FI118424B - Nukleinsyraanaloger och deras användning i diagnostiska och analytiska procedurer - Google Patents
Nukleinsyraanaloger och deras användning i diagnostiska och analytiska procedurer Download PDFInfo
- Publication number
- FI118424B FI118424B FI935208A FI935208A FI118424B FI 118424 B FI118424 B FI 118424B FI 935208 A FI935208 A FI 935208A FI 935208 A FI935208 A FI 935208A FI 118424 B FI118424 B FI 118424B
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- Finland
- Prior art keywords
- nucleic acid
- analogue
- hydrogen
- pna
- acid analogue
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- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 125000006853 reporter group Chemical group 0.000 description 1
- 239000012508 resin bead Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229940043230 sarcosine Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 238000011894 semi-preparative HPLC Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000003836 solid-state method Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 229940063673 spermidine Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 235000018553 tannin Nutrition 0.000 description 1
- 229920001864 tannin Polymers 0.000 description 1
- 239000001648 tannin Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- OWAMQHJPVUGZSB-UHFFFAOYSA-N tert-butyl n-(2,3-dihydroxypropyl)carbamate Chemical compound CC(C)(C)OC(=O)NCC(O)CO OWAMQHJPVUGZSB-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- ZEMGGZBWXRYJHK-UHFFFAOYSA-N thiouracil Chemical compound O=C1C=CNC(=S)N1 ZEMGGZBWXRYJHK-UHFFFAOYSA-N 0.000 description 1
- 229950000329 thiouracil Drugs 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Claims (36)
1. En nukleinsyreanalog för användning till uppfängning, konstatering, detektering, isolering, identifiering eller kvantifiering av en eller 5 flera kemiska eller mikrobiologiska helheter, kännetecknad av att analogen är en peptidnukleinsyra (PNA), där det i polyamidstommen som innefattas i denna finns otaliga ligander i motsvarande positioner som ligger längs nämnda stomme och pä nägot avständ frän varandra, varvid varje ligand oberoende av varandra är nukleobaser som förekommer i 10 naturen, nukleobaser som inte förekommer i naturen eller grupper som binder nukleobaser, och varvid varje ligand är direkt eller indirekt bunden tili en i stommen befintlig kväveatom och varvid huvudsakligen minst 4-8 intermediala atomer separerar dessa kväveatomer, i vilka den nämnda liganden ligger fast, frän varandra i denna stomme, varvid ett 15 detekterbart märke innefattas i nämnda analog eller är konjugerat med den.
2. En nukleinsyreanalog enligt patentkrav 1, kännetecknad av att envar av kväveatomerna, i vilka nämnda ligander ligger fast, i nämnda stomme 20 är azakväveatomer.
3. En nukleinsyreanalog för användning tili uppfängning, konstatering, detektering, isolering, identifiering eller kvantifiering av en eller flera kemiska eller mikrobiologiska helheter, kännetecknad av att • * .··*, 25 analogen är en nukleinsyreanalog som kan hybridisera sig tili en • · “*. nukleinsyra som innefattar en komplementär sekvens sä att det bildas en • · · *· *· hybrid som är stabilare mot denaturering under inverkan frän värme än en • · ·.· ; hybrid som har bildats frän nämnda nukleinsyra och en konventionell ·*·*; deoxiribonukleotid som motsvarar nämnda analog, varvid ett detekterbart • « 30 märke innefattas i nämnda analog eller är konjugerat tili den. • · ·
