LV15670B - Novel adenosylmercaptane derivatives as viral mrna cap methyltransferase inhibitors - Google Patents
Novel adenosylmercaptane derivatives as viral mrna cap methyltransferase inhibitors Download PDFInfo
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- LV15670B LV15670B LVP-21-16A LVP2021000016A LV15670B LV 15670 B LV15670 B LV 15670B LV P2021000016 A LVP2021000016 A LV P2021000016A LV 15670 B LV15670 B LV 15670B
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- 230000003612 virological effect Effects 0.000 title abstract description 12
- 239000003697 methyltransferase inhibitor Substances 0.000 title abstract description 6
- 101710121537 mRNA (guanine-N(7))-methyltransferase Proteins 0.000 title 1
- 102100040949 mRNA cap guanine-N7 methyltransferase Human genes 0.000 title 1
- 101710144593 mRNA cap guanine-N7 methyltransferase Proteins 0.000 title 1
- 101710082804 mRNA cap methyltransferase Proteins 0.000 title 1
- 101710167437 mRNA-capping enzyme small subunit Proteins 0.000 title 1
- -1 adenosyl mercaptan derivatives Chemical class 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 30
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- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
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- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
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- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 1
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- ZAOSQJHLUDMSTB-WOUKDFQISA-N s-[[(2s,3s,4r,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl] ethanethioate Chemical compound O[C@@H]1[C@H](O)[C@@H](CSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZAOSQJHLUDMSTB-WOUKDFQISA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/167—Purine radicals with ribosyl as the saccharide radical
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- Chemical Kinetics & Catalysis (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
Izgudrojums attiecas uz medicīnu, galvenokārt uz vīrusu infekcijas ārstēšanu, konkrētāk uz vīrusu m-RNS kapinga metiltransferāzes inhibitoriem. Piedāvāti jauni adenozilmerkaptāna atvasinājumi, to farmaceitiskās kompozīcijas un to izmantošana par m-RNS kapinga metiltransferāzes inhibitoriem.The invention relates to medicine, mainly to the treatment of viral infection, more specifically to viral m-RNA capping methyltransferase inhibitors. New adenosyl mercaptan derivatives, their pharmaceutical compositions and their use as m-RNA capping methyltransferase inhibitors are proposed.
Description
IZGUDROJUMA APRAKSTSDESCRIPTION OF THE INVENTION
[001] Izgudrojums attiecas uz medicīnu, galvenokārt uz vīrusu infekciju ārstēšanu, konkrētāk uz vīrusu m-RNS kapinga metiltransferāžu inhibitoriem. It īpaši izgudrojums attiecas uz jauniem adenozilmerkaptāna atvasinājumiem, to farmaceitiskām kompozīcijām un to izmantošanu par m-RNS kapinga metiltransferāžu inhibitoriem.[001] The invention relates to medicine, mainly to the treatment of viral infections, more specifically to inhibitors of viral m-RNA capping methyltransferases. In particular, the invention relates to new adenosyl mercaptan derivatives, their pharmaceutical compositions and their use as inhibitors of m-RNA capping methyltransferases.
Zināmais tehnikas līmenisThe known state of the art
[002] Koronavīrusi ir izveidojuši m-RNS kapinga sistēmu, lai aizsargātu 5’-galu ar kapinga grupu, kas neatšķiras no eikariotiskā m-RNS kapinga struktūras [1], Kapinga procesu veic metiltransferāzes Nspl4 unNspl6, kas modificē vīrusa m-RNS 5’-gala guanozīna N7 pozīciju un divu secīgo nukleotīdu 2’-OH grupas [2], m-RNS 5’-galaN7-metilguanozīna (m7G) kapings ir nepieciešams efektīvai vīrusa proteīnu translācijai, savukārt divu secīgo nukleotīdu 2'-Ometilēšana ir nozīmīga, lai izvārītos no saimniekorganisma imūnās atbildes [3,4],[002] Coronaviruses have developed an m-RNA capping system to protect the 5'-end with a capping group that does not differ from the eukaryotic m-RNA capping structure [1], the capping process is carried out by the methyltransferases Nspl4 and Nspl6, which modify the viral m-RNA 5' Capping of the -terminal guanosine N7 position and the 2'-OH group of two consecutive nucleotides [2], m-RNA 5'-terminalN7-methylguanosine (m7G) is necessary for efficient viral protein translation, while the 2'-O-methylation of two consecutive nucleotides is important for would result from the host's immune response [3,4],
[003] Pētījumi ar SARS-CoV-1 ir parādījuši, ka Nspl4 un Nspl6 gēnu mutācijas noved pie būtiski vājināta vīrusa, ko atpazīst iedzimtā (nespecifiskā) imūnsistēma [4,5,6],[003] Studies with SARS-CoV-1 have shown that mutations in the Nspl4 and Nspl6 genes lead to a significantly weakened virus that is recognized by the innate (non-specific) immune system [4,5,6],
[004] Bez tam, pētījumi ar Nspl4 un Nspl6 S-adenozilmetionīna (SAM) analogiem ir parādījuši, ka Nspl4 vai Nspl6 inhibīciju var izmantot, lai ārstētu koronavīrusu infekcijas [7], Tomēr, neskatoties uz līdzšinējām pūlēm, neviens no metiltransferāžu inhbitoriem nav attīstīts līdz klīniskajiem pētījumiem.[004] In addition, studies with S-adenosylmethionine (SAM) analogs of Nspl4 and Nspl6 have shown that inhibition of Nspl4 or Nspl6 can be used to treat coronavirus infections [7] However, despite efforts to date, none of the methyltransferase inhibitors have been developed to clinical trials.
Izgudrojuma mērķis un būtībaPurpose and essence of the invention
[005] Vienā aspektā izgudrojums piedāvā metodi vīrusa infekciju ārstēšanai cilvēkiem vai dzīvniekiem, ievadot cilvēkam vai dzīvniekam, kam tas nepieciešams, terapeitiski efektīvu daudzumu savienojuma vai tā zāļu priekštečvielas, vai minētā savienojuma vai tā priekštečvielas farmaceitiski pieņemama sāļa, hidrāta, solvāta vai polimorfa, kur savienojums ir vīrusu m-RNS kapinga metiltransferāzes inhibitors.[005] In one aspect, the invention provides a method for treating viral infections in humans or animals by administering to a human or animal in need thereof a therapeutically effective amount of a compound or prodrug thereof, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug thereof, wherein the compound is an inhibitor of viral m-RNA capping methyltransferase.
