characterization have been done. Cell viability assay showed that 1 (IC50 = 16.81 ± 1.33 μM) exhibits cytotoxicity at much lower concentration in comparison to oxaliplatin (IC50 = 31.4 ± 0.69 μM) against MCF-7 cells for 24 h of therapy without being overly toxic to human PBMCs (IC50 ≥ 60 μM). Additional in vitro studies demonstrated that 1 induces apoptosis via G2-M cell cycle arrest and reduces cell proliferation as well as cell migration in MCF-7 cells. In vivo subacute toxicity (28 days) and systemic chronic toxicity (40 days) studies were carried out in normal Swiss albino mice showed 1 is significantly nontoxic to the host. SignificanceThe readily synthesizable, significantly nontoxic cobalt complex with appreciable anticancer activity implies that it might be an effective chemotherapeutic agent for new-age anti-tumor medication.

Calcium Overload or Underload? The Effects of Doxorubicin on the Calcium Dynamics in Guinea Pig Hearts

The severe doxorubicin (DOXO) side effect of cardiomyopathy limits it clinical application as an effective anticancer drug. Although Ca2+ overload was postulated as one of the mechanisms for this toxicity, its role was, however, disputable in terms of the contractile dysfunction. In this work, the dynamics of the intracellular Ca2+ signal were optically mapped in a Langendorff guinea pig heart. We found that DOXO treatment: (1) Delayed the activation of the Ca2+ signal. With the reference time set at the peak of the action potential (AP), the time lag between the peak of the Ca2+ signal and AP (Ca-AP-Lag) was significantly prolonged. (2) Slowed down the intracellular Ca2+ releasing and sequestering process. Both the maximum rising (MRV) and falling (MFV) velocity of the Ca2+ signal were decreased. (3) Shortened the duration of the Ca2+ signal in one cycle of Ca2+ oscillation. The duration of the Ca2+ signal at 50% amplitude (CaD50) was significantly shortened. These results suggested a reduced level of intracellular Ca2+ after DOXO treatment. Furthermore, we found that the effect of tachypacing was similar to that of DOXO, and, interestingly, DOXO exerted contradictory effects on the tachypaced hearts: it shortened the Ca-AP-Lag, accelerated the MRV and MFV, and prolonged the CaD50. We, therefore, concluded that DOXO had a different effect on intracellular Ca2+. It caused Ca2+ underload in hearts with sinus rhythm; this might relate to the contractile dysfunction in DOXO cardiomyopathy. It led to Ca2+ overload in the tachypaced hearts, which might contribute to the Ca2+-overload-related toxicity.

Potential anticancer activities of securinine and its molecular targets

BackgroundSecurinine is an alkaloid identified from the roots and leaves of the shrub Flueggea suffruticosa (Pall.) Baill. The molecular structure of securinine consists of four rings, including three chiral centers. It has been suggested that securinine can be chemically synthesized from tyrosine and lysine. Securinine has long been used to treat central nervous system diseases. In recent years, more and more evidence shows that securinine also has anticancer activity, which has not been systematically discussed and analyzed. PurposeThis study aims to propose an overall framework to describe the molecular targets of securinine in different signal pathways, and discuss the current status and prospects of each pathway, so as to provide a theoretical basis for the development securinine as an effective anticancer drug. MethodsThe research databases on the anticancer activity of securinine from PubMed, Scopus, Web of Science and ScienceDirect to 2021 were systematically searched. This paper follows the Preferred Reporting Items and Meta-Analysis guidelines. ResultsSecurinine has the ability to kill a variety of human cancer cells, including, leukemia as well as prostate, cervical, breast, lung, and colon cancer cells. It can regulate the signal pathways of phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin, Wnt and Janus kinase-signal transducer and activator of transcription, promote cancer cell apoptosis and autophagy, and inhibit cancer cell metastasis. Securinine also has the activity of inducing leukemia cell differentiation. ConclusionAlthough there has been some experimental evidence indicating the anticancer effect of securinine and its possible pharmacology, in order to design more effective anticancer drugs, it is necessary to study the synergy of intracellular signaling pathways. More in vivo experiments and even clinical studies are needed, and the synergy between securinine and other drugs is also worth studying.

