Anticancer mechanisms of ß-carbolines.

ß-Carboline nucleus is therapeutically valuable in medicinal chemistry for the treatment of varied number of diseases, most importantly cancer. The potent and wide-ranging activity of ß-carboline has established them as imperative pharmacological scaffolds especially in the cancer treatment. Numerous derivatives such as Tetrahydro ß-carbolines, metal complexed ß-carbolines, mono, di and tri substituted ß-carbolines have been reported to possess dynamic anticancer activity. These different substituted ß-carboline derivatives had shown different mechanism of action and plays important role in anticancer drug discovery and development. The review is an update of the chemistry of ß-carbolines, both synthetic and natural origin acting through various targets against cancerous cells. In addition to this, studies of multitarget molecules designed by coupling ß-carbolines along with other mechanisms for treatment of neoplasm are also summarized.

Lipid-Polymer Hybrid Nanosystems: A Rational Fusion for Advanced Therapeutic Delivery.

Lipid nanoparticles (LNPs) are spherical vesicles composed of ionizable lipids that are neutral at physiological pH. Despite their benefits, unmodified LNP drug delivery systems have substantial drawbacks, including a lack of targeted selectivity, a short blood circulation period, and in vivo instability. lipid-polymer hybrid nanoparticles (LPHNPs) are the next generation of nanoparticles, having the combined benefits of polymeric nanoparticles and liposomes. LPHNPs are being prepared from both natural and synthetic polymers with various techniques, including one- or two-step methods, emulsification solvent evaporation (ESE) method, and the nanoprecipitation method. Varieties of LPHNPs, including monolithic hybrid nanoparticles, core-shell nanoparticles, hollow core-shell nanoparticles, biomimetic lipid-polymer hybrid nanoparticles, and polymer-caged liposomes, have been investigated for various drug delivery applications. However, core-shell nanoparticles having a polymeric core surrounded by a highly biocompatible lipid shell are the most commonly explored LPHNPs for the treatment of various diseases. In this review, we will shed light on the composition, methods of preparation, classification, surface functionalization, release mechanism, advantages and disadvantages, patents, and clinical trials of LPHNPs, with an emphasis on core-shell-structured LPHNPs.

Caspase-3: A primary target for natural and synthetic compounds for cancer therapy.

Caspases, a group of protease enzymes (cysteine proteases), exist as inactive zymogens in the cells and execute apoptosis (programmed cell death). Caspase-3, an executioner caspase, plays an imperative role in apoptosis and becomes a primary target for cancer treatment. A number of analogues of quinazoline, quinazolinone, indoloquinazolines, quinone, naphthoquinones, pyrroloiminoquinones, styrylquinolines, tetheredtetrahydroquinoline, fluoroquinolone, thiosemicarbazones, benzotriazole, pyrimidines, chalcone, and carbazoles have been reported till date, representing caspase-3 mediated apoptosis for cancer therapy. Simultaneously, plant isolates, including lysicamine, podophyllotoxin, and majoranolide, have also been claimed for caspase-3-mediated apoptosis-induced cytotoxicity. Procaspase-activating compound-1 (PAC-1) is the first FDA approved orphan drug, and its synthetic derivative WF-208 also showed fascinating caspase-3 mediated anticancer activity. Till date, a large number of compounds have been reported and patented for their caspase-3-mediated cytotoxicity and now scientist is also focusing to introduce new compounds in market to encompass anticancer activity.

1,3,4-oxadiazole and its derivatives: A review on recent progress in anticancer activities.

The 1,3,4-oxadiazole nucleus is a biologically imperative scaffold possesses numerous biological activities. The broad and potent activity of 1,3,4-oxadiazole and their derivatives has established them as important pharmacological scaffolds especially in the treatment of cancer disease. Several di-, tri-, aromatic, and heterocyclic substituted 1,3,4-oxadiazole derivatives have been reported to possess potent anticancer activity. These substituted 1,3,4-oxadiazoles had shown different mechanism of action and participated in anticancer drug discovery and development. This review is complementary to earlier reviews and aims to review the work reported on anticancer activities of 1,3,4-oxadiazole derivatives from year 2000 to the beginning of 2020.