[006] Otrā aspektā izgudrojums piedāvā farmaceitisku kompozīciju vīrusu infekciju ārstēšanai, kas satur terapeitiski efektīvu daudzumu kompozīcijas, kas satur (i) savienojumu vai tā zāļu priekštečvielu, vai minētā savienojuma vai tā priekštečvielas farmaceitiski pieņemamu sāli, hidrātu, solvātu vai polimorfu un (ii) farmaceitiski pieņemamu nesēju, kur savienojums ir vīrusu m-RNS kapinga metiltransferāzes inhibitors.[006] In a second aspect, the invention provides a pharmaceutical composition for the treatment of viral infections comprising a therapeutically effective amount of a composition comprising (i) a compound or a drug prodrug thereof, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or a prodrug thereof, and (ii) a pharmaceutically acceptable carrier, wherein the compound is an inhibitor of viral m-RNA capping methyltransferase.
[007] Citā aspektā izgudrojums apraksta savienojuma vai tā zāļu priekštečvielas, vai minētā savienojuma vai tā priekštečvielas farmaceitiski pieņemama sāļa, hidrāta, solvāta vai polimorfa, kur minētais savienojums ir vīrusu m-RNS kapinga metiltransferāzes inhibitors, izmantošanu medikamenta ražošanā vīrusa infekciju ārstēšanai un profilaksei.[007] In another aspect, the invention describes the use of a compound or a drug precursor thereof, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph of said compound or its precursor, wherein said compound is a viral m-RNA cap methyltransferase inhibitor, in the manufacture of a medicament for the treatment and prevention of viral infections.
[008] Citā aspektā izgudrojums piedāvā savienojuma vai tā zāļu priekštečvielas, vai minētā savienojuma vai tā priekštečvielas farmaceitiski pieņemamu sāļa vai estera, kur minētais savienojums ir vīrusu m-RNS kapinga metiltransferāzes inhibitors, izmantošanu vīrusa infekciju ārstēšanā un profilaksē.[008] In another aspect, the invention provides the use of a compound or a drug precursor thereof, or a pharmaceutically acceptable salt or ester of said compound or a precursor thereof, wherein said compound is an inhibitor of viral m-RNA capping methyltransferase, in the treatment and prevention of viral infections.
[009] Vienā no izgudrojuma realizācijas variantiem vīrusu m-RNS kapinga metiltransferāzes inhibitors ir savienojums ar formulu (I):[009] In one embodiment of the invention, the viral m-RNA capping methyltransferase inhibitor is a compound of formula (I):
kur R1, R2, R3 R4 neatkarīgi ir H, Ci-6alkilgrupa, Cs-iacikloalkilgrupa, C3-i2cikloalkil-Ci6alkilgrupa, C2-6alkenilgrupa, C2-6alkinilgrupa, arilgrupa, biarilgrupa, Ci-6arilalkilgrupa, C26arilalkenilgrupa, C2-6arilakinilgrupa, heteroarilgrupa, Ci-6heteroarilalkilgrupa, C26heteroarilalkenilgrupa, R5O(CH2)n, R5S(CH2)n, R5OC(=O)(CH2)n, R5N(R6)C(=O)(CH2)n, R5N(R6)(CH2)n, -F, -Cl, -Br, -I, -CF3, -CH2CF3, -CF2CF2H, -OH, -L-OH,-O-L-OH, -OR5, -OL-NH2, -O-L-NHR5, -O-L-N(R5)R6, -L-OR5,-O-L-OR5,-OCF3, -OCH2CF3, -OCF2CF2H, -LOR5,-O-L-OR5,-OCF3, -OCH2CF3, -OCF2CF2H, SR5, SCF3, -CN, -NO2, -NO2, -NH2, -NHR5, NR52, -N(R5)R6, -L-NH2, -L-NHR5, -L-NR52, -L-N(R5) R6,-NH-L-NH2, -NH-L-NHR5, -NH-LN(R5)R6, -NH-L-N(R5)R6,-NR5-L-NH2, -NR5-L-NHR5, -NR5-L-N(R5)R6, -NR5-L-N(R5)R6, N(R5)R6, -C(=O)OH, -C(=O)OR5, -C(=O)NH2, -C(=O)NHR5, -C(=O)N(R5)R6, C(=O)N(R5)R6, -NHC(=O)R5, -NR5C(=O)R6, -NHC(=O)OR5, -NR5C(=O)OR6, -OC(=O)NH2, -OC(=O)NHR5, -OC(=O)N(R5)R6, -OC(=O) R5NR6, -OC(=O)R5, -C(=O)R5, -NHC(=O)NH2, NHC(=O)NHR6, -NHC(=O)NR52, -NHC(=O)N(R5)R6, -NR5C(=O)NH2, -N(R5)C(=O)NHR6, NR5C(=O)N (R5)R6, [010] kur:where R 1 , R 2 , R 3 R 4 are independently H, C 1-6 alkyl, C 5-10 cycloalkyl, C 3-12 cycloalkyl-C 16 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, biaryl, C 1-6 arylalkyl, C 26 arylalkenyl, C 2-6 arylalkynyl , heteroaryl, C1-6heteroarylalkyl, C26heteroarylalkenyl, R 5 O(CH2) n , R 5 S(CH2)n, R 5 OC(=O)(CH2)n, R 5 N(R 6 )C(=O)( CH2)n, R 5 N(R 6 )(CH2) n , -F, -Cl, -Br, -I, -CF3, -CH2CF3, -CF2CF2H, -OH, -L-OH, -OL-OH, -OR 5 , -OL-NH2 , -OL-NHR 5 , -OLN(R 5 )R 6 , -L-OR 5 ,-OL-OR 5 ,-OCF3, -OCH2CF3, -OCF2CF2H, -LOR 5 ,- OL-OR 5 ,-OCF3, -OCH2CF3, -OCF2CF2H, SR 5 , SCF3, -CN, -NO2, -NO2, -NH2, -NHR 5 , NR 5 2, -N(R 5 )R 6 , -L -NH2, -L-NHR 5 , -L-NR 5 2, -LN(R 5 ) R 6 ,-NH-L-NH2, -NH-L-NHR 5 , -NH-LN(R 5 )R 6 , -NH-LN(R 5 )R 6 ,-NR 5 -L-NH2, -NR 5 -L-NHR 5 , -NR 5 -LN(R 5 )R 6 , -NR 5 -LN(R 5 ) R 6 , N(R 5 )R 6 , -C(=O)OH, -C(=O)OR 5 , -C(=O)NH2, -C(=O)NHR 5 , -C(=O )N(R 5 )R 6 , C(=O)N(R 5 )R 6 , -NHC(=O)R 5 , -NR 5 C(=O)R 6 , -NHC(=O)OR 5 , -NR 5 C(=O)OR 6 , -OC(=O)NH2, -OC(=O)NHR 5 , -OC(=O)N(R 5 )R 6 , -OC(=O) R 5 NR 6 , -OC(=O)R 5 , -C(=O)R 5 , -NHC(=O)NH2, NHC(=O)NHR 6 , -NHC(=O)NR 5 2, -NHC (=O)N(R 5 )R 6 , -NR 5 C(=O)NH 2 , -N(R 5 )C(=O)NHR 6 , NR 5 C(=O)N (R 5 )R 6 , [010] where:
n ir vesels skaitlis robežās no 0 līdz 1;n is an integer between 0 and 1;
un optiskie izomēri, farmaceitiski pieņemami sāļi, hidrāti, solvāti un polimorfi. Izņemot gadījumus, kad: R1, R2, R3, R4 ir Η; n nav 0,and optical isomers, pharmaceutically acceptable salts, hydrates, solvates and polymorphs. Except for the cases when: R 1 , R 2 , R 3 , R 4 are Η; n is not 0,
R1, R2, R4 ir H; R3 ir NO2; n nav 0.R 1 , R 2 , R 4 are H; R 3 is NO 2 ; n is not 0.
