Rohitukine inhibits NF-κB activation induced by LPS and other inflammatory agents.

Rohitukine (referred to as RHK) is a bioactive chromone alkaloid isolated from the leaves of plant Dysoxylum binectariferum, which has been reported to possess diverse pharmacological properties for the treatment of inflammatory bowel disease (IBD), diarrhoea and anti-lipidemic. However, the underlying mechanism by which RHK exerts its anti-inflammatory activity has not yet demonstrated. This study aimed to elucidate the anti-inflammatory mechanism of RHK using lipopolysaccharide (LPS) - stimulated J774A.

Impurity profiling of anticancer preclinical candidate, IIIM-290.

IIIM-290, an orally bioavailable preclinical candidate is effective in human xenograft models of leukemia, colon and pancreatic cancer. The promising preclinical data of this lead candidate has shown its potential for clinical development. As a part of its preclinical development, impurity profiling of pilot scale batches is one of the most important component of the CMC documentation.

Inhibitors of Aβ42-induced endoplasmic reticular unfolded protein response (UPR), in yeast, also rescue yeast cells from Aβ42-mediated apoptosis.

Aggregated Aβ peptides which cause amyloid deposits, a characteristic of Alzheimer's disease (AD), activate a stress response in the endoplasmic reticulum (ER), known as the unfolded protein response, UPR. Nascent UPR induction helps in reducing ER stress by eliminating accumulated misfolded/aggregated secretory proteins. However, prolonged UPR induction may trigger apoptosis.

In vitro evaluation of dinactin, a potent microbial metabolite against Mycobacterium tuberculosis.

Current long duration treatment options and the emergence of drug resistance in tuberculosis (TB) have led to renewed interest in discovery of novel anti-tubercular agents or the scaffolds exhibiting enhanced efficacy with current anti-TB drugs. Herein, dinactin, a potent bioactive macrotetrolide isolated from Streptomyces puniceus AS13, was evaluated against Mycobacterium tuberculosis H37Rv and other susceptible and drug-resistant clinical isolates of M. tuberculosis.

Room Temperature Metal-Catalyzed Oxidative Acylation of Electron-Deficient Heteroarenes with Alkynes, Its Mechanism, and Application Studies.

Herein, we report an original one-step, simple, room-temperature, regioselective Minisci reaction for the acylation of electron-deficient heteroarenes with alkynes. The method has broad functional group compatibility and gives exclusively monoacylated products in good to excellent yields. The mechanistic pathway was analyzed based on a series of experiments confirming the involvement of a radical pathway.

Synthesis and Biological Evaluation of Novel Osthol Derivatives as Potent Cytotoxic Agents.

Background: Natural product, osthol has been found to have important biological and pharmacological roles particularly having inhibitory effect on multiple types of cancer.

Objective: The unmet needs in cancer therapeutics make its derivatization an important and exciting field of research. Keeping this in view, a whole new series of diverse analogues of osthol (1) were synthesized.

Why Are the Majority of Active Compounds in the CNS Domain Natural Products? A Critical Analysis.

Small-molecule natural products (NPs) have a long and successful track record of providing first-in-class drugs and pharmacophore (scaffolds) in all therapeutic areas, serving as a bridge between modern and traditional medicine. This trajectory has been remarkably successful in three key areas of modern therapeutics: cancers, infections, and CNS diseases. Beginning with the discovery of morphine 200 years ago, natural products have remained the primary source of new drugs/scaffolds for CNS diseases.

CD44 targeted PLGA nanomedicines for cancer chemotherapy.

In recent years scientific community has drawn a great deal of attention towards understanding the enigma of cluster of differentiation-44 (CD44) in order to deliver therapeutic agents more selectively towards tumor tissues. Moreover, its over-expression in variety of solid tumors has attracted drug delivery researchers to target this receptor with nanomedicines. Conventional nanomedicines based on biodegradable polymers such as poly(lactide-co-glycolide) (PLGA) are often associated with insufficient cellular uptake by cancer cells, due to lack of active targeting moiety on their surface.

Antiproliferative efficacy of curcumin mimics through microtubule destabilization.

Curcumin possesses an attractive chemical structure with highly conjugated diferuloylmethane core. Curcumin mimics have been designed and prepared with an additional bridged phenyl ring in conjugation. Fourteen diverse analogues were evaluated against a panel of human cancer cell lines.

