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02:39 EDT 31st March 2015 | BioPortfolio

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Showing PubMed Articles 1–25 of 2,000+ from Journal of medicinal chemistry


Synthesis and Biological Evaluation of Nitrated 7-, 8-, 9-, and 10-Hydroxyindenoisoquinolines as Potential Dual Topoisomerase I (Top1)-Tyrosyl-DNA Phosphodiesterase I (TDP1) Inhibitors.

The structure-activity relationships and hit-to-lead optimization of dual Top1-TDP1 inhibitors in the indenoisoquinoline drug class were investigated. A series of nitrated 7-, 8-, 9-, and 10-hydroxyindenoisoquinolines were synthesized and evaluated. Several compounds displayed potent dual Top1-TDP1 inhibition. The 9-hydroxy series exhibited potencies and cytotoxicities vs Top1 that surpassed those of camptothecin (CPT), the natural alkaloid that is being used as a standard in the Top1-mediated DNA cleavage ...


Rational design of triazolo-lipopeptides analogs of kisspeptin inducing a long-lasting increase of gonadotropins.

New potent and selective KISS1R agonists were designed using a combination of rational chemical modifications of the endogenous neuropeptide kisspeptin 10 (KP10). Improved resistance to degradation and presumably reduced renal clearance were obtained by introducing a 1,4-disubstituted 1,2,3-triazole as a proteolysis-resistant amide mimic and a serum albumin-binding motif, respectively. These triazolo-lipopeptides are highly potent full agonist of KISS1R and are >100 selective over the closely related NPFF1R...

Monday 18th September 1200

Progress Toward the Development of Noscapine and Derivatives as Anti-cancer Agents.

Many alkaloids derived from plant origins are bioactive and play a significant role in human health and emerging medicine. Noscapine, a phthalideisoquinoline alkaloid derived from Papaver somniferum, has been used as a cough suppressant since the mid 1950s, illustrating a good safety profile. Noscapine has since been discovered to arrest cells at mitosis, albeit with moderately weak activity. Immunofluorescence staining of microtubules after 24 hours of noscapine exposure at 20 μM elucidated chromosomal ab...

Thursday 11th May 1200

Discovery of orally available runt-related transcription factor 3 (RUNX3) modulators for anticancer chemotherapy by epigenetic activation and protein stabilization.

Recently, we identified a novel strategy for anticancer chemotherapy by restoring runt-related transcription factor 3 (RUNX3) levels via lactam-based histone deacetylase (HDAC) inhibitors that stabilize RUNX3. Described here are the synthesis, biological evaluation, and pharmacokinetic evaluation of new synthetic small molecules based on pyridone-based HDAC inhibitors that specifically stabilize RUNX3 by acetylation and regulate its function. Many of the newly synthesized compounds showed favorable RUNX act...


New organochalcogen Multi-target Drug: Synthesis, Antioxidant and Antitumoral Activities of Chalcogenozidovudine derivatives.

In this article we present the synthesis, characterization, and in vitro biological and biochemical activ-ities of new chalcogenozidovudine derivatives as antioxidant (inhibition of TBARS in brain membranes and thiol peroxidase-like activity) as well as antitumoral agents in Bladder Carcinoma 5637. For the se-lected chalcogenonucleosides, a prominent response was obtained showing effective antioxidant and antitumoral activities.


Modulating the Anticancer Activity of Ruthenium(II)-arene Complexes.

Following the identification of [Ru(η6-p-cymene)Cl2(1H,1H,2H,2H-perfluorodecyl-3-(pyridin-3-yl)propanoate)], a ruthenium(II)-arene complex with a perfluoroalkyl-modified ligand, that displays remarkable in vitro cancer cell selectivity, a series of structurally related compounds were designed. In the new derivatives, the p-cymene ring and/or the chloride ligands are substituted by other ligands to modulate the steric bulk or aquation kinetics. The new compounds were evaluated in both in vitro (cytotoxicity...

Sunday 3rd July 1199

Discovery of potent inhibitors of Schistosoma mansoni NAD(+) catabolizing enzyme.

The blood fluke Schistosoma mansoni is the causative agent of the intestinal form of schistosomiasis (or bilharzia). Emergence of Schistosoma mansoni with reduced sensitivity to praziquantel, the drug currently used to treat this neglected disease, has underlined the need for development of new strategies to control schistosomiasis. The rationale for inquiry of anti-schistosomal compounds is hampered by the lack of validated targets. In the present work, we describe a virtual screening approach to identify ...


X-ray Crystal Structures of Escherichia coli RNA Polymerase with Switch Region Binding Inhibitors Enable Rational Design of Squaramides with an Improved Fraction Unbound to Human Plasma Protein.