[011] Vienā variantā ārstēšana ir slimības vai disfunkcijas ārstēšana, kurā iesaistīta vīrusa mRNS kapinga metiltransferāze cilvēka m-RNS kapinga metiltransferāze.[011] In one embodiment, the treatment is the treatment of a disease or dysfunction involving a viral mRNA capping methyltransferase human m-RNA capping methyltransferase.
[012] Vienā variantā ārstēšana ir slimības vai disfunkcijas ārstēšana, ko veicina vīrusa m-RNS kapinga metiltransferāze cilvēka m-RNS kapinga metiltransferāzes inhibēšana.[012] In one embodiment, the treatment is treating the disease or dysfunction mediated by the viral m-RNA capping methyltransferase by inhibiting the human m-RNA capping methyltransferase.
[013] Vienā variantā ārstēšana ir slimības vai disfunkcijas ārstēšana, kas ir ārstēta ar vīrusa mRNS kapinga metiltransferāzes vai cilvēka m-RNS kapinga metiltransferāzes inhibitoriem.[013] In one embodiment, the treatment is the treatment of the disease or dysfunction that has been treated with inhibitors of viral mRNA capping methyltransferase or human m-RNA capping methyltransferase.
[014] Citā aspektā izgudrojums piedāvā komplektu, kas ietver adenozilmerkaptāna atvasinājumus, kā aprakstīts šeit, vēlams, nodrošināta kā farmaceitiskā kompozīcija un piemērotā konteinerā un/vai piemērotā iepakojumā.[014] In another aspect, the invention provides a kit comprising adenosyl mercaptan derivatives as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or suitable package.
[015] Citā aspektā izgudrojums piedāvā savienojumus, kas iegūstami pēc šeit aprakstītām sintēzes metodēm vai metodēm, kas satur šeit aprakstīto sintēzes metodi.[015] In another aspect, the invention provides compounds obtainable by synthetic methods described herein or methods comprising a synthetic method described herein.
[016] Citā aspektā izgudrojums piedāvā savienojumus, kas iegūti, izmantojot šeit aprakstīto sintēzes metodi, vai metodi, kas satur šeit aprakstīto sintēzes metodi.[016] In another aspect, the invention provides compounds obtained using a synthetic method described herein or a method comprising a synthetic method described herein.
[017] Citā aspektā izgudrojums piedāvā jaunus starpproduktus, kas aprakstīti šeit un, kas ir piemēroti lietošanai šeit aprakstītajās sintēzes metodēs .[017] In another aspect, the invention provides novel intermediates described herein that are suitable for use in the synthetic methods described herein.
[018]Kā būs redzams šīs nozares speciālistam, izgudrojuma viena aspekta iezīmes un vēlamie varianti attieksies arī uz citiem izgudrojuma aspektiem.[018] As will be apparent to one skilled in the art, the features and preferred embodiments of one aspect of the invention will also apply to other aspects of the invention.
Izgudrojuma detalizēts aprakstsDetailed description of the invention
[019] Vīrusa nestrukturālie proteīni (Nsp) ir identificēti kā daudzsološa bioloģisko mērķu grupa plaša spektra pretvīrusu zāļvielu izveidošanai pret koronovīrusiem [4,5,6,7].[019] Viral nonstructural proteins (Nsp) have been identified as a promising group of biological targets for the development of broad-spectrum antiviral drugs against coronaviruses [4,5,6,7].
[020] Testējot jaunus adenozilmerkaptāna atvasinājumus ar vispārīgo formulu (I) un iegūstot datus par to spēju inhibēt Nspl4 un Nspl6, mēs negaidīti atklājām, ka minētie atvasinājumi uzrāda izteiktas inhibitorās īpašības pret minētajiem nestrukturālajiem proteīniem, tāpēc tie ir nozīmīgi vīrusu infekciju ārstēšanā.[020] By testing new adenosyl mercaptan derivatives of the general formula (I) and obtaining data on their ability to inhibit Nspl4 and Nspl6, we unexpectedly discovered that said derivatives show pronounced inhibitory properties against said non-structural proteins, so they are important in the treatment of viral infections.
[021] Saskaņā ar šī izgudrojuma rezultātiem Nspl4 un Nspl6 inhibēšanas pētījumi demonstrē, ka adenozilmerkaptāna atvasinājumi ir jauna nestrukturālo inhibitoru klase. Vairāki savienojumi no šī izgudrojuma uzrāda nanomolāru vai zemu mikromolāru inhibitoro aktivitāti. Stereoķīmija[021] According to the results of this invention, Nspl4 and Nspl6 inhibition studies demonstrate that adenosyl mercaptan derivatives are a new class of non-structural inhibitors. Several compounds of the present invention exhibit nanomolar or low micromolar inhibitory activity. Stereochemistry
[022] Vairākām no šeit parādītajām struktūrām ir norādīta viena vai vairākas specifiskās stereoķīmiskās konfigurācijas. Tāpat vairākām no šeit parādītajām struktūrām nav attēlota stereoķīmiska konfigurācija. Līdzīgi daudzām ķīmiskām struktūrām parādītas stereoķīmiskās konfigurācijas vienā vai vairākās pozīcijās, savukārt citām pozīcijām konfigurācija nav attēlota vienā vai vairākās pozīcijās. Ja ķīmiskajai struktūrai stereoķīmiskā konfigurācija nav attēlota, tad jāuzskata, ka struktūra ietver visus iespējamos stereoizomērus gan individuāli, gan kā stereoizomēru maisījumu (piem., racēmiskos maisījumu).[022] Several of the structures presented herein have one or more specific stereochemical configurations indicated. Also, several of the structures shown here have no stereochemical configuration depicted. Similarly, many chemical structures show stereochemical configurations at one or more positions, while others do not show a configuration at one or more positions. If the stereochemical configuration is not shown for a chemical structure, then the structure should be considered to include all possible stereoisomers, either individually or as a mixture of stereoisomers (eg, a racemic mixture).