Detailed account on activation mechanisms of ruthenium coordination complexes and their role as antineoplastic agents.

Ruthenium (Ru) complexes are known for their promising anticancer activity presumably due to octahedral coordination geometry, slow ligand exchange rate, the range of different oxidation states and target specificity. This review article summarizes the physicochemical processes which are responsible for the selectivity of Ru complexes toward cancer cells over the normal cells. Emphasis has been given on the activation mechanism of Ru(III) complex administered as a prodrug and then the release of active species in an acidic environment of cancer cell through normal or photo induced hydrolysis or ligand oxidation.

Correction: Four new carbazole alkaloids from Murraya koenigii that display anti-inflammatory and anti-microbial activities.

Correction for 'Four new carbazole alkaloids from Murraya koenigii that display anti-inflammatory and anti-microbial activities' by Yedukondalu Nalli et al., Org. Biomol.

Discovery and Preclinical Development of IIIM-290, an Orally Active Potent Cyclin-Dependent Kinase Inhibitor.

Rohitukine (1), a chromone alkaloid isolated from Indian medicinal plant Dysoxylum binectariferum, has inspired the discovery of flavopiridol and riviciclib, both of which are bioavailable only via intravenous route. With the objective to address the oral bioavailability issue of this scaffold, four series of rohitukine derivatives were prepared and screened for Cdk inhibition and cellular antiproliferative activity. The 2,6-dichloro-styryl derivative IIIM-290 (11d) showed strong inhibition of Cdk-9/T1 (IC 1.

The shikimate pathway enzyme that generates chorismate is not required for the development of Plasmodium berghei in the mammalian host nor the mosquito vector.

In Plasmodium, the shikimate pathway is a potential target for malaria chemotherapy owing to its absence in the mammalian host. Chorismate, the end product of this pathway, serves as a precursor for aromatic amino acids, Para-aminobenzoic acid and ubiquinone, and is synthesised by Chorismate synthase (CS). Therefore, it follows that the Cs locus may be refractory to genetic manipulation.

Simultaneous quantitative determination of bioactive terpene indole alkaloids in ethanolic extracts of Catharanthus roseus (L.) G. Don by ultra high performance liquid chromatography-tandem mass spectrometry.

A rapid, sensitive and reproducible method using ultra-high-performance liquid chromatography coupled with electrospray ionization hybrid triple quadrupole-linear ion trap mass spectrometry (UHPLC-ESI-QqQ-MS/MS) in multiple reaction monitoring (MRM) mode was developed and validated for simultaneous quantitation of anticancer (vincristine, vinblastine, vindesine), antihypertensive (ajmaline, ajmalicine, reserpine), aphrodisiac (yohimbine), sedative (serpentine) agents, dietary supplement (vinpocetine, yohimbine) and precursor of vinblastine (vindoline) from crude extracts of Catharanthus roseus. The precursor to product ion transitions for these compounds were observed at m/z 327 → 144, 355 → 144, 754 → 355, 353 → 144, 349 → 317, 825 → 225, 811 → 224, 458 → 188, 351 → 280 and 609 → 195, respectively in positive ionization mode. Chromatographic separation of all targeted TIAs was performed on ACQUITY UPLC BEH™ C column (1.

Design of Novel 3-Pyrimidinylazaindole CDK2/9 Inhibitors with Potent In Vitro and In Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model.

In the present study, a novel series of 3-pyrimidinylazaindoles were designed and synthesized using a bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription. The present approach gives new dimensions to the existing SAR and opens a new opportunity for the lead optimizations from comparatively inexpensive starting materials. The study led to the identification of the alternative lead candidate 4ab with a nanomolar potency against CDK2 and CDK9 and potent antiproliferative activities against a panel of tested tumor cell lines along with a better safety ratio of ∼33 in comparison to reported leads.

Oxidant-Controlled C-sp/sp-H Cross-Dehydrogenative Coupling of N-Heterocycles with Benzylamines.

Oxidant controlled ionic liquid mediated cross-dehydrogenative coupling (CDC) of benzylamines with N-heterocycles having sp or sp carbon resulted in the formation of C-benzoylated or alkenylated products. Benzoylation of N-heterocycles occurs via (NH)SO catalyzed benzoyl radical formation. An oxidative alkenylation of N-heterocycles having C-sp carbon (2-methylaza-arenes) occurs via deamination of benzylamine followed by C-sp-H bond activation in high stereoselectivity.