4. En nukleinsyreanalog för användning tili uppfängning, konstatering, • · ; detektering, isolering, identifiering eller kvantifiering av en eller ;***j flera kemiska eller mikrobiologiska helheter, kännetecknad av att * * * ,* 35 analogen är en nukleinsyreanalog som kan hybridisera sig tili en • · · *. *! dubbelsträngad.nukleinsyra, där sekvensen i en sträng är ett komplement *;**; som kompletterar den nämnda analogen sä att den andra strängen ,*, undanträngs frän nämnda ena sträng, varvid ett detekterbart märke • · · *·*·* innefattas i nämnda analog eller är konjugerat tili den. • · · 40 126 118424
5. En märkt nukleinsyreanalog enligt patentkrav l, kännetecknad av att den innefattar en nukleinsyra av den allmänna formeln: L' L2 L" I . I, I
5 A1 A2 An -B1 .0' B2 ,,C2-... J" ,1 ^C1 "D "C2 "D2 "“~cn "Dn där: n är minst 2, 10 varje L1-Ln har oberoende av varandra valts ur en grupp som bestär av väte, hydroxy, (Ci-C4)-alkanoyl, nukleobaser som förekommer i naturen, nukleobaser som inte förekommer i naturen, aromatiska grupper, DNA-mellangrupper, grupper som binder nukleobaser och reporterligander sä att minst en av symbolerna L1-Ln avser en nukleobas som förekommer i 15 naturen, en nukleobas som inte förekommer i naturen, en DNA-mellangrupp eller en grupp som binder nukleobaser; varje A1-An är en enkel bindning, en metylengrupp eller en grupp med formeln: 20 [Ri ri1 r $-1] r r1] --C--Y--C--eller--<:--y--<;--1— R2 R2 ft2 r2 LJpLJq LJrlJ£ • » C!: 25 där: :/.: X är O, S, Se, NR3, CH2 eller C(CH3)2; j ;*· Y är en enkel bindning, o, S eller NR4; IM · !*.*. säväl p som g är ett heltal i intervallet 1-5, varvid summan p+q är *..I högst 10; • · · • * · • 30 säväl r som s är noll eller ett heltal i intervallet 1-5, varvid summan r+s är högst 10; ·· I ** säväl R1 som R2 har oberoende av varandra valts ur en grupp som bestär av • · m väte, en (C1-C4)-alkyl som eventuellt har substituerats med hydroxy eller alkoxy eller alkyltio, hydroxy, alkoxy, alkyltio, amino och halogen; och · a *,* 35 säväl R3 som R4 har oberoende av varandra valts ur en grupp som bestär av • · *·“* väte, (C1-C4)-alkyl, en (Cx-Ci)-alkyl som har substituerats med hydroxy ·*·*; eller alkoxy eller alkyltio, hydroxy, alkoxy, alkyltio och amino; • · .*# : varje B1-Bn är N eller R3N+, där R3 är enligt den ovan framförda • «· definitionen; 127 118424 varje C^-C" är CR6R7< CHR6CHR7 eller CR6R7CH2, där R6 är väte och R7 har valta ur en grupp som bestir av sidokedjor pi alfa-aminosyror som förekommer i naturen eller R6 och R7 har oberoende av varandra valta ur en grupp som bestir av vite, (C2-C6)-alkyl, aryl, aralkyl, heteroaryl, 5 hydroxy, (C!-C6)-alkoxy, (Ci-C6) alkyltio, NR3R4 och SR5, i vilka formler R3 och R4 är enligt de ovan framförda definitionerna, och R5 ar väte, en (C!-C6) -alkyl, en (Ci-C6) -alkyl som substituerats med hydroxy, alkoxy eller alkyltio, eller R6 och R7 tillsammans kompletterar ett subcykliskt eller heterocykliskt system; 10 varje tf-TP kr CR6R7, CH2CR6R7 eller CHR6CHR7, där R6 och R7 är enligt de ovan framförda definitionerna; varje G1-Gnl är -CONR3-, -CSNR3-, -SONR3- eller -S02NR3-orienterad pa nigotdera godtyckligt sätt, och i vilka formler R3 är enligt den ovan framförda definitionen;