KombinācijasCombinations
[023] Šeit nepārprotami ir atklāta katra un jebkura saderīga iepriekšminēto variantu kombinācija tā, it kā katra un ikviena kombinācija būtu individāli un tieši uzskaitīta.[023] Each and every compatible combination of the foregoing variants is expressly disclosed herein as if each and every combination were individually and directly enumerated.
Izgudrojuma īstenošanas piemēriExamples of implementation of the invention
[024] Sekojošie piemēri papildus ilustrē izgudrojumu, taču to nekādā veidā nevar interpretēt kā izgudrojuma pielietojuma ierobežojumu.[024] The following examples further illustrate the invention, but should in no way be construed as limiting the application of the invention.
[025] Kā šī izgudrojuma piemēri tika iegūti šādi adenozilmerkaptāna atvasinājumi ar vispārīgo formulu (I):[025] As examples of the present invention, the following adenosyl mercaptan derivatives of the general formula (I) were obtained:
Vispārīgais sintēzes aprakstsGeneral description of the synthesis
[026] Savienojumi (1.11.4) ir iegūti, izmantojot 1. sintēzes shēmu. Vispirms adenozīnu (2) pārveidoja par hlorīdu (3), tad hlorīdu (3) izmantoja merkaptobenzoskābju alkilēšanas reakcijās.[026] Compounds (1.11.4) were obtained using Synthesis Scheme 1. First, adenosine (2) was converted to chloride (3), then chloride (3) was used in the alkylation reactions of mercaptobenzoic acids.
1. shēma:Scheme 1:
nh2 nh 2
Reaģenti un apstākļi: (a) i SOCb, piridīns, MeCN, 0 °C - istabas temperatūra; ii NH4OH, MeOH; (b) 3-merkaptobenzoskābe, CS2CO3, DMF, istabas temperatūra.Reagents and conditions: (a) i SOCb, pyridine, MeCN, 0 °C - room temperature; ii NH4OH, MeOH; (b) 3-mercaptobenzoic acid, CS2CO3, DMF, room temperature.
[027] Savienojuma (1.5) iegūšanai kā izejvielu izmanto aizsargātu adenozīnu (4) (2. shēma). Vispirms to pārveido par S-acetil-5'-tioadenozīnu (5), tad to deacetilē un alkilē, lai iegūst starpproduktu (6.1). Pēc acetonīda aizsarggrupas nošķelšanas iegūst mērķsavienojumu (1.5).[027] To obtain the compound (1.5) protected adenosine (4) is used as a starting material (Scheme 2). It is first converted to S-acetyl-5'-thioadenosine (5), then deacetylated and alkylated to give the intermediate (6.1). After cleavage of the acetonide protecting group, the target compound (1.5) is obtained.
2. shēma:Scheme 2:
Reaģenti un apstākļi: (a) DIAD, PPha, AcSH, THF, 0 °C; (b) RHal, NaOMe, MeOH, -30 °C istabas temperatūra; (c) LiOH, THF, H2O, istabas temperatūra; (d) HCOOH, ūdens, istabas temperatūra vai 50 °C.Reagents and conditions: (a) DIAD, PPha, AcSH, THF, 0 °C; (b) RHal, NaOMe, MeOH, −30 °C room temperature; (c) LiOH, THF, H2O, room temperature; (d) HCOOH, water, room temperature or 50 °C.
5'-Hloro-5'-dezoksiadenozīns (3)5'-Chloro-5'-deoxyadenosine (3)
[028] Adenozīna (2) (1,50 g, 5,61 mmol) suspensijai sausajā acetonitrilā (6 ml) argona atmosfērā piepilina tionilhlorīdu (1,2 ml, 16,5 mmol) temperatūrā zem 4 °C, dzesējot reakcijas maisījumu ledus vannā. Tad pievieno piridīnu (0,9 ml, 11,1 mmol) temperatūrā zem 4 °C un maisa ledus vannā 3 stundas, tad istabas temperatūrā 16 stundas. Reakcijas maisījumam pievieno ūdeni (15 ml). Šķīdumu neitralizē, lēni pievienojot nātrija bikarbonātu līdz pH 5.[028] To a suspension of adenosine (2) (1.50 g, 5.61 mmol) in dry acetonitrile (6 mL) under an argon atmosphere was added thionyl chloride (1.2 mL, 16.5 mmol) at a temperature below 4 °C, cooling the reaction mixture with ice in the bath. Pyridine (0.9 mL, 11.1 mmol) is then added at a temperature below 4 °C and stirred in an ice bath for 3 hours, then at room temperature for 16 hours. Water (15 mL) was added to the reaction mixture. The solution is neutralized by slowly adding sodium bicarbonate to pH 5.
[029] Nogulsnes nofiltrē, mazgā ar aukstu ūdeni (2x5 ml), žāvē vakuumā un iegūst 1,36 g (77 %) sulfmiladenozīna. Sulfiniladenozīna (1,36 g) suspensijai metanolā (15 ml) pievieno amonija hidroksīdu (1,5 ml) un maisa 1 stundu. Nogulsnes nofiltrē, mazgā ar aukstu metanola un amonija hidroksīda šķīdumu (10:1,2x5 ml), tad žāvē vakuumā un iegūst 1,11 g (69 %) produkta (3). Balta cieta viela.[029] The precipitate is filtered off, washed with cold water (2x5 ml), dried under vacuum and 1.36 g (77%) of sulfmiladenosine is obtained. Ammonium hydroxide (1.5 mL) was added to a suspension of sulfinyl adenosine (1.36 g) in methanol (15 mL) and stirred for 1 hour. The precipitate is filtered off, washed with a cold solution of methanol and ammonium hydroxide (10:1.2x5 ml), then dried under vacuum and 1.11 g (69%) of the product (3) is obtained. A white solid.