Anticancer Agents Based on Vulnerable Components in a Signalling Pathway.

Traditional cancer treatment includes surgery, chemotherapy, radiotherapy and immunotherapy that are clinically beneficial, but are associated with drawbacks such as drug resistance and side effects. In quest for better treatment, many new molecular targets have been introduced in the last few decades. Finding new molecular mechanisms encourages researchers to discover new anticancer agents. Exploring the mechanism of action also facilitates anticipation of potential resistance mechanisms and optimization of rational combination therapies. The write up describes the leading molecular mechanisms for cancer therapy, including mTOR, tyrosine Wee1 kinase (WEE1), Janus kinases, PI3K/mTOR signaling pathway, serine/threonine protein kinase AKT, checkpoint kinase 1 (Chk1), maternal embryonic leucine-zipper kinase (MELK), DNA methyltransferase I (DNMT1), poly (ADP-ribose) polymerase (PARP)-1/-2, sphingosine kinase-2 (SK2), pan-FGFR, inhibitor of apoptosis (IAP), murine double minute 2 (MDM2), Bcl-2 family protein and reactive oxygen species 1 (ROS1). Additionally, the manuscript reviews the anticancer drugs currently under clinical trials.

Molecular therapy using siRNA: Recent trends and advances of multi target inhibition of cancer growth.

RNA interference (RNAi) therapy, harnessed to produce a new class of drugs for treatment, has drawn attention and seen steady progress over the years. Molecular therapy using biological macromolecules small interfering RNA (siRNA) for gene silencing has received significant attention to target cancer-related genes. Basically, siRNA molecules bind to messenger RNAs (mRNA) by complementary base pairing, to induce degradation of the mRNA and/or block protein synthesis. Numerous genes and gene related proteins have been reported till date to target in siRNA based cancer therapy. Furthermore, a combination of siRNA with traditional anticancer drugs produces synergistic anticancer effect, or overcomes drug resistance, enhances targeting abilities and minimizes side-effects. Current review highlights various functional properties of genes that can be selectively knocked down by siRNAs. In addition, we have also discussed the interaction of siRNA-mediated gene-silencing with chemotherapeutic agents in nanoformulation which constitutes a valuable and safe approach for cancer treatment.

Confronting Penetration Threshold via Fluidic Terpenoid Nanovesicles.

BACKGROUND: Improvisation of the nanosized vesicular systems has led to a series of useful developments including the deformable vesicles namely transfersomes, ethosomes and invasomes. The former two have been explored extensively, however, literature on invasomes is relatively scanty. METHOD: Invasomal formulations researched for various applications have been reviewed using search engine "Scopus". The present review focuses on the update of the research activity on effectiveness and permeation enhancing effects of invasomes for dermal and topical delivery. RESULT: Many research reports could be found on invasomes in the literature but scarce patent citations were found. The present write up elaborates the mechanism of penetration, and compiles literature dental applications of the invasomes, the detection ability, use in photodynamic therapy, pilosebaceous targeting, and for delivery of macromolecules. The use of massage and microneedles for penetration enhancement is the newer element in this area. Interestingly, the majority of research has been reported on temoporfin molecule but scarce literature is available for other molecules, so the area provides ample research opportunities. The review also highlights toxicity fact sheet of commonly used terpenes for invasome formulation. CONCLUSION: Though invasomes present an advantageous system for enhanced topical delivery but it needs to be assessed for dermatopharmacokinetics; safety and toxicity issues on long term usage.

Anticancer Potential of Thiazole Derivatives: A Retrospective Review.

This review brings forth the potential of thiazole derivatives for their anticancer activities. The emphasis is placed on the structural diversity of thiazole derivatives, responsible for their specific anticancer activity. Multiple classes of thiazole derivatives such as Schiff base, mono-, di-, tri-, and heterocyclic substituents that possess anticancer activity have been exemplified. Molecular modelling of compounds that predicts enhanced anticancer activity of the modified structures has also been elaborated in the review. Significant advancements in synthetic chemistry related to cytotoxicity can now better position the drug discovery team to undertake thiazoles as valuable leads. The beneficial thiazole derivatives possessing anticancer activity will reignite the interest of medicinal chemists in thiazole and their derivatives.