15 Q är -C02H, -CONR1R", -S03H eller -S02NR'R" eller ett aktiverat derivat av gruppen -C02H eller -S03H; och I är -NHR" 'R"" eller -NR"'C(0)R"", i vilka formler R', R", R'" och R"" har oberoende av varandra valts ur en grupp som bestir av väte, alkyl, aminoskyddande grupper, reporterligander, mellangrupper, kelatbildare, 20 peptider, proteiner, kolhydrater, lipider, steroider, oligonukleotider samt lösliga och olösliga polymerer, varvid ett detekterbart märke innefattas i nämnda analog eller är , , konjugerat till den. • · » • · · • · ··· *...· 25 6. En märkt nukleinsyreanalog enligt patentkrav 1, kännetecknad av att • * ·Β*·ϊ den innefattar en nukleinsyreanalog med den allmänna formeln: t · ::v }' l1 L" : V I , I I A1 a2 !n
30. I I I 1 g2 λ 2 n I [·.. c O’ "C2' 'D2'0 ""—-c"' Ό"' * · » : : där: ··· • · 1 n ·· varje A -a ar en enkel bindning eller en grupp med formeln: • * · 35 ··:·· f?1] f f1] C f] r ?i] .·. ; --<---Y--<:--eller--C--γ--c--1— • ♦· • · A2 A2 - A2 A2 P Jq L J r L J s 128 118424 n, varje L1-!/1, X, Y, p, q, r och s är säsom har definierats i patentkrav 5, säväl R1 som R2 har oberoende av varandra valts ur en grupp som bestär av väte, (Cx-C*) -alkyl som eventuellt har substituerats med hydroxy eller 5 alkoxy, hydroxy, alkoxy, amino och halogen; och säväl R3 som R4 har oberoende av varandra valts ur en grupp som bestir av väte, (C3.-C4) -alkyl, en (^-04)-alkyl som har substituerats med hydroxy eller alkoxy, hydroxy, alkoxy och amino,· varje B1-Bn är N eller R3N% där R3 är enligt den ovan framförda 10 definitionen; varje C^-C" är CR6R7, CHR6CHR7 eller CR6R7CH2, där R6 är väte och R7 har valts ur en grupp som bestär av sidokedjor pä alfa-aminosyror som förekommer i naturen, eller R6 och R7 har oberoende av varandra valts ur en grupp som bestär av väte, (C2-C6)-alkyl, aryl, aralkyl, heteroaryl, 15 hydroxy, metoxy NR3R4 och SR5, i vilka formler R3 och R4 är enligt de ovan framförda definitionerna, och R5 är väte, (Ci-C6) -alkyl, en (C!-C6)-alkyl som substituerats med hydroxy eller alkoxy, eller R6 och R7 tillsammans kompletterar ett subcykliskt system; varje D1-Dn är CH2CR6R7 eller CHR6CHR7, där R6 och R7 är enligt de ovan 20 framförda definitionerna; varje G1-Gn"1 är säsom har definierats i patentkrav 5, som innefattar ett detekterbart märke eller i vilket har konjugerats ett detekterbart märke. • » « · # # · · • · ·"**: 25 7. En märkt nukleinsyreanalog enligt patentkrav 6, kännetecknad av att ··· : den innefattar en nukleinsyreanalog med den allmänna formeln: • · • · r— • · · :.: : l l ·· · I I • · · I I • · I I ·*:*· ®sS. j^(CH2)| O I’*.. R* . <· (CH2)k N ^(CH2)m --(CH2)k .N ^(CH2)m V Y Yr Y Yh-r ··:·· IT H T :V: or7' R7' • * :: L _l n ··· .*!*. där: • · · * *. varje L har oberoende av varandra valts ur en grupp som bestär av väte, • ·· * * 30 fenyl, nukleobaser som förekommer i naturen och nukleobaser som inte förekommer i naturen; 129 118424 varje R7' har oberoende av varandra valts ur en grupp som bestär av väte och sidokedjor pä alfa-aminosyror som förekommer i naturen; n är ett heltal i intervallet 1-60; säväl k som m oberoende av varandra är noll eller ett; och varje I 5 oberoende av varandra är i intervallet 0-5; Rh är OH, NH2 eller -NHLysNH2; och R1 är H eller COCH3, som innefattar ett detekterbart märke eller i vilket har konjugerats ett detekterbart märke. 10
8. En märkt nukleinsyreanalog enligt patentkrav 7, kännetecknad av att den innefattar en nukleinsyreanalog med den allmänna formeln: L