[030] Ή KMR (300 MHz, DMSO-cfe) δ 8,34 (s, 1H), 8,15 (s, 1H), 7,29 (br s, 2H), 5,93 (d, J = 5,6 Hz, 1H), 5,60 (br d, 1H), 5,46 (br d, 1H), 4,75 (q, J= 5,2 Hz, 1H), 4,22 (d, J= 4,5 Hz, 1H), 4,26^1,18 (m, 1H), 4,14-4,05 (m, 1H), 3,94 (dd, J= 11,6; 5,0 Hz, 1H), 3,84 (dd, J= 11,6; 6,3 Hz, 1H).[030] Ή NMR (300 MHz, DMSO-cfe) δ 8.34 (s, 1H), 8.15 (s, 1H), 7.29 (br s, 2H), 5.93 (d, J = 5.6 Hz, 1H), 5.60 (br d, 1H), 5.46 (br d, 1H), 4.75 (q, J= 5.2 Hz, 1H), 4.22 (d, J= 4.5 Hz, 1H), 4.26^1.18 (m, 1H), 4.14-4.05 (m, 1H), 3.94 (dd, J= 11.6; 5, 0 Hz, 1H), 3.84 (dd, J= 11.6; 6.3 Hz, 1H).
[031] Savienojumu (1.1-1.4) iegūšana. Vispārīgā metode A.[031] Preparation of compounds (1.1-1.4). General method A.
3-((((25,35,47?,57?)-5-(6-amino-97T-purin-9-il)-3,4-dihidroksitetrahidrofuran-2il)metil)tio)benzoskābe (1.4)3-((((25,35,47?,57?)-5-(6-amino-97T-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2yl)methyl)thio)benzoic acid (1.4)
[032] 5’-Hloro-5'-dezoksiadenozīna (3) (70 mg, 0,25 mmol), 3-merkaptobenzoskābes (42 mg, 0,27 mmol) un cēzija karbonāta (0,18 g, 0,55 mmol) maisījumu sausā DMF (1,2 ml) maisa slēgtā ampulā argona atmosfērā 5 stundas. Šķīdinātāju ietvaicē, tad atlikumu izšķīdina ūdenī (5 ml), atdzesē ledus vannā un neitralizē līdz pH 5 ar 1 N HC1. Nogulsnes nofiltrē, mazgā ar ūdeni (2x2 ml) un žāvē vakuumā. Atlikumu hromatografē uz apgrieztās fāzes C18, eluents acetonitrils - 0,1 % HCOOH, gradients 5-80 %, tad liofilizēja un ieguva 30 mg (30 %) produkta (1.4). Balta cieta viela. AEŠH tīrība 97 %.[032] 5'-Chloro-5'-deoxyadenosine (3) (70 mg, 0.25 mmol), 3-mercaptobenzoic acid (42 mg, 0.27 mmol) and cesium carbonate (0.18 g, 0.55 mmol ) mixture was stirred in dry DMF (1.2 mL) in a sealed ampoule under argon for 5 h. The solvent is evaporated, then the residue is dissolved in water (5 mL), cooled in an ice bath and neutralized to pH 5 with 1 N HCl. The precipitate is filtered off, washed with water (2x2 ml) and dried under vacuum. The residue was chromatographed on reverse phase C18, eluent acetonitrile - 0.1% HCOOH, gradient 5-80%, then lyophilized and obtained 30 mg (30%) of product (1.4). A white solid. AEŠH purity 97%.
[033] 'HKMR(400 MHz, DMSO-tZ6) δ 8,33 (s, 1H), 8,15 (s, 1H), 7,85 (t,J= 1,6 Hz, 1H), 7,73 (dt, 7,8; 1,3 Hz, 1H), 7,59 (ddd, J= 7,8; 1,9; 1,1 Hz, 1H), 7,41 (t, J= Ί,8 Hz, 1H), 7,29 (s, 2H), 5,89 (d, 5,9 Hz, 1H), 5,53 (d, J = 6,1 Hz, 1H), 5,41 (d, J=4,9 Hz, 1H), 4,82 (q, J =[033] 'HKMR(400 MHz, DMSO-tZ6) δ 8.33 (s, 1H), 8.15 (s, 1H), 7.85 (t,J= 1.6 Hz, 1H), 7, 73 (dt, 7.8; 1.3 Hz, 1H), 7.59 (ddd, J= 7.8; 1.9; 1.1 Hz, 1H), 7.41 (t, J= Ί, 8 Hz, 1H), 7.29 (s, 2H), 5.89 (d, 5.9 Hz, 1H), 5.53 (d, J = 6.1 Hz, 1H), 5.41 (d , J=4.9 Hz, 1H), 4.82 (q, J =
5,6 Hz, 1H), 4,23 - 4,18 (m, 1H), 4,01 (ddd, J = 7,0; 5,9; 3,3 Hz, 1H), 3,53-3,30 (m, 2H, pārklājas ar ūdeni). 13CKMR(100 MHz, DMSO-d6) δ 166,9; 156,1; 152,7; 149,5; 140,0; 136,8; 132,3; 131,7; 129,4; 128,4; 126,7; 119,3; 87,6; 82,8; 72,8; 72,6; 35,1. HRMS (ESI/TOF-Q) m/z: [M + H]+ aprēķ. C17H18N5O5S, 404,1029; atrasts: 404,1036.5.6 Hz, 1H), 4.23 - 4.18 (m, 1H), 4.01 (ddd, J = 7.0; 5.9; 3.3 Hz, 1H), 3.53-3 ,30 (m, 2H, covered with water). 13 CKMR (100 MHz, DMSO-d6) δ 166.9; 156.1; 152.7; 149.5; 140.0; 136.8; 132.3; 131.7; 129.4; 128.4; 126.7; 119.3; 87.6; 82.8; 72.8; 72.6; 35.1. HRMS (ESI/TOF-Q) m/z: [M + H] + calcd. C17H18N5O5S, 404.1029; found: 404.1036.
Pec vispārīgās metodes A tika iegūti sekojoši savienojumi:Following general method A, the following compounds were obtained:
[0341 5'-Acetiltio-5'-dezoksi-2',3'-O-izopropilidenadenozīns (5)[0341 5'-Acetylthio-5'-deoxy-2',3'-O-isopropylidenadenosine (5)
Diizopropilazidokarboksilātu (0,6 ml, 3,05 mmol) piepilina 5 min laikā trifenilfosfina (0,80 g, 3,06 mmol) šķīdumam sausajā THF (5 ml), dzesējot maisījumu ledus vannā. Pēc 30 min pievieno 2',3'-O-izopropilidēnadenozīnu (4) (0,47 g, 1,53 mmol) un turpina maisīšanu 0°C temperatūrā 10 min. Tad reakcijas maisījumam pievieno tioetiķskābes (0,22 ml, 3,08 mmol) šķīdumu sausajā THF (5 ml), maisa 1 stundu ledus vannā, tad sasilda līdz istabas temperatūrai. Šķīdinātāju ietvaicē un atlikumu hromatografe uz silikagela, eluents EtOAc:EtOH (3:1) petrolejas ēteris, gradients 20-80 %, iegūst 0,44 g (78 %) produkta (5). Balta cieta viela.Diisopropyl azidocarboxylate (0.6 mL, 3.05 mmol) was added dropwise over 5 min to a solution of triphenylphosphine (0.80 g, 3.06 mmol) in dry THF (5 mL), cooling the mixture in an ice bath. After 30 min, 2',3'-O-isopropylidene adenosine (4) (0.47 g, 1.53 mmol) was added and stirring was continued at 0°C for 10 min. Then a solution of thioacetic acid (0.22 mL, 3.08 mmol) in dry THF (5 mL) was added to the reaction mixture, stirred in an ice bath for 1 hour, then warmed to room temperature. Evaporation of the solvent and chromatography of the residue on silica gel, eluent EtOAc:EtOH (3:1) petroleum ether, gradient 20-80%, afforded 0.44 g (78%) of product (5). A white solid.