REPURPOSING DRUGS FOR CANCER THERAPY

Cancer remains a second leading cause of death worldwide. The economic burden of cancer is increasing day by day due to the morbidity, recurrence, and poor prognosis of this disease. Over the last decades, there is an increasing need to discover and development effective and safe therapeutic agents for cancer. Traditionally, the development and approval of new drugs are long term and also costly. Therefore, this has encouraged scientists to repurposing of known drugs for the treatment of cancer. This strategy has been considered as a good way to offer safe, effective and cost-effective new anticancer drugs. Approximately, 300 non-cancer drugs have been shown to exhibit anticancer effect on different cancer cells, thus they are promising anticancer potential and, candidates for development. However, the appropriate and comprehensive research is required in order to define exact mechanism, dosage and toxicity potential of repurposed drugs. A broad range of therapeutic strategies should be used in order to assess the success of repurposed drugs in replacement of conventional cancer therapies or enhancement of chemotherapy. 

Spectro-electrochemical, fluorometric and biothermodynamic evaluation of pharmacologically active morpholine scaffold single crystal ligand and its metal(II) complexes: A comparative study on in-vitro and in-silico screening towards DNA/BSA/SARS-CoV-19

A novel series of metal(II) complexes (1–5) [MII(L)2]{Where M = Cu (1), Co (2), Mn (3), Ni (4) and Zn (5)} constructed from 2-(4-morpholinobenzylideneamino)phenol Schiff base ligand (HL) in a 1:2 M ratio and the spectral and analytical results put forward square planar geometry. Spectro-electrochemical, hydrodynamic, gel electrophoresis, and DNA binding/cleavage results for all the compounds demonstrate that complex (1) had excellent DNA binding/cleavage properties compared to other compounds. The observation also suggests that test compounds could intercalate with DNA, and the biothermodynamic property more strongly supports the stabilizing of the double helix DNA with the complexes. BSA binding constant results show that complex (1) exposes the best binding property via a static mode, which is further confirmed by FRET calculations. The DFT calculations and docking results for all compounds towards DNA, BSA and SARS-CoV-19 main protease (3CLPro), reveal the binding energies were in the range of −7.8 to −9.4, −6.6 to −10.2 and − 6.1 – −8.2 kcal/mol for all test compounds respectively. In this case, complexes showed favorable binding energies compared to free ligand, which stimulates further studies aimed at validating the predicted activity as well as contributing to tackling the current and future viral pandemics. The in-vitro antioxidant, antimicrobial, and anticancer results for all compounds revealed that copper complex (1) has better activity compared to others. This might result in an effective anticancer drug for future research, which is especially promising since the observed experimental results for all cases were in close agreement with the theoretical calculations.

The potential interplay between G-quadruplex and p53: their roles in regulation of ferroptosis in cancer.

Ferroptosis is a novel form of regulated cell death trigged by various biological processes, and p53 is involved in different ferroptosis regulations and functions as a crucial regulator. Both DNA and RNA can fold into G-quadruplex in GC-rich regions and increasing shreds of evidence demonstrate that G-quadruplexes have been associated with some important cellular events. Investigation of G-quadruplexes is thus vital to revealing their biological functions. Specific G-quadruplexes are investigated to discover new effective anticancer drugs. Multiple modulations have been discovered between the secondary structure G-quadruplex and p53, probably further influencing the ferroptosis in cancer. G-quadruplex binds to ferric iron-related structures directly and may affect the p53 pathways as well as ferroptosis in cancer. In addition, G-quadruplex also interacts with p53 indirectly, including iron-sulfur cluster metabolism, telomere homeostasis, lipid peroxidation, and glycolysis. In this review, we summarized the latent interplay between G-quadruplex and p53 which focused mainly on ferroptosis in cancer to provide the potential understanding and encourage future studies.

Trends in accessibility of negotiated targeted anti-cancer medicines in Nanjing, China: An interrupted time series analysis.