15 J 0\ J jV jV R7 R7 20 L J n där; L, R1' och n är säsom har definierats i patentkrav 7, som innefattar ett detekterbart märke eller i vilket har konjugerats ett detekterbar märke. • · • · · • ♦ · • · ,···. 25 9. En märkt nukleinsyreanalog enligt patentkrav 8, kännetecknad av att • * ***. varje L oberoende av varandra har valts ur en grupp som bestär av • · · • *· nukleobaserna tyrnin, adenin, cytosin, guanin och urasil; • Φ ·,* · varje R7' är väte; och ·*·*; n är ett heltal i intervallet 1-30. *·.* 30 • * · • · · • 10. En märkt nukleinsyreanalog enligt nägot av ovan nämnda patentkrav, kännetecknad av att märket är ett radioisotopiskt märke, ett enzymmärke, • · • · j biotin, en fluorofor, ett kemiluminescensmärke, en antigen, en antikropp ·1· eller ett spin-märke. *·# Ä 35 • e • · m *. *! 11. En märkt nukleinsyreanalog enligt patentkrav 1, 2 eller nägot av *"*ϊ patentkraven 5-10, kännetecknad av att nämnda ligander är tyrnin ,*, och/eller cytosin. • · • · · • * • t • « *«· 118424 130
12. Användning in vitro av en nukleinsyreanalog för uppfängning, konstatering, detektering, isolering, identifiering eller kvantifiering av en eller flera kemiska eller mikrobiologiska helheter, kännetecknad av att nukleinsyreanalogen är en peptidnukleinsyra (PNA), där det i 5 polyamidstommen som innefattas i denna finns otaliga ligander i motsvarande positioner som ligger längs nämnda stomme och pä nägot avständ frän varandra, varvid varje ligand oberoende av varandra är nukleobaser som förekommer i naturen, nukleobaser som inte förekommer i naturen eller grupper som binder nukleobaser, och varvid varje ligand är 10 direkt eller indirekt bunden tili en i stommen befintlig kväveatom och varvid huvudsakligen minst 4-8 intermediala atomer separerar dessa kväveatomer, i vilka den nämnda liganden ligger fast, frän varandra i denna stomme.
13. Användning enligt patentkrav 12, kannetecknad av att envar av kväveatomerna, i vilka nämnda ligander ligger fast i nämnda stomme, är azakväveatomer.
14, Användning in vitro av en nukleinsyreanalog för uppfängning, 20 konstatering, detektering, isolering, identifiering eller kvantifiering av en eller flera kemiska eller mikrobiologiska helheter, kännetecknad av att nukleinsyreanalogen är en nukleinsyreanalog som kan hybridisera sig tili en nukleinsyra som innefattar en komplementär sekvens sk att • 1 2 2 2 det bildas en hybrid som är stabilare mot denaturering under inverkan • · 25 frän värme än en hybrid som har bildats frän nämnda nukleinsyra och en • 1 • , konventionell deoxiribonukleotid som motsvarar nämnda analog. ! · · • Il • 1 · • « a J.2 1 15. Användning in vrtro av en nukleinsyreanalog för uppfängning, ·· · ; · ; konstatering, detektering, isolering, identifiering eller kvantifiering • » 30 av en eller flera kemiska eller mikrobiologiska helheter, kännetecknad · · av att nukleinsyreanalogen är en nukleinsyreanalog som kan hybridisera sig tili en dubbelsträngad nukleinsyra, där sekvensen i en sträng är ett ;,· ; komplement som kompletterar den nämnda analogen sä att den andra : 2 3· strängen undanträngs frän nämnda ena sträng. ··« • 35 • · • · · *· 1ί 16. Användning.av en nukleinsyreanalog enligt nägot av patentkraven 12- ♦ *"1J 15, kännetecknad av att nukleinsyran har den allmänna formeln: · • · · • · · 2 • · 3 i : 40 • I· ~v 131 118424 l' F2 L"
1. I A1 A2 a" 1 1 1 i2 | . Q\ ,'B ,"B 2-g2*-~ -Βπ -I
5. D ^C2 "02 ~~"Cn vDn där: n är ätminstone 2, varje L1-!/1 har oberoende av varandra valts ur en grupp som bestir av 10 väte, hydroxy, (Ci-C*)-alkanoyl, nukleobaser som förekommer i naturen, nukleobaser som inte förekommer i naturen, aromatiska grupper, DNA-mellangrupper, grupper som binder nukleobaser och reporterligander si att minst en av symbolerna L1-Ln avser en nukleobas som förekommer i naturen, en nukleobas som inte förekommer i naturen, en DNA-mellangrupp 15 eller en grupp som binder nukleobaser; varje A1-An är en enkel bindning, metylengrupp eller grupp med formeln: ' Rlj Γ Rl] [ Ϋ Ϋ — --γ— -c--eller--y--Y--r--^—