Synthesis and Biological Activities of Oxadiazole Derivatives: A Review.

Recently, there has been wide interest in compounds containing the oxadiazole scaffold because of their unique chemical structure and their broad spectrum of biological properties. This review provides readers with an overview of the main synthetic methodologies for oxadiazoles and of their broad spectrum of pharmacological activities such as, anti-microbial, anti-fungal activity, antiviral, anti-tubercular, anti-inflammatory, anti-convulsant, anti-angiogenic, anti-proliferative, analgesic, anti-oedema and in alzheimer activity, which were reported over the past years.

Does a High-Risk Recommendation in Mammography Reports Increase Attendance at a Breast Cancer Risk Assessment Clinic?

PURPOSE: This study evaluates the effectiveness of introducing, in 2012, a standardized recommendation into mammography reports, to recruit women at high risk for breast cancer into our risk assessment clinic. METHODS: The study population was comprised of patients presenting for screening or diagnostic mammography, in 2011 and 2013, who were identified as having a ≥20% lifetime risk for breast cancer. Mammographic reports were assessed for annotations addressing the patients' risk status and referral to a provider at the clinic. The percentage of patients given a high-risk recommendation who did, versus did not, consult a provider at the clinic, within 1 year of their mammogram, was analyzed. RESULTS: A total of 173 patients in 2011, and 241 patients in 2013, were identified as having a ≥20% lifetime risk of developing breast cancer. Of these, 40.5% were given a recommendation to attend our risk assessment clinic in 2011, versus 75.5% in 2013. Despite the overall increase in such recommendations by radiologists, only a modest increase occurred, from 11.4% to 14.3%, in patients that subsequently attended our risk assessment clinic. CONCLUSIONS: Although the number of referrals to our high-risk clinic increased modestly after institution of a standardized reporting recommendation, >85% of patients at high risk, in 2013, did not consult a provider for patients at high risk, regarding their elevated lifetime risk of breast cancer.

1,3,4-thiadiazole and its derivatives: a review on recent progress in biological activities.

The 1,3,4-thiadiazole nucleus is one of the most important and well-known heterocyclic nuclei, which is a common and integral feature of a variety of natural products and medicinal agents. Thiadiazole nucleus is present as a core structural component in an array of drug categories such as antimicrobial, anti-inflammatory, analgesic, antiepileptic, antiviral, antineoplastic, and antitubercular agents. The broad and potent activity of thiadiazole and their derivatives has established them as pharmacologically significant scaffolds. In this study, an attempt has been made with recent research findings on this nucleus, to review the structural modifications on different thiadiazole derivatives for various pharmacological activities.

Metabotropic glutamate receptors: a review on prospectives and therapeutic aspects.

The metabotropic glutamate (mGluRs) receptors are a distinct class of G-protein-coupled receptors that act through activation of phospholipase C and/or inhibition of adenylate cyclase. They encompass seven-transmembrane domain proteins, comprehensively expressed in neuronal and glial cells within the brain, spinal cord and periphery and are involved in controlling pathophysiology of a number of diseases. These receptors may be sorted into three groups based on similarity of amino acid sequence, pharmacology and the transducer pathways they couple. The agonists and antagonists act at the N-terminal glutamate binding site and present a pharmacological strategy to modulate pathogenesis. A number of these compounds are positive or negative allosteric modulators that bind within the receptor transmembrane heptahelical domains. This imparts improved subtype selectivity, improved bioavailability and better drug like properties (e.g. CNS penetration). The mGluRs are presently the focal point of sizeable attention because of their potential as drug targets for the treatment of neurological and psychiatric disorders of the brain including Schizophrenia, Alzheimer's disease, Parkinson's disease, addiction, anxiety, depression, epilepsy and pain. The present review focuses on signal transduction mechanisms implicated to control and functionally upregulate the glutamatergic transmission system. The article also hallmarks agonists and antagonists for mGluRs as pivotal agents to ameliorate an array of neurological and psychiatric disorders.