BackgroundIn order to establish a long-term strategy for bearing the costs of anti-cancer drugs, the state had organized five rounds of national-level pricing negotiations and introduced the National Health Insurance Coverage (NHIC) policy since 2016. In addition, the National Healthcare Security Administration (NHSA) introduced the volume-based purchasing (VBP) pilot program to Nanjing in September 2019. Taking non-small cell lung cancer as an example, the aim of the study was to verify whether national pricing negotiations, the NHIC policy and the VBP pilot program had a positive impact on the accessibility of three targeted anti-cancer drugs.MethodsBased on the hospital procurement data, interrupted time series (ITS) design was used to analyze the effect of the health policy on the accessibility and affordability of gefitinib, bevacizumab and recombinant human endostatin from January 2013 to December 2020 in Nanjing, China.ResultsThe DDDs of the three drugs increased significantly after the policy implementation (P < 0.001, P < 0.001, P = 0.008). The trend of DDDc showed a significant decrease (P < 0.001, P < 0.001, P < 0.001). The mean availability of these drugs before the national pricing negotiation was <30% in the surveyed hospitals, and increased significantly to 60.33% after 2020 (P < 0.001, P = 0.001, P < 0.001). The affordability of these drugs has also increased every year after the implementation of the insurance coverage policy. The financial burden is higher for the rural patients compared with the urban patients, although the gap is narrowing.ConclusionThe accessibility of targeted anti-cancer drugs has increased significantly after the implementation of centralized prices, the NHIC policy and the VBP pilot program, and has shown sustained long-term growth. Multi-pronged supplementary measures and policy approaches by multiple stakeholders will facilitate equitable access to effective and affordable anti-cancer drugs.

Computational study on novel natural compound inhibitor targeting IDH1_R132H.

Isocitrate dehydrogenases (IDH) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. IDH1 mutation has been reported in various tumors especially Cholangiocarcinoma, while the IDH1_R132H is reported to be the most common mutation of IDH1. IDH1_R132H inhibitors are effective anti-cancer drugs and have shown significant therapeutic effects in clinical. In this study, two novel natural compounds were identified to combine respectively with IDH1_R132H with a stronger binding force with conductive to interaction energy. They also showed low toxicity potential. Molecular dynamics simulation analysis demonstrated that the candidate ligands-IDH1_R132H complexes is stable in natural circumstances with favorable potential energy. Thus, Styraxlignolide F and Tremulacin were screened as promising IDH1_R132H inhibitors. We provide a solid foundation for the design and development of IDH1_R132H targeted drugs.

Poly-β-Cyclodextrin-coated neodymium-containing copper sulphide nanoparticles as an effective anticancer drug carrier

This study aims at tuning the properties of the nanoparticles by incorporating neodymium, exploring the sustained release of drug, and the anticancer activity on breast cancer cells. The crystal characteristics of NdCuS2 nanoparticles are analysed using X-ray diffraction. The morphology and size of the nanoparticles were characterised using Transmission Electron Microscope and particle size analyser. The rate of release of the encapsulated camptothecin and anticancer effects on breast cancer cells are investigated. The nanoparticles are rod-shaped, 132 ± 8 nm long and 27 ± 7 nm wide. The band gap of the nanoparticles is 4.85 eV. The drug encapsulation efficiency is 94.76% (w/w). The drug is released in a sustained manner, over a period of 180 h. The cytotoxicity of the camptothecin-loaded NPs is examined on MDA-MB-231 cells and the IC50 is 4.39 µg mL−1. The NdCuS2 nanoparticles are promising as theranostic agents considering their material characteristics and anticancer activity.

Cancer Chemotherapy via Natural Bioactive Compounds.

Cancer-induced mortality is increasingly prevalent globally, which skyrocketed the necessity to discover new/novel, safe and effective anticancer drugs. Cancer is characterized by the continuous multiplication of cells in the human, which is unable to control. Scientific research is drawing its attention toward naturally-derived bioactive compounds as they have fewer side effects compared to the current synthetic drugs used for chemotherapy. Drugs isolated from natural sources and their role in the manipulation of epigenetic markers in cancer are discussed briefly in this review article. With advancing medicinal plant biotechnology and microbiology in the past century, several anticancer phytomedicines were developed. Modern pharmacopeia contains at least 25% herbal-based remedies, including clinically used anticancer drugs. These drugs mainly include the podophyllotoxin derivatives vinca alkaloids, curcumin, mistletoe plant extracts, taxanes, camptothecin, combretastatin, and colchicine artesunate, homoharringtonine, ellipticine, roscovitine, maytansine, tapsigargin,and bruceantin. Compounds (psammaplin, didemnin, dolastin, ecteinascidin, and halichondrin) isolated from marine sources and animals such as microalgae, cyanobacteria, heterotrophic bacteria, invertebrates. They have been evaluated for their anticancer activity on cells and experimental animal models and used chemotherapy.Drug-induced manipulation of epigenetic markers plays an important role in the treatment of cancer. The development of a new drug from isolated bioactive compounds of plant sources has been a feasible way to lower the toxicity and increase their effectiveness against cancer. Potential anticancer therapeutic leads obtained from various ethnomedicinal plants, foods, marine, and microorganisms are showing effective yet realistically safe pharmacological activity. This review will highlight important plant-based bioactive compounds like curcumin, stilbenes, terpenes, other polyphenolic phyto-compounds, and structurally related families that are used to prevent/ ameliorate cancer. However, a contribution from all possible fields of science is still a prerequisite for discovering safe and effective anticancer drugs.