20. I r2 k.2 R2 r2 L ip L -lq L Jr L Js där: • · \V X är O, S, Se, NR3, CH2 eller C(CH3)2; #** ί#β#ϊ 25 Y är en enkel bindning, O, S eller NR4; säväl p som q är ett heltal i intervallet 1-5, varvid summan p+q är Ϊ högst 10; • a* a ··.·. säväl r som s är noli eller ett heltal i intervallet 1-5, varvid summan a a r+s är högst 10; a a a • 30 säväl R1 som R2 har oberoende av varandra valts ur en grupp som bestär av väte, en (C1-C4)-alkyl som eventuellt har substituerats med hydroxy aa ; *·· eller alkoxy eller alkyltio, hydroxy, alkoxy, alkyltio, amino och ; *j halogen; och aaa säväl R3 som R4 har oberoende av varandra valts ur en grupp som bestär av *#* 35 väte, (Ci-C4) -alkyl, en (C1-C4)-alkyl som har substituerats med hydroxy • a *···* eller alkoxy eller alkyltio, hydroxy, alkoxy, alkyltio och amino; ·*·*· varje Bl-B" är N eller R3N+, där R3 är enligt den ovan framförda a a .·. · definitionen; • «a varje C^-C" är CR6R7, CHR7CHR7 eller CR6R7CH2, där R6 är väte och R7 har 1 valts ur en grupp som bestär av sidokedjor pä alfa-aminosyror som 132 118424 förekommer i naturen eller R6 och R7 har oberoende av varandra valts ur en grupp som bestär av väte, (C2-C6)-alkyl, aryl, aralkyl, heteroaryl, hydroxy, (Cx-C6)-alkoxy, (Cx-C6) alkyltio, NR3R4 och SR5, i vilka formler R3 och R4 är enligt de ovan framförda definitionerna, och R5 är väte, (Cx-5 C6) -alkyl, en (Cx-C6) -alkyl som substituerats med hydroxy, alkoxy eller alkyltio eller Rs och R7 tillsammans kompletterar ett subcykliskt eller heterocykliskt system; varje D1-Dn är CRSR7, CH2CR6R7 eller CHR6CHR7, där R6 och R7 är enligt de ovan framförda definitionerna; 10 varje G1-Gn'1 är -CONR3-, -CSNR3-, -SONR3- eller -S02NR3- orienterad pä nägotdera godtyckligt sätt, och i vilka formler R3 är enligt den ovan framförda definitionen; Q är -C02H, -CONR'R", -S03H eller -S02NR'R" eller ett aktiverat derivat av gruppen -C02H eller -S03H; och
15 I är -NHR" 'R" " eller -NR" ’C(O)R"", i vilka formler R', R" , R" ' och R"" har oberoende av varandra valts ur en mängd som bestär av väte, alkyl, aminoskyddande grupper, reporterligander, mellangrupper, kelatbildare, peptider, proteiner, kolhydrater, lipider, steroider, oligonukleotider samt lösliga och olösliga polymerer. 20
17. Användning enligt nägot av patentkraven 12-15, kännetecknad av att nukleinsyreanalogen har den allmänna formeln: *:0 L1 L2 ·12· I I I - ·...· 25 A1 A2 A : Q. X1 .G1 2.B2 2.G2—_ Λη _.l Xc1 vd "c2 V -c d • » · • · ··· där: • · · • · f 30 varje Al-A" är en enkel bindning, eller en grupp med formeln: *“1· Γ Γ T R1" Λ --C- -Y- -c--eller--C- -Y- -t--Ϊ— • · · • · i3: 35 Ä2 r2 r2 r2 ... LjpLJq L Jr L Js 5, Φ • · · • ♦ « 2 « · S n, varje L1-!,11, X, Y, p, q, r och s är säsom har definierats i patentkrav 3 • · 133 118424 siväl R1 sorti R2 har oberoende av varandra valts ur en grupp som bestir av väte, en (C1-C4)-alkyl som eventuellt har substituerats med hydroxy eller alkoxy, hydroxy, alkoxy, amino och halogen; ooh siväl R3 som R4 har oberoende av varandra valts ur en grupp som bestir av 5 väte, {C1-C4)-alkyl, en (Ci-C^)-alkyl som har substituerats med hydroxy eller alkoxy, hydroxy, alkoxy och amino; varje Bl-B" är N