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Giordanetto F.,Medicinal Chemistry | Schafer A.,TU Eindhoven | Ottmann C.,TU Eindhoven
Drug Discovery Today | Year: 2014

Protein-protein interactions (PPIs) are implicated in every disease and mastering the ability to influence PPIs with small molecules would considerably enlarge the druggable genome. Whereas inhibition of PPIs has repeatedly been shown to work successfully, targeted stabilization of PPIs is underrepresented in the literature. This is all the more surprising because natural products like FK506, rapamycin, brefeldin, forskolin and fusicoccin confer their physiological activity by stabilizing specific PPIs. However, recently a number of very interesting synthetic molecules have been reported from drug discovery projects that indeed achieve their desired activities by stabilizing either homo- or hetero-oligomeric complexes of their target proteins. © 2014 Elsevier Ltd. All rights reserved.


It was found that synthesized molecules could potentially be used as anticancer agents with good selectivity index. Hydantoin moiety and its derivatives can be found in many drug molecules, including nilutamide, which is used in chemotherapy for prostate cancer, and dantrolene, which helps to relax skeletal muscles and prevent cramps. Selenohydantoins are derivatives of hydantoins in which one of the oxygen atoms is replaced by selenium. It was found that drug molecules containing selenium possess anticancer activity and can be used as effective antioxidants. Selenium can be found in a number of known drug molecules, such as Ebselen, an antioxidant with a broad spectrum of therapeutic activity. In the study, the scientists have synthesized novel selenium-containing hydantoin derivatives. The structures of the molecules obtained were confirmed by NMR (Nuclear Magnetic Resonance) spectroscopy, high resolution mass spectrometry, and X-ray analysis. It was found that in the presence of Cu2+ copper cations, a spatial transformation is observed and a stable isomer is formed. Isomers are molecules with the same atomic composition, but different spatial structure. The interest lies in the fact that the isomers differ in terms of their properties and activity. The scientists used quantum-chemical calculations to explain the mechanism of the transformation they had discovered. The results of electromechanical studies showed that the synthesized molecules possess antioxidant activity, which means they are able to slow down the process of oxidation. They are also able to bind to receptors that protect the body from oxidation. "We have examined the effect of selenium on the activity of the synthesized molecules. The next step is to investigate the pharmacological potential of the most active molecules in vivo and in vitro," said Yan Ivanenkov, the head of the Laboratory of Medical Chemistry and Bioinformatics, when commenting on the prospects of the research. The results of the study highlighted the important role of selenium in the structure of hydantoin derivatives. Structural modification such as this has a significant influence on the spectrum of biological activity and properties of the molecules. Explore further: Scientists find new way to detect ortho-para conversion in water More information: Yan A. Ivanenkov et al. Synthesis, isomerization and biological activity of novel 2-selenohydantoin derivatives, Bioorganic & Medicinal Chemistry (2016). DOI: 10.1016/j.bmc.2015.12.050


Pesticides are used around the world to control insects that destroy crops. However, in recent years their use has been criticized, because of the detrimental effect they can have on ecosystems, ravaging food chains and damaging the environment. One of the problems with many pesticides is that they kill indiscriminately. For rice plants, this means pesticides kill the natural enemies of one of their biggest pests, the white-backed planthopper Sogatella furcifera. This pest attacks rice, leading to yellowing or "hopper burn," which causes the plants to wilt and can damage the grains. It also transmits a virus disease called, southern rice black-streaked dwarf virus, which stunts the plants' growth and stops them from "heading," which is when pollination occurs. Left untreated, many of the insects' eggs would be eaten, but when pesticides are used these hatch, leading to even more insects on the plants. What's more, in some areas as many as a third of the planthoppers are resistant to pesticides. "The extensive application of chemical insecticides not only causes severe environmental and farm produce pollution but also damages the ecosystem," explained Dr. Jun Wu, one of the authors of the study and professor at Zhejiang Universityin China. "Therefore, developing safe and effective methods to control insect pests is highly desired; this is why we decided to investigate these chemicals." Because of the problems of using pesticides, it's vital to find new solutions to help protect rice plants from infestation. Plants have natural self-defense mechanisms that kick in when they are infested with pests like the planthopper. This defense mechanism can be switched on using chemicals that do not harm the environment and are not toxic to the insects or their natural enemies. In the new study, researchers from Zhejiang Universityin China developed a new way of identifying these chemicals. Using a specially designed screening system, they determined to what extent different chemicals switched on the plants' defense mechanism. The team designed and synthesized 29 phenoxyalkanoic acid derivatives. Of these, they identified five that could be effective at triggering the rice plants to defend themselves. The researchers used bioassays to show that these chemicals could trigger the plant defense mechanism and repel the white-backed planthopper. This suggests that these chemicals have the potential to be used in insect pest management. "We demonstrate for the first time that some phenoxyalkanoic acid derivatives have the potential to become such plant protection agents against the rice white-backed planthopper," said Dr. Yonggen Lou, one of the authors of the study and professor at Zhejiang Universityin China. "This new approach to pest management could help protect the ecosystem while defending important crops against attack." The next step for the research will be to explore how effective the chemicals are at boosting the plants' defenses and controlling planthoppers in the field. Explore further: Rice Institute calls for cuts in pesticide use More information: Xingrui He et al. Finding new elicitors that induce resistance in rice to the white-backed planthopper Sogatella furcifera, Bioorganic & Medicinal Chemistry Letters (2015). DOI: 10.1016/j.bmcl.2015.10.041