Azithromycin as Potent Inhibitor of Cell Migration in Tumor Cell Line

Continuous obstacles behind the discovery of novel drugs for cancer therapy have necessitated the development of alternative strategy of drug repurposing—the development of old drugs for new therapeutic purposes. With an improved understanding of the hallmarks of cancer, this strategy offers a cost-effective process for the treatment of human neoplastic disease, thereby facilitating rapid clinical translation. In this regard, macrolide antibiotics (MAs), which include a wide spectrum of activities against Gram-positive bacteria, have also been proposed as anticancer drugs for multiple tumor types. Over the past few years, significant progress has been achieved in anticancer therapy, but development of resistance and unavoidable side effects have weakened these attainments. Considering this severe condition, a number of drugs with novel antitumor mechanisms are under investigations including antimicrobials that have been shown to possess anti-inflammatory, immunomodulatory, and cytotoxic effects. In this regard, both conventional and novel antimicrobials are being studied to explore their anticancer potential along with underlying mechanisms that may render them as effective anticancer drugs in the future. Hence, in the latest study, we tested the role of a macrolide antibiotic drug, Azithromycin (AZM) alone, in combination with standard chemotherapeutic agent Sorafenib (Sorafenib/AZM) and its gold conjugated nanoparticles (AuAZM) as an anti angiogenic agent in hepatoma cell line hepG2 through wound healing assay. The migratory potential of HepG2 cells after being exposed to different treatments (AZM, Sorafenib, Sorafenib/AZM, and Au-AZM at IC50 concentrations) was observed at 0, 6, 24, 48, and 72 hours. The results of our study showed that AZM exhibited highly significant reduction in wound healing with p-value (&lt; 0.001) up till 72 hours, while Sorafenib, Sorafenib/AZM, and Au-AZM inhibited wound healing up to 48 hours (p-value &lt; 0.001). The current study revealed a comparatively higher antiangiogenic potential of AZM in cancer cells, thereby suggesting its clinical application for cancer treatment.

Structural and Biofunctional Insights into the Cyclo(Pro-Pro-Phe-Phe-) Scaffold from Experimental and In Silico Studies: Melanoma and Beyond.

Short peptides have great potential as safe and effective anticancer drug leads. Herein, the influence of short cyclic peptides containing the Pro-Pro-Phe-Phe sequence on patient-derived melanoma cells was investigated. Cyclic peptides such as cyclo(Leu-Ile-Ile-Leu-Val-Pro-Pro-Phe-Phe-), called CLA, and cyclo(Pro-homoPro-β3homoPhe-Phe-), called P11, exert the cytotoxic and the cytostatic effects in melanoma cells, respectively. CLA was the most active peptide as it reduced the viability of melanoma cells to 50% of control at about 10 µM, whereas P11 at about 40 µM after 48 h incubation. Interestingly, a linear derivative of P11 did not induce any effect in melanoma cells confirming previous studies showing that cyclic peptides exert better biological activity compared to their linear counterparts. According to in silico predictions, cyclic tetrapeptides show a better pharmacokinetic and toxic profile to humans than CLA. Notably, the spatial structure of those peptides containing synthetic amino acids has not been explored yet. In the Cambridge Structural Database, there is only one such cyclic tetrapeptide, cyclo((R)-β2homoPhe-D-Pro-Lys-Phe-), while in the Protein Data Bank—none. Therefore, we report the first crystal structure of cyclo(Pro-Pro-β3homoPhe-Phe-), denoted as 4B8M, a close analog of P11, which is crucial for drug discovery. Comparative molecular and supramolecular analysis of both structures was performed. The DFT findings revealed that 4B8M is well interpreted in the water solution. The results of complex Hirshfeld surface investigations on the cooperativity of interatomic contacts in terms of electrostatic and energetic features are provided. In short, the enrichment ratio revealed O…H/H…O and C…H/H…C as privileged intercontacts in the crystals in relation to basic and large supramolecular H-bonding synthon patterns. Furthermore, the ability of self-assemble 4B8M leading to a nanotubular structure is also discussed.