eller R3N*, där R3 är enligt den ovan framförda definitionen; varje C^-C" är CRSR7, CHRSCHR7 eller CR6R7CH2, där R6 är väte och R7 har 10 valts ur en grupp som bestir av sidokedjor pi alfa-aminosyror som förekommer i naturen eller R6 och R7 har oberoende av varandra valts ur en grupp som bestir av väte, (C2-C6)-alkyl, aryl, aralkyl, heteroaryl, hydroxy, metoxy NR3R4 och SR5, i vilka formler R3 och R4 är enligt de ovan framförda definitionerna, och R5 är väte, (Ci-C6) -alkyl, en (Cx-C6)-alkyl 15 som substituerats med hydroxy eller alkoxy eller R6 och R7 tillsammans kompletterar ett subcykliskt system; varje D1-D" är CH2CR6R7 eller CHR6CHR7, där R6 och R7 är enligt de ovan framförda definitionerna; varje G^G"'1 är sisom har definierats i patentkrav 5. 20
18. Användning av en nukleinsyreanalog enligt patentkrav 16, kännetecknad av att nukleinsyreanalogen är av den allmänna formeln: . . L L !ϊ·: I I :***: 0. /(Ch2), o. .(ch2), • « · I • ·· I • · I j.:*: RY ,(ch2)k .n ^(CH2)m J--(CH2)k .n ^(CH2)m Γ·;: YyV H Y ^ :T: or7' R7' _ _J n • * • · ♦ • · · ··· · .··*. 25 där: * · • varje L har oberoende av varandra valts ur en grupp som bestir av väte, * · •t*·· fenyl, nukleobaser som förekommer i naturen och nukleobaser som inte ····· förekommer i naturen; • varje R7' har oberoende av varandra valts ur en grupp som bestir av väte i · · ·.**· 30 och sidokedjor pä alfa-aminosyror som förekommer i naturen; } J n är ett heltal i intervallet 1-60; ··· 118424 134 säväl k som m oberoende av varandra är noll eller ett; och varje I oberoende av varandra ar i intervallet 0-5; Rh är OH, NHZ eller -NHLysNH2; och R‘ är H eller COCH3. 5
19. Användning av en nukleinsyreanalog enligt patentkrav 18, kännetecknad av att nukleinsyreanalogen har den allmänna formeln: * Jv «V R7' R7' 15 L J n där: L, R7' och n är säsom har definierats i patentkrav 7.
20. Användning enligt patentkrav 19, kännetecknad av att 20 varje L har oberoende av varandra valts ur gruppen bestäende av nukleobaserna tyrnin, adenin, cytosin, guanin och urasil; varje R7' är väte; och n är ett heltal i intervallet 1-30. • · • · · * · · • · ,*··. 25 21. Användning av en nukleinsyreanalog enligt patentkrav 12, 13 eller • · ***# nägot av patentkraven 16-20, kännetecknad av att nämnda ligander är » · · *· *· tyrnin och/eller cytosin. • * • · · • t · IM · **·*· 22. Anvandning av en nukleinsyreanalog enligt nägot av patentkraven 12- • · _ *** 30 21, kännetecknad av att nukleinsyreanalogen innefattar ett detekterbart • · · * märke eller att ett detekterbart märke har konjugerats i den. • · jtj j 23. Användning av en nukleinsyreanalog enligt patentkrav 22, .***. kännetecknad av att märket är ett radioisotopiskt märke, ett enzymmärke, ··· • 35 biotin, en fluorofor, ett kemiluminescensmärke, en antigen, antikropp • · · •# #J eller spin-märke. e • ·
24. In vitro-metod för uppfängning av en nukleinsyra, kännetecknad av • * · *·*·* att nukleinsyran bringas i kontakt under hybridiserande förhällanden med • M 40 en i en fast bärare immobiliserad nukleinsyreanalog enligt nägot av 118424 135 patentkraven 12-23, vilken nukleinsyreanalog innefattar en sekvens av ligander som är lämplig för hybridisering tili nämnda nukleinsyra.
25. Metod enligt patentkrav 24, kännetecknad av att den uppfängande 5 nukleinsyran detekteras, konstateras, kvantifieras eller identifieras genom att den behandlas med ett ämne som identifierar nukleinsyran dä den är bunden tili den immobiliserade nukleinsyreanalogen.