[035] Ή KMR (300 MHz, CDC13) δ 8,36 (s, 1H), 7,90 (s, 1H), 6,06 (d, J= 2,1 Hz, 1H), 5,72 (brs, 2H), 5,51 (dd,J=6,4; 2,1 Hz, 1H), 4,97 (dd, J = 6,4; 3,1 Hz, 1H), 4,34 (td, J= 6,9; 3,1 Hz, 1H), 3,29 (dd, J= 13,8; 7,2 Hz, 1H), 3,18 (dd, J= 13,8; 6,6 Hz, 1H), 2,34 (s, 3H), 1,60 (s, 3H), 1,39 (s, 3H).[035] Ή NMR (300 MHz, CDC1 3 ) δ 8.36 (s, 1H), 7.90 (s, 1H), 6.06 (d, J= 2.1 Hz, 1H), 5.72 (brs, 2H), 5.51 (dd,J=6.4; 2.1 Hz, 1H), 4.97 (dd, J = 6.4; 3.1 Hz, 1H), 4.34 ( td, J= 6.9; 3.1 Hz, 1H), 3.29 (dd, J= 13.8; 7.2 Hz, 1H), 3.18 (dd, J= 13.8; 6, 6 Hz, 1H), 2.34 (s, 3H), 1.60 (s, 3H), 1.39 (s, 3H).
[036] Savienojumu (6) iegūšana. Vispārīgā metode B.[036] Obtaining compounds (6). General method B.
3-(((((3 a5,45,6J?,6a/?)-6-(6-amino-9/7-purin-9-il)-2,2-dimetiltetrahidrofuro [3,4d][1.3]dioksol-4-il)metil)tio)metil)benzoskābe (6.1).3-((((3 a5,45,6J?,6a/?)-6-(6-amino-9/7-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4d][1.3 ]dioxol-4-yl)methyl)thio)methyl)benzoic acid (6.1).
[037] 5'-Acetiltio-5'-dezoksi-2',3'-O-izopropilidēnadenozīna (5) (0,11 g, 0,30 mmol) un metilm3-(bromometil)benzoskābes estera (76 mg, 0,33 mmol) šķīdumam sausajā metanolā (1,5 ml) argona atmosfērā -30 °C temperatūrā piepilināja nātrija metoksīda šķīdumu metanolā (5,4 M, 0,12 ml, 0,65 mmol). Šķīdumu maisa 1 stundu -30°C temperatūrā, tad istabas temperatūrā 3 stundas. Šķīdinātāju ietvaicē. Atlikumu atšķaida ar EtOAc, mazgā ar pies. NH4CI šķīdumu, ūdeni, pies. NaCl šķīdumu, žāvē virs bezūdens Na2SO4 un ietvaicē.[037] 5'-Acetylthio-5'-deoxy-2',3'-O-isopropylidene adenosine (5) (0.11 g, 0.30 mmol) and methyl m3-(bromomethyl)benzoic acid ester (76 mg, 0, 33 mmol) in dry methanol (1.5 mL) was added dropwise a solution of sodium methoxide in methanol (5.4 M, 0.12 mL, 0.65 mmol) under an argon atmosphere at -30 °C. The solution is stirred for 1 hour at -30°C, then at room temperature for 3 hours. The solvent is evaporated. The residue was diluted with EtOAc, washed with aq. NH4CI solution, water, add. NaCl solution, dried over anhydrous Na2SO4 and evaporated.
[038] Atlikumu hromatografe uz silikagela, eluents EtOAc:EtOH (3:1) - petrolejas ēteris, gradients 20-60 %, iegūst 90 mg starpprodukta ar piemaisījumiem, kuru uzreiz izmantoja nākamajā reakcijā. Šo jēlproduktu maisa ar LiOH (14 mg, 0,58 mmol) THF (2 ml) un ūdeni (1 ml) istabas temperatūrā 22 stundas. Šķīdinātāju ietvaicē un atlikumu izšķīdina ūdenī (3 ml), paskābina līdz pH 3 ar 1 N HC1. Produktu ekstrahē ar EtOAc (2 xl5 ml), mazgā ar ūdeni, pies. NaCl šķīdumu, žāvē virs bezūdens NazSO4 un ietvaicē. Atlikumu mazgā ar metanolu, žāvē vakuumā un iegūst 70 mg (50 %) produkta (6.1). Balta cieta viela.[038] Chromatography of the residue on silica gel, eluent EtOAc:EtOH (3:1) - petroleum ether, gradient 20-60%, yields 90 mg of an intermediate with impurities, which was immediately used in the next reaction. This crude product was stirred with LiOH (14 mg, 0.58 mmol) in THF (2 mL) and water (1 mL) at room temperature for 22 h. Evaporate the solvent and dissolve the residue in water (3 mL), acidify to pH 3 with 1 N HCl. The product was extracted with EtOAc (2 x 5 mL), washed with water, conc. NaCl solution, dried over anhydrous NazSO4 and evaporated. The residue is washed with methanol, dried under vacuum and 70 mg (50%) of the product (6.1) is obtained. A white solid.
