Allosteric inhibition of PPM1D serine/threonine phosphatase via an altered conformational state.

PPM1D encodes a serine/threonine phosphatase that regulates numerous pathways including the DNA damage response and p53. Activating mutations and amplification of PPM1D are found across numerous cancer types. GSK2830371 is a potent and selective allosteric inhibitor of PPM1D, but its mechanism of binding and inhibition of catalytic activity are unknown. Here we use computational, biochemical and functional genetic studies to elucidate the molecular basis of GSK2830371 activity. These data confirm that GSK2830371 binds an allosteric site of PPM1D with high affinity. By further incorporating data from hydrogen deuterium exchange mass spectrometry and sedimentation velocity analytical ultracentrifugation, we demonstrate that PPM1D exists in an equilibrium between two conformations that are defined by the movement of the flap domain, which is required for substrate recognition. A hinge region was identified that is critical for switching between the two conformations and was directly implicated in the high-affinity binding of GSK2830371 to PPM1D. We propose that the two conformations represent active and inactive forms of the protein reflected by the position of the flap, and that binding of GSK2830371 shifts the equilibrium to the inactive form. Finally, we found that C-terminal truncating mutations proximal to residue 400 result in destabilization of the protein via loss of a stabilizing N- and C-terminal interaction, consistent with the observation from human genetic data that nearly all PPM1D mutations in cancer are truncating and occur distal to residue 400. Taken together, our findings elucidate the mechanism by which binding of a small molecule to an allosteric site of PPM1D inhibits its activity and provides insights into the biology of PPM1D.

Targeting cancer cells with nanotherapeutics and nanodiagnostics: Current status and future perspectives.

Nanotechnology is reshaping health care strategies and is expected to exert a tremendous impact in the coming years offering better healthcare facilities. It has led to not only therapeutic drug delivery feasibility but also to diagnostics. Materials in the size of nano range (1-100 nm) used in the design, fabrication, regulation, and application of therapeutic drugs or devices are classified as medical nanotechnology and nanopharmacology. Delivery of more complex molecules to the specific site of action as well as gene therapy has pushed forward the nanoparticle-based drug delivery to its maximum. Areas that benefit from nano-based drug delivery systems are cancer, diabetes, infectious diseases, neurodegenerative diseases, blood disorders and orthopedic-related ailments. Moreover, development of nanotherapeutics with multi-functionalities has a considerable potential to fill the gaps that exist in the present therapeutic domain. In cancer treatment, nanomedicines have superiority over current therapeutic practices as they can effectively deliver the drug to the affected tissues, thus reducing drug toxicities. Along this line, polymeric conjugates of asparaginase and polymeric micelles of paclitaxel have recently been recommended for the treatment of various types of cancers. Nanotechnology-based therapeutics and diagnostics provide greater effectiveness with less or no toxicity concerns. Similarly, diagnostic imaging holds promising future applications with newer nano-level imaging elements. Advancements in nanotechnology have emerged to a newer direction which use nanorobotics for various applications in healthcare. Accordingly, this review comprehensively highlights the potentialities of various nanocarriers and nanomedicines for multifaceted applications in diagnostics and drug delivery, especially the potentialities of polymeric nanoparticle, nanoemulsion, solid-lipid nanoparticle, nanostructured lipid carrier, self-micellizing anticancer lipids, dendrimer, nanocapsule and nanosponge-based therapeutic approaches in the field of cancer. Furthermore, this article summarizes the most recent literature pertaining to the use of nano-technology in the field of medicine, particularly in treating cancer patients.

Anticancer Perspectives on the Fungal-Derived Polyphenolic Hispolon.

