Articolul precedent |
Articolul urmator |
907 4 |
Ultima descărcare din IBN: 2021-10-14 15:50 |
SM ISO690:2012 SUCMAN, Natalia, BOLDESCU, Veaceslav, UNCU, Livia, VALICA, Vladimir, MAKAEV, Fliur. Non‐nucleoside reverstranscriptase inhibitors with targeted activation in macrophages. In: Chemistry, Structure and Function of Biomolecules, 22-25 mai 2018, Minsk. Minsk, Belorusia : Institute of Bioorganic Chemistry, 2018, Ediția a VI-a, pp. 137-139. |
EXPORT metadate: Google Scholar Crossref CERIF DataCite Dublin Core |
Chemistry, Structure and Function of Biomolecules Ediția a VI-a, 2018 |
|||||||
Conferința "Chemistry, Structure and Function of Biomolecules" Minsk, Belarus, 22-25 mai 2018 | |||||||
|
|||||||
Pag. 137-139 | |||||||
|
|||||||
Descarcă PDF | |||||||
Rezumat | |||||||
The foundation of the mononuclear phagocyte system are macrophages that derive The main objective of the current study was design and synthesis of a new group of For a specific prodrug concept, based on the research results obtained by Needham Interestingly, 1a analogues with different groups (Br, Cl, NO2) in positions 5 and 7 |
|||||||
|
Dublin Core Export
<?xml version='1.0' encoding='utf-8'?> <oai_dc:dc xmlns:dc='http://purl.org/dc/elements/1.1/' xmlns:oai_dc='http://www.openarchives.org/OAI/2.0/oai_dc/' xmlns:xsi='http://www.w3.org/2001/XMLSchema-instance' xsi:schemaLocation='http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd'> <dc:creator>Sucman, N.S.</dc:creator> <dc:creator>Boldescu, V.V.</dc:creator> <dc:creator>Uncu, L.V.</dc:creator> <dc:creator>Valica, V.V.</dc:creator> <dc:creator>Macaev, F.Z.</dc:creator> <dc:date>2018</dc:date> <dc:description xml:lang='en'><p>The foundation of the mononuclear phagocyte system are macrophages that derive<br />from bone marrow’s monoblasts and promonoblasts. First, monoblasts and<br />promonoblasts get transformed in circulating monocytes, which, after migration in<br />extravascular tissue, differentiate into macrophages.<br />The main role of macrophages is defense of the organism against various infectious<br />agents. Furthermore, macrophages have been found to play an important part in the<br />pathology of different diseases: atherosclerosis (foam cells), cancer (tumorassociated<br />macrophages), infectious diseases for which macrophages play the role<br />of host cells (e. g. tuberculosis, HIV, leishmaniasis, dengue virus), etc. Thus, recent<br />studies have detected high viral load in tissue macrophages at all stages of HIV-1,<br />which persists in them even under combination antiretroviral therapy.1 Therefore,<br />macrophages make one of important targets for anti-HIV drug design and<br />development.</p><p>The main objective of the current study was design and synthesis of a new group of<br />non-nucleoside reverse transcriptase inhibitors with targeted activation in<br />macrophages the feature that would improve pharmacodynamic and<br />pharmacokinetic parameters of this class of compounds, reduce viral load in<br />macrophages, and thus improve the outcomes of the antiretroviral therapy.<br />Human carboxylesterase-1 (hCE-1) is highly expressed in macrophages and,<br />therefore, could play a role of activator enzyme in activation of prodrugs of nonnucleoside<br />reverse transcriptase inhibitors targeting these cells.1 Such activation<br />guarantees a cell-type specific approach and accumulation of the active drug in<br />higher concentrations on the intracellular level. The occurring intracellular ester<br />hydrolysis of a drug-ester conjugate results in the production of a potentially active<br />compound with a charged nature. This would ultimately lead to a drop in the drugs<br />ability to leave the cell and consequently to a beneficial accumulation in the<br />targeted cells.2 For a successful delivery of intracellular active compounds to hCE1-<br />expressing cells, a sensitive motif (see the figure below) for aforementioned<br />enzyme has to be attached to a drug.