[039]'H KMR (400 MHz, metanols-^) δ 8,24 (s, 1H), 8,15 (s, 1H), 7,92 (t, J= 1,5 Hz, 1H), 7,83 (dt, J= 7,7; 1,4 Hz, 1H), 7,37 (dt, J= 7,7; 1,6 Hz, 1H), 7,29 (t, J= Ί,Ί Hz, 1H), 6,12 (d, J = 2,4 Hz, 1H), 5,42 (dd, J= 6,4; 2,4 Hz, 1H), 4,94 (dd, J= 6,4; 3,2 Hz, 1H), 4,27 (td, J= 6,T, 3,2 Hz, 1H), 3,73 (s, 2H), 2,73 (dd, J= 13,8; 6,8 Hz, 1H), 2,66 (dd, J= 13,8; 6,6 Hz, 1H), 1,54 (s, 3H), 1,33 (s, 3H). 13C KMR (100 MHz, metanols-^) δ 169,6; 156,7; 152,9; 150,0; 142,2; 140,3; 134,5; 132,2; 131,1; 129,5; 129,4; 120,6; 115,5; 91,6; 88,2; 85,2; 85,1; 36,8; 34,5; 27,4; 25,5. HRMS (ESI/TOF-Q) m/z: [M + H]+ aprēķ. C22H24N5O5S, 458,1493; atrasts: 458,1500.[039]'H NMR (400 MHz, methanol-^) δ 8.24 (s, 1H), 8.15 (s, 1H), 7.92 (t, J= 1.5 Hz, 1H), 7 .83 (dt, J= 7.7; 1.4 Hz, 1H), 7.37 (dt, J= 7.7; 1.6 Hz, 1H), 7.29 (t, J= Ί,Ί Hz, 1H), 6.12 (d, J = 2.4 Hz, 1H), 5.42 (dd, J= 6.4; 2.4 Hz, 1H), 4.94 (dd, J= 6 ,4; 3.2 Hz, 1H), 4.27 (td, J= 6,T, 3.2 Hz, 1H), 3.73 (s, 2H), 2.73 (dd, J= 13, 8; 6.8 Hz, 1H), 2.66 (dd, J= 13.8; 6.6 Hz, 1H), 1.54 (s, 3H), 1.33 (s, 3H). 13 C NMR (100 MHz, methanol-^) δ 169.6; 156.7; 152.9; 150.0; 142.2; 140.3; 134.5; 132.2; 131.1; 129.5; 129.4; 120.6; 115.5; 91.6; 88.2; 85.2; 85.1; 36.8; 34.5; 27.4; 25.5. HRMS (ESI/TOF-Q) m/z: [M + H] + calcd. C22H24N5O5S, 458.1493; found: 458.1500.
[040] Savienojuma (1.5) iegūšana. Vispārīgā metode C.[040] Preparation of compound (1.5). General method C.
il)metil)tio)metil)benzoskābe (1.5).yl)methyl)thio)methyl)benzoic acid (1.5).
Acetonīdu (6.1) (70 mg, 0,15 mmol) izšķīdina ledus aukstajā HCOOH šķīdumā ūdenī (50 %, 1 ml) un maisa istabas temperatūrā 20 stundas. Šķīdinātāju ietvaicē, atlikumu aplej ar EtOH un ietvaicē. Atlikumu mazgā ar karstu metanolu, tad ar acetonitrilu, žāvē vakuumā un iegūst 46 mg (72 %) produkta (1.5). Balta cieta viela. AEŠH tīrība 91 %.Acetonide (6.1) (70 mg, 0.15 mmol) was dissolved in an ice-cold solution of HCOOH in water (50%, 1 mL) and stirred at room temperature for 20 h. The solvent is evaporated, the residue is quenched with EtOH and evaporated. The residue is washed with hot methanol, then with acetonitrile, dried in vacuo to give 46 mg (72 %) of the product (1.5). A white solid. AEŠH purity 91 %.
[041] Ή KMR (400 MHz, DMSO-ūk) δ 12,95 (br s, 1H), 8,33 (s, 1H), 8,12 (s, 1H), 7,89 (ī,J = 1,5 Hz, 1H), 7,80 (dt, J= 7,7; 1,5 Hz, 1H), 7,46 (dt, J= Ί,Ί-, 1,5 Hz, 1H), 7,39 (t, J = Ί,Ί Hz, 1H), 7,28 (s, 2H), 5,87 (d, J= 5,6 Hz, 1H), 5,48 (d, J = 6,0 Hz, 1H), 5,30 (d, J= 5,1 Hz, 1H), 4,73 (q, J=5,6 Hz, 1H), 4,18-4,13 (m, 1H), 4,01 (td, J= 6,4; 3,9 Hz, 1H), 3,82 (s, 2H), 2,84 (dd, J= 13,9; 5,9 Hz, 1H), 2,70 (dd, J= 13,9; 6,9 Hz, 1H). 13C KMR (100 MHz, DMSO-J6) δ 167,2; 156,1; 152,7; 149,4; 140,0; 139,2; 133,3; 131,0; 129,7; 128,6; 127,8; 119,2; 87,6; 83,6; 72,6; 72,5; 35,2; 33,4. HRMS (ESI/TOF-Q) m/z: [M + H]+ aprēķ. C18H20N5O5S, 418,1180; atrasts: 418,1189.[041] Ή NMR (400 MHz, DMSO-uc) δ 12.95 (br s, 1H), 8.33 (s, 1H), 8.12 (s, 1H), 7.89 (η,J = 1.5 Hz, 1H), 7.80 (dt, J= 7.7; 1.5 Hz, 1H), 7.46 (dt, J= Ί,Ί-, 1.5 Hz, 1H), 7 .39 (t, J = Ί,Ί Hz, 1H), 7.28 (s, 2H), 5.87 (d, J= 5.6 Hz, 1H), 5.48 (d, J = 6, 0 Hz, 1H), 5.30 (d, J= 5.1 Hz, 1H), 4.73 (q, J=5.6 Hz, 1H), 4.18-4.13 (m, 1H) , 4.01 (td, J= 6.4; 3.9 Hz, 1H), 3.82 (s, 2H), 2.84 (dd, J= 13.9; 5.9 Hz, 1H), 2.70 (dd, J= 13.9; 6.9 Hz, 1H). 13 C NMR (100 MHz, DMSO-J 6 ) δ 167.2; 156.1; 152.7; 149.4; 140.0; 139.2; 133.3; 131.0; 129.7; 128.6; 127.8; 119.2; 87.6; 83.6; 72.6; 72.5; 35.2; 33.4. HRMS (ESI/TOF-Q) m/z: [M + H] + calcd. C18H20N5O5S, 418.1180; found: 418.1189.
In vitro testiIn vitro tests
[042] Savienojumiem pārbaudīta Nspl4 and Nspl6 inhibitoru inhibitora aktivitāte in vitro atbilstoši aprakstītai procedūrai.[042] Compounds were tested for inhibitory activity of Nspl4 and Nspl6 inhibitors in vitro according to the described procedure.
[043] Methiltransferāzes aktvitāte noteikta ar EPIgeneous Methyltransferase Assay komplektu, kas mēra SAM konversiju SAH, atbilstoši ražotāja norādījumiem.[043] Methyltransferase activity was determined with the EPIgeneous Methyltransferase Assay kit, which measures the conversion of SAM to SAH, according to the manufacturer's instructions.