BACKGROUND: Cancer is a dreadful disease causing thousands of deaths per year worldwide, which requires precision diagnostics and therapy. Although the selection of therapeutic regimens depends on the cancer type, chemotherapy remains a sustainable treatment strategy despite some of its known side-effects. To date, a number of natural products and their derivatives or analogues have been investigated as potent anticancer drugs. These drug discoveries have aimed for targeted therapy and reduced side-effects, including natural therapeutic regimens. OBJECTIVE: This review introduces a prospective fungal-derived polyphenol, Hispolon (HIS), as an anticancer agent. Accordingly, this review focuses on exploring the anticancer effect of hispolon based on information extracted from databases such as PubMed, ScienceDirect, MedLine, Web of Science, and Google Scholar. METHODS: A literature search in PubMed, ScienceDirect, MedLine, Web of Science, and Google Scholar was accomplished, using the keyword 'Hispolon', pairing with 'cancer', 'cytotoxicity', 'cell cycle arrest', 'apoptosis', 'metastasis', 'migration', 'invasion', 'proliferation', 'genotoxicity', 'mutagenicity', 'drug-resistant cancer', 'autophagy', and 'estrogen receptor. RESULTS: Database-dependent findings from reported research works suggest that HIS can exert anticancer effects by modulating multiple molecular and biochemical pathways, including cell cycle arrest, apoptosis, autophagy, inhibition of proliferation, metastasis, migration, and invasion. Moreover, HIS inhibits the estrogenic activity and exhibits chemoprevention prospects, possibly due to its protective effects such as anticancer and anti-inflammatory mechanisms. To date, a number of HIS derivatives and analogues have been introduced for their anticancer effects in numerous cancer cell lines. CONCLUSION: Data obtained from this review suggest that hispolon and some of its derivatives can be promising anticancer agents, and may become plant-based cancer chemotherapeutic leads for the development of potent anticancer drugs, alone or in combination with other chemotherapeutic agents.

Arctium Species Secondary Metabolites Chemodiversity and Bioactivities.

Arctium species are known for a variety of pharmacological effects due to their diverse volatile and non-volatile secondary metabolites. Representatives of Arctium species contain non-volatile compounds including lignans, fatty acids, acetylenic compounds, phytosterols, polysaccharides, caffeoylquinic acid derivatives, flavonoids, terpenes/terpenoids and volatile compounds such as hydrocarbons, aldehydes, methoxypyrazines, carboxylic and fatty acids, monoterpenes and sesquiterpenes. Arctium species also possess bioactive properties such as anti-cancer, anti-diabetic, anti-oxidant, hepatoprotective, gastroprotective, antibacterial, antiviral, antimicrobial, anti-allergic, and anti-inflammatory effects. This review aims to provide a complete overview of the chemistry and biological activities of the secondary metabolites found in therapeutically used Arctium species. Summary of pharmacopeias and monographs contents indicating the relevant phytochemicals and therapeutic effects are also discussed, along with possible safety considerations.

Asymmetric Catalysis Using Chiral Salen-Metal Complexes: Recent Advances.

Chiral salen-metal complexes are among the most versatile asymmetric catalysts and have found utility in fields ranging from materials chemistry to organic synthesis. These complexes are capable of inducing chirality in products formed from a wide variety of chemical processes, often with close to perfect stereoinduction. Salen ligands are tunable for steric as well as electronic properties, and their ability to coordinate a large number of metals gives the derived chiral salen-metal complex very broad utility in asymmetric catalysis. This review primarily summarizes developments in chiral salen-metal catalysis over the last two decades with particular emphasis on those applications of importance in asymmetric synthesis.

Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer.