26. Metod enligt patentkrav 25, kännetecknad av att den uppfängande 10 nukleinsyran omfattar ett första omräde, som har hybridiserat sig med den immobiliserade nukleinsyreanalogen, sarat ett andra omräde, som inte har hybridiserat sig pä sä sätt, och som behandlas med en märkt nukleinsyra eller en märkt nukleinsyreanalog, som är anpassad för att hybridisera sig tili minst nägon del i detta andra omräde och nämnda 15 märke detekteras.
27. Metod enligt patentkrav 24 för uppfängande av mRNA, kännetecknad av att den immobiliserade nukleinsyreanalogen innefattar sekventiella ligander, som kan hybridisera sig tili poly-A-svansar i detta mRNA för 20 uppfängning av mRNA.
28. Metod enligt patentkrav 24, kännetecknad av att de sekventiella liganderna är tyrnin. • · • ft · • · · • ft .···, 25 29. Metod enligt nägot av patentkraven 24 eller 27 eller 28, • ft *** kännetecknad av att den redan uppfängande nukleinsyran befrias ur en * · · *· *· immobiliserad nukleinsyreanalog genom att ställa den immobiliserade • · •#j · nukleinsyreanalogen och den uppfängande nukleinsyran under **«*j dehybridiserande förhällanden. 3o • · · • ♦ e
30. En nukleinsyreanalog definierad i nägot av patentkraven 12-23, kännetecknad av att den har immobiliserats i en fast bärare. • ft • · ft ft · • ft* ft ·***· 31. En immobiliserad nukleinsyreanalog enligt patentkrav 30, *·· • Jo kännetecknad av att har inkluderats i en fängslande kolumn baserad pä • · ·,*·; affinitet. • ·
32. In vitro-metod för konstatering, detektering eller kvantifiering av • · · *·*·* mälnukleinsyra, kännetecknad av att mälnukleinsyran hybridiseras tili en • ft· 40 märkt nukleinsyreanalog enligt patentkraven 1-11 som har en tillräckligt 118424 136 kompletterande komplementär sekvens för att kunna hybridi3era sig till mälnukleinsyran under hybridiserande förhällanden, varefter det i den till mälnukleinsyran sälunda hybridiserade nukleinsyreanalogen befintliga market detekteras och kvantifieras. 5
33. En metod enligt patentkrav 32, känneteeknad av att mälnukleinsyran har före hybridiseringen immobilisera.ts till ett substrat.
34. En metod enligt patentkrav 33, känneteeknad av att mälnukleinsyran 10 har immobiliserats till substratet genom hybridisering av ett däri ingäende första omräde till en fängslande nukleinsyra eller nukleinsyreanalog som har en tillräckligt kompletterande komplementär sekvens för att den skall kunna hybridisera sig därtill, och som för sin del själv är immobiliserad i detta substrat, och att denna märkta 15 nukleinsyreanalog hybridiserar sig tili ett andra omräde i mälnukleinsyran.
35. In vitro-metod för undanträngning av en sträng frän en nukleinsyraduplex, känneteeknad av att tili denna nukleinsyraduplex 20 hybridiseras en sädan nukleinsyreanalog enligt patentkrav 3 som relativt den andra strängen i denna nukleinsyraduplex har tillräcklig affinitet för att kunna undantränga en sträng ur den. ·1·2· 36. In vitro-metod för detektering, identifiering eller kvantifiering av • · ··· 25 en dubbelsträngad mälnukleinsyra, känneteeknad av att tili den • · ***t hybridiseras en sädan undanträngande nukleinsyreanalog enligt patentkrav • · · *· 1i 3, som kan undantränga en sträng ur den dubbelsträngade mälnukleinsyran, • · j vars andra sträng har en komplementär sekvens som kompletterar “·2· nukleinsyreanalogen som undantränger denna, varvid den undanträngande ♦ ·1 ··· 30 nukleinsyreanalogen innefattar en komplementär sekvens som tillräckligt • · · * kompletterar den andra strängen i den dubbelsträngade mälnukleinsyran för att kunna hybridisera sig tili denna sä att nämnda första sträng i • 2 • : ΐ mälnukleinsyran undanträngs därifrän i ensträngad form, varefter ··· · 3. närvaron av denna första undanträngda sträng detekteras eller ··· Λ g * 35 kvantifieras. • « • · ♦ • M • · ····· 37. En metod enligt patentkrav 36, känneteeknad av att den undanträngda * strängen spjälks i styeken, vars närvaro detekteras. • m · • · · • · · 2 • · 3 ··♦ 137 1 1 8424
38. En metod enligt patentkrav 37, kännetecknad av att den undanträngda strängen spjälks genom att den behandlas med ett nukleas.