Ultrasensitive and Specific Detection of Anticancer Drug 5-Fluorouracil in Blood Samples by a Surface-Enhanced Raman Scattering (SERS)-Based Lateral Flow Immunochromatographic Assay.

5-Fluorouracil (5-FU) is an effective anticancer drug widely used in the world. To improve therapy efficiency and reduce side effects, it is very important to frequently detect the concentration of 5-FU in blood samples of patients. In this work, a new type of lateral flow immunochromatographic assay (LFIA) based on surface-enhanced Raman scattering (SERS) for ultrasensitive and specific detection of 5-FU in blood samples was developed. Au@Ag/Au nanoparticles (NPs) employing Au particles as the core and Ag/Au alloy as the shell were synthesized, characterized and used as the substrate in SERS-LFIA due to their high SERS enhancement and biocompatibility. The immunoprobe was made in the form of AuMBA@Ag/Au-Ab in which mercaptobenzoic acid (MBA, a common Raman active reporter) was embedded in the core–shell layer and the monoclonal antibody (mAb) against 5-FU was immobilized on the surface. The performance of SERS-LFIA was similar to that in colloidal gold based-LFIA, and the entire assay time was within 20 min. According to the color intensity on the testing (T) lines of LFIA strips visualized by eyes, the contents of 5-FU in the samples could be qualitatively or semi-quantitatively identified. Furthermore, by measuring the characteristic Raman intensities of MBA on T lines, quantitative detection of 5-FU in the samples were achieved. The IC50 and limit of detection (LOD) of the LFIA for 5-FU were found to be 20.9 pg mL−1 and 4.4 pg mL−1, respectively. There was no cross-reactivity (CR) of the LFIA with nine relative compounds, and the CR with cytosine, tegafur and carmofur were less than 4.5%. The recoveries of 5-FU from spiked blood samples were in the range of 78.6~86.4% with the relative standard deviation (RSD) of 2.69~4.42%. Five blood samples containing 5-FU collected from the Cancer Hospital were measured by SERS-LFIA, and the results were confirmed by LC-MS/MS. It was proven that the proposed method was able to simply and rapidly detect 5-FU in blood samples with high sensitivity, specificity, accuracy and precision.

Antiproliferative activity of a new derivative from the class of N-glycoside of indolo[2,3-a]pyrrolo[3,4-c]carbazoles

Introduction: The creation of highly effective original anticancer drugs remains an urgent direction of scientific research in tumor therapy. One of the promising groups in this regard is indolocarbazoles and their derivatives, which are capable of initiating various pathways of tumor cell death. The aim of the study was to evaluate an antiproliferative activity of a new, Russian derivative of N-glycoside substituted indolocarbazole 6-amino-12-(α-L-arabinopyranosyl)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione (LCS-1208) on models of transplantable tumors of mice and on human tumors in Balb/c nude mice.&#x0D; Materials and methods: Indolocarbazole sensitivity to LCS-1208 was assessed on transplantable tumors of mice – lymphatic leukemia L-1210, cervical carcinoma (CC-5), and colon adenocarcinoma (CAC) by five-fold intraperitoneal administration (ip) of the LCS-1208 substance in single doses of 50, 75, 100 mg/kg. Investigation into the effectiveness of the LCS-1208 lyo dosage form was performed on subcutaneous xenografts of human colon cancer SW620 by an in­travenous administration (iv). The antitumor effect was evaluated by the tumor growth inhibition (TGI) and an increase in life span (ILS) of the treated animals as compared with the control ones. Evaluation of specific antitumor activity on xenografts was performed according to the tumor/control (T/C%) criterion (maximum criterion T/C≤42%).&#x0D; Results and discussion: According to the results of the study, the most sensitive to the action of the LCS-1208 sub­stance in the case of an ip administration of a total dose of 375 mg/kg were CAC with TGI=97–62%, p≤0.001 up to 16 days after the treatment, and ILS=36% (criteria for TGI≥70% and ILS≥25%). On xenografts of a human colon cancer SW620, the effectiveness of the LCS-1208 lyo drug dosage form within the range of total doses from 50 to 150 mg/kg in case of iv to Balb/c nude mice was set at T/C = 35–2% (criterion T/C&lt;42%).&#x0D; Conclusion: The presented results suggest possible effectiveness of LCS-1208 in treatment of colon malignant tumors of humans.