Biotransformation of Chrysin to Baicalein: Selective C6-Hydroxylation of 5,7-Dihydroxyflavone Using Whole Yeast Cells Stably Expressing Human CYP1A1 Enzyme.

Naturally occurring polyphenolic compounds are of medicinal importance because of their unique antioxidant, anticancer, and chemopreventive properties. Baicalein, a naturally occurring polyhydroxy flavonoid possessing a diverse range of pharmacological activities, has been used in traditional medicines for treatment of various ailments. Apart from its isolation from natural sources, its synthesis has been reported via multistep chemical approaches.

Fusion of Structure and Ligand Based Methods for Identification of Novel CDK2 Inhibitors.

Cyclin dependent kinases play a central role in cell cycle regulation which makes them a promising target with multifarious therapeutic potential. CDK2 regulates various events of the eukaryotic cell division cycle, and the pharmacological evidence indicates that overexpression of CDK2 causes abnormal cell-cycle regulation, which is directly associated with hyperproliferation of cancer cells. Therefore, CDK2 is regarded as a potential target molecule for anticancer medication.

Natural alkaloids as P-gp inhibitors for multidrug resistance reversal in cancer.

The biggest challenge associated with cancer chemotherapy is the development of cross multi-drug resistance to almost all anti-cancer agents upon chronic treatment. The major contributing factor for this resistance is efflux of the drugs by the p-glycoprotein pump. Over the years, inhibitors of this pump have been discovered to administer them in combination with chemotherapeutic agents.

Biopharmaceutic parameters, pharmacokinetics, transport and CYP-mediated drug interactions of IIIM-017: A novel nitroimidazooxazole analogue with anti-tuberculosis activity.

Nitroimidazoles are emerging as a new class of therapeutic agents with potent anti-tubercular activity. CSIR-IIIM has synthesized a novel nitrohydroimidazooxazole (NHIO) analogue, IIIM-017 with a MIC of 0.37μg/ml (against H37Rv).

Dendrimer encapsulated and conjugated delivery of berberine: A novel approach mitigating toxicity and improving in vivo pharmacokinetics.

Berberine (BBR) is a nitrogenous cyclic natural alkaloid with potential anticancer activity. However it has been less explored due to its poor pharmacokinetic profile. Dendrimers (e.

Revelation and cloning of valinomycin synthetase genes in Streptomyces lavendulae ACR-DA1 and their expression analysis under different fermentation and elicitation conditions.

Streptomyces species are amongst the most exploited microorganisms due to their ability to produce a plethora of secondary metabolites with bioactive potential, including several well known drugs. They are endowed with immense unexplored potential and substantial efforts are required for their isolation as well as characterization for their bioactive potential. Unexplored niches and extreme environments are host to diverse microbial species.

Identification of Potent and Selective CYP1A1 Inhibitors via Combined Ligand and Structure-Based Virtual Screening and Their in Vitro Validation in Sacchrosomes and Live Human Cells.

Target structure-guided virtual screening (VS) is a versatile, powerful, and inexpensive alternative to experimental high-throughput screening (HTS). To discover potent CYP1A1 enzyme inhibitors for cancer chemoprevention, a commercial library of 50 000 small molecules was utilized for VS guided by both ligand and structure-based strategies. For experimental validation, 300 ligands were proposed based on combined analysis of fitness scores from ligand based e-pharmacophore screening and docking score, prime MMGB/SA binding affinity and interaction pattern analysis from structure-based VS.

Exploring Derivatives of Quinazoline Alkaloid l-Vasicine as Cap Groups in the Design and Biological Mechanistic Evaluation of Novel Antitumor Histone Deacetylase Inhibitors.

l-Vasicine is a quinazoline alkaloid with an electron dense ring and additional functionalities in its structure. Employing target oriented synthesis (TOS) based on in silico studies, molecules with significant docking scores containing different derivatives of l-vasicine as caps were synthesized. Interestingly, one molecule, i.

Anti-tubercular drug discovery: in silico implications and challenges.

Tuberculosis (TB) has been reported as a major public health concern, especially in the developing countries. WHO report on tuberculosis 2016 shows a high mortality rate caused by TB leading to 1.8 million deaths worldwide (including deaths due to TB in HIV positive individuals), which is one of the top 10 causes of mortality in 2015.