Canal C.E.,Northeastern University | Felsing D.,Medicinal Chemistry | Kondabolu K.,Medicinal Chemistry | Rowland N.E.,University of Florida | And 5 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2014

Development of 5-HT2C agonists for treatment of neuropsychiatric disorders, including psychoses, substance abuse, and obesity, has been fraught with difficulties, because the vast majority of reported 5-HT2C selective agonists also activate 5-HT2A and/or 5-HT2B receptors, potentially causing hallucinations and/or cardiac valvulopathy. Herein is described a novel, potent, and efficacious human 5-HT2C receptor agonist, (2)-trans-(2S,4R)-4-(39[meta]- bromophenyl)- N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-Amine (2)-MBP), that is a competitive antagonist and inverse agonist at human 5-HT2A and 5-HT2B receptors, respectively. (2)-MBP has efficacy comparable to the prototypical second-generation antipsychotic drug clozapine in three C57Bl/6 mouse models of drug-induced psychoses: the head-twitch response elicited by [2,5]-dimethoxy- 4-iodoamphetamine; hyperlocomotion induced by MK-801 [(5R, 10S)-(1)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine hydrogen maleate (dizocilpine maleate)]; and hyperlocomotion induced by amphetamine. (2)-MBP, however, does not alter locomotion when administered alone, distinguishing it from clozapine, which suppresses locomotion. Finally, consumption of highly palatable food by mice was not increased by (2)-MBP at a dose that produced at least 50%maximal efficacy in the psychoses models. Compared with (2)-MBP, the enantiomer (1)-MBP was much less active across in vitro affinity and functional assays using mouse and human receptors and also translated in vivo with comparably lower potency and efficacy. Results indicate a 5-HT2C receptor-specific agonist, such as (2)-MBP, may be pharmacotherapeutic for psychoses, without liability for obesity, hallucinations, heart disease, sedation, or motoric disorders.Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.


Chen D.,Medicinal Chemistry | Wang X.,Medicinal Chemistry | Agarwal A.,New Haven Pharmaceuticals | Phadke A.,Medicinal Chemistry | Deshpande M.,Medicinal Chemistry
Antimicrobial Agents and Chemotherapy | Year: 2013

Treatment of hepatitis C patients with direct-acting antiviral drugs involves the combination of multiple small-molecule inhibitors of distinctive mechanisms of action. ACH-806 (or GS-9132) is a novel, small-molecule inhibitor specific for hepatitis C virus (HCV). It inhibits viral RNA replication in HCV replicon cells and was active in genotype 1 HCV-infected patients in a proof-of-concept clinical trial (1). Here, we describe a potential mechanism of action (MoA) wherein ACH-806 alters viral replication complex (RC) composition and function. We found that ACH-806 did not affect HCV polyprotein translation and processing, the early events of the formation of HCV RC. Instead, ACH-806 triggered the formation of a homodimeric form of NS4A with a size of 14 kDa (p14) both in replicon cells and in Huh-7 cells where NS4A was expressed alone. p14 production was negatively regulated by NS3, and its appearance in turn was associated with reductions in NS3 and, especially, NS4A content in RCs due to their accelerated degradation. A previously described resistance substitution near the N terminus of NS3, where NS3 interacts with NS4A, attenuated the reduction of NS3 and NS4A conferred by ACH-806 treatment. Taken together, we show that the compositional changes in viral RCs are associated with the antiviral activity of ACH-806. Small molecules, including ACH-806, with this novel MoA hold promise for further development and provide unique tools for clarifying the functions of NS4A in HCV replication. Copyright © 2013, American Society for Microbiology.

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