Recent developments and biological activities of thiazolidinone derivatives: a review.

Thiazolidinone is considered as a biologically important active scaffold that possesses almost all types of biological activities. Successful introduction of ralitoline as a potent anti-convulsant, etozoline as a antihypertensive, pioglitazone as a hypoglycemic agent and thiazolidomycin activity against streptomyces species proved potential of thiazolidinone moiety. This diversity in the biological response profile has attracted the attention of many researchers to explore this skeleton to its multiple potential against several activities. This review is complementary to earlier reviews and aims to review the work reported on various biological activities of thiazolidinone derivatives from year 2000 to the beginning of 2011. Data are presented for active compounds, some of which have passed the preclinical testing stage.

Predicting anti-cancer activity of quinoline derivatives: CoMFA and CoMSIA approach.

The 3D quantitative structure-activity relationships of 31 quinoline nuclei containing compounds and their biological activity have been investigated to establish various models. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies resulted in reliable and significant computational models. The obtained CoMFA model showed high predictive ability with q(2) = 0.592, r(2) = 0.966 and standard error of estimation (SEE) = 0.167, explaining majority of the variance in the data with two principal components. Predictions obtained with CoMSIA steric, electrostatic, hydrophobic, hydrogen-bond acceptor and donor fields (q(2) = 0.533, r(2) = 0.985) showed high prediction ability with minimum SEE (0.111) and four principal components. The information obtained from the CoMFA and CoMSIA contour maps can be utilized for the design and development of topoisomerase-II inhibitors for synthesis.

Bioconjugation of polymers: a novel platform for targeted drug delivery.

Bioconjugation, a novel technique is usually exploited to improve the biopharmaceutical aspects of a bioactive as well as afford its spatial and temporal distribution. The strategy enlightens newer vistas for delivery of drugs, peptides, enzymes, and oligonucleotides. Site specific delivery may be obtained by tailoring the conjugates as an inactive prodrug and designing polymer drug linkages susceptible to cleavage by specific enzymes or pH. These prodrugs substantially change the mechanisms of cellular entry, pharmacokinetic disposition and ultimately target the drug. The conjugate vehicles are being exploited for targeting pharmacological agents to visceral tissues viz brain, colon etc. These biomaterials are bringing into play, novel drug delivery systems for selectively and specifically ferrying drugs to the desired organ. Noteworthy contributions reported with bioconjugated nanoparticles for biosensing and bioimaging incorporate cell staining, DNA detection, separation and recombination relevance in DNA protection. Only recently, these tailor-made polymers have also gained impetuous for enzyme therapy, gene therapy, insulin therapy, cancer therapy and management of AIDS with the interception of minimal side effects. The present review exhaustively provides an insight to the polymer bioconjugates and their implications for targeted delivery. The article also discusses the therapeutic aspects of these conjugates and that these may serve as fascinating tools for drug delivery.

Metronidazole loaded pectin microspheres for colon targeting.

A multiparticulate system having pH-sensitive property and specific enzyme biodegradability for colon-targeted delivery of metronidazole was developed. Pectin microspheres were prepared using emulsion-dehydration technique. These microspheres were coated with Eudragit(R) S-100 using oil-in-oil solvent evaporation method. The SEM was used to characterize the surface of these microspheres and a distinct coating over microspheres could be seen. The in vitro drug release studies exhibited no drug release at gastric pH, however continuous release of drug was observed from the formulation at colonic pH. Further, the release of drug from formulation was found to be higher in the presence of rat caecal contents, indicating the effect of colonic enzymes on the pectin microspheres. The in vivo studies were also performed by assessing the drug concentration in various parts of the GIT at different time intervals which exhibited the potentiality of formulation for colon targeting. Hence, it can be concluded that Eudragit coated pectin microspheres can be used for the colon specific delivery of drug.