Overexpression of myeloid cell leukemia-1 (Mcl-1) in cancers correlates with high tumor grade and poor survival. Additionally, Mcl-1 drives intrinsic and acquired resistance to many cancer therapeutics, including B cell lymphoma 2 family inhibitors, proteasome inhibitors, and antitubulins. Therefore, Mcl-1 inhibition could serve as a strategy to target cancers that require Mcl-1 to evade apoptosis. Herein, we describe the use of structure-based design to discover a novel compound (42) that robustly and specifically inhibits Mcl-1 in cell culture and animal xenograft models. Compound 42 binds to Mcl-1 with picomolar affinity and inhibited growth of Mcl-1-dependent tumor cell lines in the nanomolar range. Compound 42 also inhibited the growth of hematological and triple negative breast cancer xenografts at well-tolerated doses. These findings highlight the use of structure-based design to identify small molecule Mcl-1 inhibitors and support the use of 42 as a potential treatment strategy to block Mcl-1 activity and induce apoptosis in Mcl-1-dependent cancers.

A systematic review on the neuroprotective perspectives of beta-caryophyllene.

Beta (ß)-caryophyllene (BCAR) is a major sesquiterpene of various plant essential oils reported for several important pharmacological activities, including antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, antimicrobial, and immune-modulatory activity. Recent studies suggest that it also possesses neuroprotective effect. This study reviews published reports pertaining to the neuropharmacological activities of BCAR. Databases such as PubMed, Scopus, MedLine Plus, and Google Scholar with keywords "beta (ß)-caryophyllene" and other neurological keywords were searched. Data were extracted by referring to articles with information about the dose or concentration/route of administration, test system, results and discussion, and proposed mechanism of action. A total of 545 research articles were recorded, and 41 experimental studies were included in this review, after application of exclusion criterion. Search results suggest that BCAR exhibits a protective role in a number of nervous system-related disorders including pain, anxiety, spasm, convulsion, depression, alcoholism, and Alzheimer's disease. Additionally, BCAR has local anesthetic-like activity, which could protect the nervous system from oxidative stress and inflammation and can act as an immunomodulatory agent. Most neurological activities of this natural product have been linked with the cannabinoid receptors (CBRs), especially the CB2R. This review suggests a possible application of BCAR as a neuroprotective agent.

Phytol: A review of biomedical activities.

Phytol (PYT) is a diterpene member of the long-chain unsaturated acyclic alcohols. PYT and some of its derivatives, including phytanic acid (PA), exert a wide range of biological effects. PYT is a valuable essential oil (EO) used as a fragrance and a potential candidate for a broad range of applications in the pharmaceutical and biotechnological industry. There is ample evidence that PA may play a crucial role in the development of pathophysiological states. Focusing on PYT and some of its most relevant derivatives, here we present a systematic review of reported biological activities, along with their underlying mechanism of action. Recent investigations with PYT demonstrated anxiolytic, metabolism-modulating, cytotoxic, antioxidant, autophagy- and apoptosis-inducing, antinociceptive, anti-inflammatory, immune-modulating, and antimicrobial effects. PPARs- and NF-κB-mediated activities are also discussed as mechanisms responsible for some of the bioactivities of PYT. The overall goal of this review is to discuss recent findings pertaining to PYT biological activities and its possible applications.

High Throughput Screen Identifies Interferon γ-Dependent Inhibitors of Toxoplasma gondii Growth.

Toxoplasma gondii is an obligate intracellular parasite capable of causing severe disease due to congenital infection and in patients with compromised immune systems. Control of infection is dependent on a robust Th1 type immune response including production of interferon gamma (IFN-γ), which is essential for control. IFN-γ activates a variety of antimicrobial mechanisms in host cells, which are then able to control intracellular parasites such as T. gondii. Despite the effectiveness of these pathways in controlling acute infection, the immune system is unable to eradicate chronic infections that can persist for life. Similarly, while antibiotic treatment can control acute infection, it is unable to eliminate chronic infection. To identify compounds that would act synergistically with IFN-γ, we performed a high-throughput screen of diverse small molecule libraries to identify inhibitors of T. gondii. We identified a number of compounds that inhibited parasite growth in vitro at low µM concentrations and that demonstrated enhanced potency in the presence of a low level of IFN-γ. A subset of these compounds act by enhancing the recruitment of light chain 3 (LC3) to the parasite-containing vacuole, suggesting they work by an autophagy-related process, while others were independent of this pathway. The pattern of IFN-γ dependence was shared among the majority of analogs from 6 priority scaffolds, and analysis of structure activity relationships for one such class revealed specific stereochemistry associated with this feature. Identification of these IFN-γ-dependent leads may lead to development of improved therapeutics due to their synergistic interactions with immune responses.