39. Användning av en oligonukleotidsyreanalog för detektering eller 5 isolering in vitro av en specifik nukleinsyra, kännetecknad av att oligonukleotidanalogen binder sig starkare till dess komplementära ssDNA- eller RNA-strang an till respektive motsvarande DNA eller RNA.
40. En reagensförpackning som är brukbar vid diagnostiska ätgärder, 10 kännetecknad av att den innefattar minst en märkt nukleinsyreanalog enligt patentkraven 1-11 samt minst en detekterbar reagens för detektering av den märkta nukleinsyreanalogen.
41. En reagensförpackning enligt patentkrav 40, kännetecknad av att den 15 dessutom innefattar en nukleinsyreanalog enligt nägot av patentkraven 12-20, som har immobiliserats i en fast bärare.
42. En reagensförpackning, kännetecknad av att den innefattar en immobiliserad nukleinsyreanalog enligt patentkrav 30 som är kombinerad 20 med minst ett ämne som identifierar nukleinsyra, under användning av en nukleinsyreanalog för detektering av närvaron av en uppfängande nukleinsyra. ·***. 43. En reagensförpackning enligt patentkrav 42, kännetecknad av att ··· 25 ämnet som identifierar nukleinsyran är en märkt nukleinsyra eller en • · *·· märkt nukleinsyreanalog. • 1 • 4« • · • ft • · · • · 1 ··· · 14 · • · « • · • · ··» • · · Φ · · * • 4 • 4 « • · # 44| · 444 » · • · ·1· • • · · 4 ·· * 1 · « ♦ · 4 4 4 4 4| • · 444 • · • · «··
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DK98791A DK98791D0 (da) | 1991-05-24 | 1991-05-24 | Fremgangsmaade til sekvensspecifik genkendelse af et dobbeltstrenget polynucleotid |
DK98691A DK98691D0 (da) | 1991-05-24 | 1991-05-24 | Oligonucleotid-analoge betegnet pna, monomere synthoner og fremgangsmaade til fremstilling deraf samt anvendelser deraf |
DK98791 | 1991-05-24 | ||
DK98691 | 1991-05-24 | ||
DK92510A DK51092D0 (da) | 1991-05-24 | 1992-04-15 | Oligonucleotid-analoge betegnet pna, monomere synthoner og fremgangsmaade til fremstilling deraf samt anvendelser deraf |
DK51092 | 1992-04-15 | ||
PCT/EP1992/001220 WO1992020703A1 (en) | 1991-05-24 | 1992-05-22 | The use of nucleic acid analogues in diagnostics and analytical procedures |
EP9201220 | 1992-05-22 |
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FI935208A FI118424B (sv) | 1991-05-24 | 1993-11-23 | Nukleinsyraanaloger och deras användning i diagnostiska och analytiska procedurer |
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EP (5) | EP1411063B1 (sv) |
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AT (3) | ATE515569T1 (sv) |
AU (2) | AU666480B2 (sv) |
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CA (2) | CA2109805A1 (sv) |
DE (2) | DE69232055T2 (sv) |
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ES (2) | ES2107552T3 (sv) |
FI (1) | FI118424B (sv) |
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1992
- 1992-04-15 DK DK92510A patent/DK51092D0/da not_active Application Discontinuation
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- 1992-05-22 WO PCT/EP1992/001219 patent/WO1992020702A1/en active IP Right Grant
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- 1992-05-22 DK DK92923579.4T patent/DK0586618T3/da active
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- 1992-05-22 EP EP00203148A patent/EP1074559B1/en not_active Expired - Lifetime
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1993
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1994
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1995
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2001
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2002
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2003
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2005
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2007
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2008
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