Squaramides constitute a novel class of RNA polymerase inhibitors of which genetic evidence and computational modeling previously have suggested an inhibitory mechanism mediated by binding to the RNA polymerase switch region. An iterative chemistry program increased the fraction unbound to human plasma protein from below minimum detection levels, i.e.,


Hotspots in an obligate homodimeric anti-cancer target. Structural and functional effects of interfacial mutations in human thymidylate synthase.

Human thymidylate synthase (hTS), a target for anti-proliferative drugs, is an obligate homodimer. Single-point mutations to alanine at the monomer-monomer interface may enable the identification of specific residues that delineate sites for drugs aimed at perturbing the protein-protein interactions critical for activity. We computationally identified putative hotspot residues at the interface and designed mutants to perturb the inter-subunit interaction. Dimer dissociation constants measured by a FRET-base...

Friday 3rd September 1198

Discovery and characterization of GSK2801, a selective chemical probe for the bromodomains BAZ2A and BAZ2B.

Bromodomains are acetyl-lysine specific protein interaction domains that have recently emerged as a new target class for the development of inhibitors that modulate gene transcription. The two closely related bromodomain containing proteins BAZ2A and BAZ2B constitute the central scaffolding protein of the Nucleolar Remodeling Complex (NoRC) that regulates the expression of non-coding RNAs. However, BAZ2 bromodomains have low predicted druggability and so far no selective inhibitors have been published. Here...

Friday 11th June 1198

Volume of Distribution in Drug Design.

Volume of distribution is one of the most important pharmacokinetic properties of a drug candidate. It is a major determinant of half-life and dosing frequency of a drug. For a similar Log P, a basic molecule will tend to exhibit higher volume of distribution than a neutral molecule. Acids often exhibit low volumes of distribution. Although a design strategy against volume of distribution can be advantageous in achieving desirable dosing regimen, it must be well-directed in order to avoid detrimental effect...

Thursday 25th February 1198

Design and Synthesis of New α-Naphthoflavones as Cytochrome P450 (CYP) 1B1 Inhibitors to Overcome Docetaxel-resistance Associated with CYP1B1 Overexpression.

CYP1B1 is recognized as a new target in cancer prevention and therapy. Taking α-naphthoflavone as a lead, a series of 6,7,10-trimethoxy-α-naphthoflavones (4a-4o) were synthesized and evaluated for their inhibitory potency against CYP1B1 and selectivity over CYP1A1 and 1A2. SARs analysis indicated that introducing methoxy groups at C(6), C(7) and C(10) on the naphthalene part and a fluoro atom at C(3') on B-ring, could sharply increase the efficiency towards CYP1B1 inhibition. Among the prepared derivative...


Neuroactive Steroids I: Positive Allosteric Modulators of the (γ-Aminobutyric Acid)A Receptor; Structure Activity Relationships of Heterocyclic Substitution at C-21.

Neuroactive steroids (NAS) have been shown to impact Central Nervous System (CNS) function through positive allosteric modulation of the GABAA receptor (GABAA-R). Herein, we report the effects on the activity and pharmacokinetic properties of a series of nor-19 pregnanolone analogs bearing a heterocyclic substituent at C-21. These efforts resulted in the identification of SGE-516, a balanced synaptic/extrasynaptic GABAA receptor modulator; and SGE-872, a selective extrasynaptic GABAA receptor modulator. Bot...


Novel Multi-Target Directed Ligands (MTDLs) with acetylcholinesterase (AChE) inhibitory and serotonergic subtype 4 receptor (5-HTR) agonist activities as potential agents against Alzheimer's disease: the design of donecopride.

In this work, we describe the synthesis and in vitro evaluation of a novel series of multi-target directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in mice. The latter displayed procognitive and antiamnesic effects and enhanced sAPPα release, accounting for a potential symptomatic and disease-modifying therapeutic benefit in the treatment ...


Synthesis of improved lysomotropic autophagy inhibitors.

Autophagy is a conserved cellular pathway used to recycle nutrients through lysosomal breakdown basally and under times of stress (e.g., nutrient deprivation, chemotherapeutic treatment). Oncogenes are known to induce autophagy, which may be exploited by cancers for cell survival. To identify autophagy inhibitors with potential therapeutic value for cancer, we screened a panel of anti-malarial agents and found that quinacrine (QN) had sixty-fold higher potency of autophagy inhibition than chloroquine (CQ), ...


Ensemble-based virtual screening for cannabinoid-like potentiators of the human glycine receptor α1 for the treatment of pain.

The human glycine receptors (hGlyRs) are chloride-selective ion channels that mediate inhibitory neurotransmission in the brain stem and spinal cord. They are also targets for compounds of potential use in analgesic therapies. Here we develop a strategy to discover analgesic drugs via structure-based virtual screening based on the recently published NMR structure of the hGlyR-α1 transmembrane domain (PDB ID: 2M6I) and the critical role of residue S296 in hGlyR-α1 potentiation by Δ9-tetrahydrocannabinol (...