Toxicogenetic study of omeprazole and the modulatory effects of retinol palmitate and ascorbic acid on Allium cepa.

Omeprazole (OME) is a proton pump inhibitor used for the treatment of various gastric and intestinal disease; however, studies on its effects on the genetic materials are still restricted. The present study aimed to evaluate possible toxicogenic effects of OME in Allium cepa meristems with the application of cytogenetic biomarkers for DNA damage, mutagenic, toxic and cytotoxic effects. Additionally, retinol palmitate (RP) and ascorbic acid (AA) were also co-treated with OME to evaluate possible modulatory effects of OME-induced cytogenetic damages. OME was tested at 10, 20 and 40 µg/mL, while RP and AA at 55 µg/mL and 352.2 µg/mL, respectively. Copper sulphate (0.6 µg/mL) and dechlorinated water were used as positive control and negative control, respectively. The results suggest that OME induced genotoxicity and mutagenicity in A. cepa at all tested concentrations. It was noted that cotreatment of OME with the antioxidant vitamins RP and/or AA significantly (p < 0.05) inhibited and/or modulated all toxicogenic damages induced by OME. These observations demonstrate their antigenotoxic, antimutagenic, antitoxic and anticitotoxic effects in A. cepa. This study indicates that application of antioxidants may be useful tools to overcome OME-induced toxic effects.

Andrographolide, a diterpene lactone from Andrographis paniculata and its therapeutic promises in cancer.

The diterpene lactone andrographolide, isolated from Andrographis paniculata, has been proven to possess several important protective biological activities, including antioxidant, anti-inflammatory, immunomodulatory, antiseptic, antimicrobial, cytotoxic, hypolipidemic, cardioprotective, hepatoprotective, and neuroprotective effects. In addition, it has been reported to play a therapeutic role in the treatment of major human diseases, such as Parkinson's disease, rheumatoid arthritis, and colitis. This systematic review aims to highlight andrographolide as a promising agent in cancer treatment. To this purpose, a number of databases were used to search for the cytotoxic/anticancer effects of andrographolide in pre-clinical and clinical studies. Among 1703 identified literature articles, 139 were included in this review; 109 were investigated as non-clinical, whereas 24, 3, and 3 were pre-clinical, clinical, and non-pre-clinical trials, respectively. Among the model systems, cultured cell lines appeared as the most frequently (79.14%) used, followed by in vivo models using rodents, among others. Furthermore, andrographolide was found to exert cytotoxic/anticancer effects on almost all types of cell lines with the underlying mechanisms involving oxidative stress, cell cycle arrest, anti-inflammatory and immune system mediated effects, apoptosis, necrosis, autophagy, inhibition of cell adhesion, proliferation, migration, invasion, anti-angiogenic activity, and other miscellaneous actions. After careful consideration of the relevant evidence, we suggest that andrographolide can be one of the potential agents in the treatment of cancer in the near future.

Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 Inhibitors Using Structure-Based Design.

Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, has emerged as an attractive target for cancer therapy. Mcl-1 upregulation is often found in many human cancers and is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here, we describe a series of potent and selective tricyclic indole diazepinone Mcl-1 inhibitors that were discovered and further optimized using structure-based design. These compounds exhibit picomolar binding affinity and mechanism-based cellular efficacy, including growth inhibition and caspase induction in Mcl-1-sensitive cells. Thus, they represent useful compounds to study the implication of Mcl-1 inhibition in cancer and serve as potentially useful starting points toward the discovery of anti-Mcl-1 therapeutics.