[044] Enzimātiskā reakcija veikta platēs ProxiPlate-384 Plus ar tilpumu 10 ml. Reakcijas buferis sastāvēja no 40 mM Tris-HCl pH 8,3 (pH 8,0 Nspl6) un 100 mM NaCl (vai 10 mM KC1 tikai Nspl6), 1 mM DTT, 2 mM MgCh, 0,01 % Tween20. Testa iedobēs, kas saturēja iepriekš izšķīdinātus inhibitorus pievieno 4 ml attīrīta rekombinantā proteīna Nspl4 ar 0,4 mM vai Nspl6 ar gala koncentrāciju 3 mM. Reakcija sākta ar 4 ml maisījuma, kas satur gan 4 mM GpppG (Jena Bioscience, kat.nr. NU854), gan ~5 μΜ m7GpppA-RNS (Nspl6 gadījumā) un SAM ar 10 mM gala koncentrāciju un inkubē 37 ° C 20 minūtes (2 stundas Nspl6).[044] The enzymatic reaction was performed in ProxiPlate-384 Plus plates with a volume of 10 ml. The reaction buffer consisted of 40 mM Tris-HCl pH 8.3 (pH 8.0 for Nspl6) and 100 mM NaCl (or 10 mM KC1 for Nspl6 only), 1 mM DTT, 2 mM MgCh, 0.01% Tween20. Add 4 ml of purified recombinant protein Nspl4 at 0.4 mM or Nspl6 at a final concentration of 3 mM to test wells containing pre-dissolved inhibitors. The reaction was started with 4 ml of a mixture containing both 4 mM GpppG (Jena Bioscience, cat. no. NU854) and ~5 μΜ m7GpppA-RNA (for Nspl6) and SAM at a final concentration of 10 mM and incubated at 37 °C for 20 min ( 2 hours Nspl6).
[045] Visi savienojumi izšķīdināti 100 % DMSO (0,1 % gala DMSO) un testēti 100 μΜ divos eksemplāros. IC50 vērtības tika noteiktas savienojumiem, kuru inhibējošā iedarbība pārsniedza 50 %.[045] All compounds were dissolved in 100% DMSO (0.1% final DMSO) and assayed at 100 μΜ in duplicate. IC50 values were determined for compounds with an inhibitory effect greater than 50%.
[046] Lai noteiktu atbrīvoto SAH daudzumu, reakcija tika apturēta pievienojot 2 ml EPIgēnu detektēšanas buferšķīduma. Pēc 10 min inkubēšanas istabas temperatūrā pievienoti detektēšanas reaģenti: vispirms 4 ml SAH-d2 konjugāta 1/16 atšķaidījumā, pēc tam 4 ml AntiSAH-Lumi4-Tb 1/100 atšķaidījumā. Homogēnās fluorescences ar izšķirtspēju laikā (HTRF) signāli reģistrēti, izmantojot Hidex Sense (Somija) ar ierosmes filtru pie 337 nm un fluorescences viļņa garuma mērījumiem pie 620 un 665 nm, integrācijas aizturi 150 ms un integrācijas laiku 400 ms.[046] To determine the amount of SAH released, the reaction was stopped by the addition of 2 ml of EPIgene detection buffer. After 10 min of incubation at room temperature, detection reagents were added: first 4 ml of SAH-d2 conjugate at 1/16 dilution, then 4 ml of AntiSAH-Lumi4-Tb at 1/100 dilution. Homogeneous time-resolved fluorescence (HTRF) signals were recorded using Hidex Sense (Finland) with excitation filter at 337 nm and fluorescence wavelength measurements at 620 and 665 nm, integration delay 150 ms and integration time 400 ms.
[047] Rezultāti tika analizēti, izmantojot divu viļņu garuma signāla attiecību: [intensitāte (665 nm)/intensitāte (620 nm)] * 104 (HTRF attiecība).[047] The results were analyzed using the signal ratio of the two wavelengths: [intensity (665 nm)/intensity (620 nm)] * 104 (HTRF ratio).
Vidējā HTRF attiecību katram paraugam tika aprēķināta sekojoši:The average HTRF ratio for each sample was calculated as follows:
Vidējais HTRF koeficients = vidējais parauga HTRF koeficients - tukšā HTRF attiecība, kur tukšais ir signāls ar savienojumu (vai DMSO kontrolparaugā) un Anti-SAH-Lumi4-Tb.Mean HTRF ratio = mean sample HTRF ratio - blank HTRF ratio, where the blank is the signal with compound (or DMSO in the control) and Anti-SAH-Lumi4-Tb.
[048] Inhibīcija procentos tika aprēķināta, izmantojot šādu formulu katram inhibitora atšķaidījumam:[048] Percent inhibition was calculated using the following formula for each inhibitor dilution:
Inhibīcija, % = 100-(maksimālā signāla komp. - minimālā signāla komp.) * 100/(maksimālā signāla kontrole - min. signāla kontrole), kur “maksimālais signāls” ir signāla attiecība bez olbaltumvielām (negatīvā kontrole) un “min. signāls” signāla attiecība izlasē. IC50 vērtība aprēķināta, izmantojot programmu Graph Pad Prism® 8.0.Inhibition, % = 100-(max signal comp. - min signal comp.) * 100/(max signal control - min. signal control), where “max signal” is the ratio of signal without protein (negative control) and “min. signal” signal ratio in sample. The IC50 value was calculated using Graph Pad Prism® 8.0.
[049] 1. Tabula Adenozilmerkaptāna atvasinājumu bioloģiskā aktivitāte:[049] Table 1 Biological activity of Adenosyl mercaptan derivatives:
Informācijas avotiSources of information
1. Decroly, et al. Nat. Rev. Microbiol. 2011, 10, 511. Decroly, et al. Nat. Rev. Microbiol. 2011, 10, 51
2. Bouvet, M et al. PLoS Pathog. 2010, 6, e 10008632. Bouvet, M et al. PLoS Pathog. 2010, 6, e 1000863
3. Decroly, E et al. PLoS Pathog. 2011, 7, el0020593. Decroly, E et al. PLoS Pathog. 2011, 7, el002059
4. Chen, Y. at al. Proc. Nati. Acad. Sci. USA 2009, 106, 34844. Chen, Y. at al. Proc. Nati. Acad. Sci. USA 2009, 106, 3484
5. Chen, Y. et al. J. Virol. 2013, 87, 62965. Chen, Y. et al. J. Virol. 2013, 87, 6296
6. Menachery, V. D. et al. J. Virol. 2014, 88, 42516. Menachery, V.D. et al. J. Virol. 2014, 88, 4251
7. Pugh, C. S. and Borchardt, R. T. Biochemistry 1982, 21, 15357. Pugh, C.S. and Borchardt, R.T. Biochemistry 1982, 21, 1535
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