Investigation of (E)-3-4-(2-oxo-3-aryl-chromen-4-yl)oxyphenylacrylic acids as Oral Selective Estrogen Receptor Down-Regulators.

A 7-hydroxycoumarin (SS5020) has been reported as a novel estrogen receptor down-regulator having antitumor effect against chemically induced mammary tumours. We wish to report our own investigation of 7-hydroxycoumarins as potential SERDs, which led us to the discovery of potent down-regulating antagonists such as 33. Subsequent optimization and removal of the 7-hydroxy group led to coumarin 59, which had both increased potency and improved rat bioavailability relative to SS5020.


Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT): Cocrystal Structures of Pyrazolopyrans with Potent Blood- and Liver-Stage Activities.

Several of the enzymes related to the folate cycle are well-known for their role as clinically validated antimalarial targets. Nevertheless for serine hydroxymethyltransferase (SHMT), one of the key enzymes of this cycle, efficient inhibitors have not been described so far. On the basis of plant SHMT inhibitors from an herbicide optimization program, highly potent inhibitors of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) SHMT with a pyrazolopyran core structure were identified. Cocrystal structures...


Design, Synthesis, in Vitro and in Vivo Anticancer and Antiangiogenic Activity of Novel 3-Arylamino Benzofuran Derivatives Targeting the Colchicine Site on Tubulin.

A new series of compounds characterized by the presence of a 2-methoxy/ethoxycarbonyl group, combined with either no substituent or a methoxy group at each of the four possible positions of the benzene portion of the 3-(3',4',5'-trimethoxyanilino)benzo[b]furan skeleton, were evaluated for antiproliferative activity against cancer cells in culture, and, for selected, highly active compounds, inhibition of tubulin polymerization, cell cycle effects and in vivo potency. The greatest antiproliferative activity ...


Utilizing CYP2D6 and BACE1 Structure Complexes to Reduce Risk of Drug-Drug Interactions with a Novel Series of Centrally Efficacious BACE1 Inhibitors.

In recent years, the first generation of β-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer's disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Herein, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for vi...


Synthesis and bioactivity of β-substituted fosmidomycin analogues targeting 1-deoxy-D-xylulose-5-phosphate reductoisomerase.

In the wake of the escalating development of resistance to currently available drugs, blocking the vital MEP pathway for isoprenoid biosynthesis in pathogens such as Plasmodia or Mycobacteria offers interesting prospects for inhibiting their growth. Although the natural product retro-hydroxamate fosmidomycin and its homologue FR900098 potently inhibit 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in the MEP pathway, their in vivo activity is compromised due to poor absorption and a sub...


Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases.

The increasing dissemination of carbapenemases in Gram-negative bacteria has threatened the clinical usefulness of the β-lactam class of antimicrobials. A program was initiated to discover a new series of serine β-lactamase inhibitors containing a boronic acid pharmacophore, with the goal of finding a potent inhibitor of serine carbapenemase enzymes that are currently compromising the utility of the carbapenem class of antibacterials. Potential lead structures were screened in silico by modeling into the ...


Design of a Potent Antibiotic Peptide Based on the Active Region of Human Defensin 5.

Human defensin 5 (HD5) is a broad-spectrum antibacterial peptide with a C-terminal active region. To promote the development of this peptide into an antibiotic, we initially substituted Glu21 with Arg because it is an electronegative residue located around the active region. Although detrimental to dimer formation, the E21R substitution markedly enhanced the antibacterial activity of HD5 and increased its ability to penetrate cell membranes, demonstrating that increasing the electropositive charge compensat...


N-Benzoyl-1,5-benzothiazepine and Its S-Oxide as Vasopres-sin Receptor Ligands: Insight into the Active Stereochemistry around the 7-Membered Ring.

The stereochemistry of N-benzoyl-1,5-benzothiazepine and its S-oxide derivatives as vasopressin receptor ligands was examined in detail by freezing the conformation with a methyl group at the C6 or C9 of 1,5-benzothiazepine. It was revealed that the active forms recognized by the receptors are (cis,aS) for 1,5-benzothiazepine (5-7)-II and (cis,1S,aS) (syn) for its S-oxide (8-10)-II. The C9-methyl derivative of 1,5-benzothiazepine S-oxide (10-II) was designed and synthesized, achieving the putative active sy...

Friday 12th July 1190

Discovery of Novel P1 Groups for Coagulation Factor VIIa Inhibition Using Fragment-Based Screening.

A multidisciplinary, fragment-based screening approach involving protein ensemble docking and biochemical and NMR assays is described. This approach led to the discovery of several structurally diverse, neutral surrogates for cationic factor VIIa P1 groups, which are generally associated with poor pharmacokinetic (PK) properties. Among the novel factor VIIa inhibitory fragments identified were aryl halides, lactams, and heterocycles. Crystallographic structures for several bound fragments were obtained, lea...

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