</p><p>For a specific prodrug concept, based on the research results obtained by Needham<br />et al.2 and the experience accumulated in our group, the cyclopentanol-ester-of-Lleucine-<br />based hCE-1 selective motif has been chosen and introduced in the<br />structures of molecules known to be highly active against HIV-1.<br />First, a known3,4 reverse transcriptase inhibitor has been obtained and its<br />diastereomers 1a and 1b have been separated. Compound 1a has been tested<br />previously in a cell-based HIV reporter infection assay and was identified to have<br />EC50 = 50 nM.3,4 At the same time, it has been detected that diastereomer 1b is<br />completely inactive, the fact that suggested that the antiviral activity of 1a is a<br />result if its specific interaction with reverse transcriptase.3,4 After the separation of<br />the diastereomers, hydrolysis of the esters has been carried out with formation of<br />individual cis- and trans-acids 2. Then the isolated cis- and trans-acids have been<br />subjected to coupling with cyclopentanol ester of L-leucine to obtain compounds<br />with general formula 3.<br />The data obtained by Jiang et al.3 indicates that there is a small space for<br />substitution in position 5 and only small hydrophobic moieties can be introduced<br />(Cl, Br, CN or vinyl) to allow optimal interaction with reverse transcriptase. In<br />addition to this, substitution in positions 4, 6, and 7 mostly leads to inactive<br />compounds.</p><p>Interestingly, 1a analogues with different groups (Br, Cl, NO2) in positions 5 and 7<br />have also shown inhibitory activity against HIV-1 integrase.5 Moreover, only cisanalogs<br />have demonstrated inhibition, while none of the trans-analogs have shown<br />any inhibition. Our further work will be directed towards obtaining of new<br />derivatives active against HIV-1 reverse transcriptase and integrase with attached<br />esterase sensitive motif.<br />REFERENCES<br />(1) Cory, T. J.; Schacker, T. W.; Stevenson, M.; Fletcher, C. V. Current opinion in HIV and AIDS,<br />2013, 8, 190.<br />(2) Needham, L. A.; Davidson, A. H.; Bawden, L. J.; Belfield, A.; Bone, E. A.; Brotherton, D. H.<br />et al. J. Pharmacol. Exp. Ther., 2011, 339, 132-142.<br />(3) Jiang, T.; Kuhen, K. L.; Wolff, K.; Yin, H.; Bieza, K.; Caldwell, J.; Bursulaya, B.; Wu,<br />T.Y.H.; He, Y. Bioorg. Med. Chem. Lett., 2006, 16, 2105-2108.<br />(4) Jiang, T.; Kuhen, K.L.; Wolff, K.; Yin, H.; Bieza, K.; Caldwell, J.; Bursulaya, B.; Tuntland,<br />T.; Zhang, K.; Karanewsky, D.; He, Y. Bioorg. Med. Chem. Lett., 2006, 16, 2109-2112.<br />(5) Surmava, S.; Elefthetiou, P.; Geronikaki, A., Petrou, C.; Macaev, F.; Sucman, N. HIV-1<br />integrase inhibition by novel spiro-isatin-cyclopropane derivatives. In: XVIII International<br />AIDS Conference. Viena: Austria, 2010, p. 56.<br />Acknowledgements: the authors are grateful for the funding support from the Science and Technology<br />Center in Ukraine and the Agency for Research and Development of the Republic of Moldova under<br />international project 17.80013.8007.10/6245STCU.</p></dc:description> <dc:source>Chemistry, Structure and Function of Biomolecules (Ediția a VI-a) 137-139</dc:source> <dc:title>Non‐nucleoside reverstranscriptase inhibitors with targeted activation in macrophages</dc:title> <dc:type>info:eu-repo/semantics/article</dc:type> </oai_dc:dc>