A comprehensive review on biological properties of citrinin.

Citrinin (CIT) is a mycotoxin which causes contamination in the food and is associated with different toxic effects. A web search on CIT has been conducted covering the timespan since 1946. The accumulated data indicate that CIT is produced by several fungal strains belonging to Penicillium, Aspergillus and Monascus genera, and is usually found together with another nephrotoxic mycotoxin, ochratoxin A. Although, it is evident that CIT exposure can exert toxic effects on the heart, liver, kidney, as well as reproductive system, the mechanism of CIT-induced toxicity remains largely elusive. It is still controversial what are the genotoxic and mutagenic effects of CIT. Until now, its toxic effect has been linked to the CIT-mediated oxidative stress and mitochondrial dysfunction in biological systems. However, the toxicity strongly depends on its concentration, route, frequency and time of exposure, as well as from the used test systems. Besides the toxic effects, CIT is also reported to possess a broad spectrum of bioactivities, including antibacterial, antifungal, and potential anticancer and neuro-protective effects in vitro. This systematic review presents the current state of CIT research with emphasis on its bioactivity profile.

Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors.

Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that when overexpressed is associated with high tumor grade, poor survival, and resistance to chemotherapy. Mcl-1 is amplified in many human cancers, and knockdown of Mcl-1 using RNAi can lead to apoptosis. Thus, Mcl-1 is a promising cancer target. Here, we describe the discovery of picomolar Mcl-1 inhibitors that cause caspase activation, mitochondrial depolarization, and selective growth inhibition. These compounds represent valuable tools to study the role of Mcl-1 in cancer and serve as useful starting points for the discovery of clinically useful Mcl-1 inhibitors. PDB ID CODES: Comp. 2: 5IEZ; Comp. 5: 5IF4.

cis-2,5-Diaminobicyclo[2.2.2]octane, a New Chiral Scaffold for Asymmetric Catalysis.

Catalysis of widely used chemical transformations in which the goal is to obtain the product as a pure enantiomer has become a major preoccupation of synthetic organic chemistry over the past three decades. A large number of chiral entities has been deployed to this end, many with considerable success, but one of the simplest and most effective catalytic systems to have emerged from this effort is that based on a chiral diamine, specifically trans-1,2-diaminocyclohexane. While there have been attempts to improve upon this scaffold in asymmetric synthesis, few have gained the recognition needed to take their place alongside this classic diamine. The challenge is to design a scaffold that retains the assets of trans-1,2-diaminocyclohexane while enhancing its intrinsic chirality and maximizing the scope of its applications. It occurred to us that cis-2,5-diaminobicyclo[2.2.2]octane could be such a scaffold. Synthesis of this diamine in enantiopure form was completed from benzoic acid, and the (1R,2R,4R,5R) enantiomer was used in all subsequent experiments in this laboratory. Condensation of the diamine with various salicyl aldehydes generated imine derivatives which proved to be excellent "salen" ligands for encapsulation of transition and other metals. In total, 12 salen-metal complexes were prepared from this ligand, many of which were crystalline and three of which, along with the ligand itself, yielded to X-ray crystallography. An advantage of this ligand is that it can be tuned sterically or electronically to confer specific catalytic properties on the salen-metal complex, and this feature was used in several applications of our salen-metal complexes in asymmetric synthesis. Thus, replacement of one of the tert-butyl groups in each benzenoid ring of the salen ligand by a methoxy substituent enhanced the catalytic efficiency of a cobalt(II)-salen complex used in asymmetric cyclopropanation of 1,1-disubstituted alkenes; the catalyst was employed in an improved synthesis of the cyclopropane-containing drug candidate Synosutine. Reduction of the pair of imine functions of the ligand to secondary amines permitted formation of a copper(I)-salen complex that catalyzed asymmetric Henry ("nitroaldol") condensation with excellent efficiency; this catalyst was applied in an economical synthesis of three drugs of the "beta-blocker" family including (S)-Propanolol. Chromium(II) and chromium(III) complexes were prepared from our bicyclooctane-salen ligand bearing a pair of tert-butyl groups in each benzenoid ring. These complexes were found to catalyze, respectively, enantioselective formation of homoallylic alcohols from Nozaki-Hiyama-Kishi allylation of aromatic aldehydes and dihydropyranones from hetero-Diels-Alder cycloaddition. Plausible reaction models emerging from knowledge of the absolute configuration of products from each of these reactions place the metal-coordinated substrate in a quadrant beneath the bicyclooctane scaffold so that one face of the substrate is blocked by an aryl ring of the salen ligand while the opposite face is left open to attack. The consistent and predictable stereochemical outcome from reactions catalyzed by salen-metal complexes derived from our diaminobicyclo[2.2.2]octane scaffold adds a valuable new dimension to asymmetric synthesis.

Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods.

Myeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 family of proteins responsible for the regulation of programmed cell death. Amplification of Mcl-1 is a common genetic aberration in human cancer whose overexpression contributes to the evasion of apoptosis and is one of the major resistance mechanisms for many chemotherapies. Mcl-1 mediates its effects primarily through interactions with pro-apoptotic BH3 containing proteins that achieve high affinity for the target by utilizing four hydrophobic pockets in its binding groove. Here we describe the discovery of Mcl-1 inhibitors using fragment-based methods and structure-based design. These novel inhibitors exhibit low nanomolar binding affinities to Mcl-1 and >500-fold selectivity over Bcl-xL. X-ray structures of lead Mcl-1 inhibitors when complexed to Mcl-1 provided detailed information on how these small-molecules bind to the target and were used extensively to guide compound optimization.

Regioselective and Enantioselective Addition of Sulfur Nucleophiles to Acyclic α,ß,γ,δ-Unsaturated Dienones Catalyzed by an Iron(III)-Salen Complex.

The first regioselective, enantioselective conjugate addition of thiols to acyclic α,ß,γ,δ-unsaturated dienones at the δ carbon is described. The reaction, catalyzed by a chiral iron(III)-salen complex derived from cis-2,5-diaminobicyclo[2.2.2]octane as the scaffold, provides δ-thia-α,ß-unsaturated ketones in high yield and enantioselectivity. The bicyclooctane scaffold of (2R,3R,5R,6R) configuration affords a δ-thia-α,ß-unsaturated ketone of (R) configuration, indicating that the sulfur nucleophile is introduced at the si face of the γ,δ-double bond. A model providing an explanation for this regio- and stereoselection is proposed.

Discovery of tricyclic indoles that potently inhibit Mcl-1 using fragment-based methods and structure-based design.

Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that is overexpressed and amplified in many cancers. Overexpression of Mcl-1 allows cancer cells to evade apoptosis and contributes to the resistance of cancer cells to be effectively treated with various chemotherapies. From an NMR-based screen of a large fragment library, several distinct chemical scaffolds that bind to Mcl-1 were discovered. Here, we describe the discovery of potent tricyclic 2-indole carboxylic acid inhibitors that exhibit single digit nanomolar binding affinity to Mcl-1 and greater than 1700-fold selectivity over Bcl-xL and greater than 100-fold selectivity over Bcl-2. X-ray structures of these compounds when complexed to Mcl-1 provide detailed information on how these small-molecules bind to the target, which was used to guide compound optimization.

A new iron(III)-salen catalyst for enantioselective Conia-ene carbocyclization.

A chiral iron(III)-salen complex based on a cis-2,5-diaminobicyclo[2.2.2]octane scaffold catalyzes asymmetric Conia-ene-type cyclization of α-functionalized ketones containing an unactivated terminal alkyne and produces an exo-methylenecycloalkane possessing a stereodefined quaternary center.