JP6302909B2 - シアリダーゼの同定および画像化のための細胞透過性プローブ - Google Patents
シアリダーゼの同定および画像化のための細胞透過性プローブ Download PDFInfo
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- JP6302909B2 JP6302909B2 JP2015527678A JP2015527678A JP6302909B2 JP 6302909 B2 JP6302909 B2 JP 6302909B2 JP 2015527678 A JP2015527678 A JP 2015527678A JP 2015527678 A JP2015527678 A JP 2015527678A JP 6302909 B2 JP6302909 B2 JP 6302909B2
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- YBKWIGSMABMNJZ-UHFFFAOYSA-N s-(2,3,4,5,6-pentachlorophenyl)thiohydroxylamine Chemical compound NSC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl YBKWIGSMABMNJZ-UHFFFAOYSA-N 0.000 description 1
- RTKRAORYZUBVGQ-UHFFFAOYSA-N s-(2,4-dinitrophenyl)thiohydroxylamine Chemical compound NSC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O RTKRAORYZUBVGQ-UHFFFAOYSA-N 0.000 description 1
- LOVVSIULYJABJF-UHFFFAOYSA-N s-(2-nitrophenyl)thiohydroxylamine Chemical compound NSC1=CC=CC=C1[N+]([O-])=O LOVVSIULYJABJF-UHFFFAOYSA-N 0.000 description 1
- BDEZGPKAMAVGBE-UHFFFAOYSA-N s-(3-nitropyridin-2-yl)thiohydroxylamine Chemical compound NSC1=NC=CC=C1[N+]([O-])=O BDEZGPKAMAVGBE-UHFFFAOYSA-N 0.000 description 1
- LOFZYSZWOLKUGE-UHFFFAOYSA-N s-benzyl carbamothioate Chemical compound NC(=O)SCC1=CC=CC=C1 LOFZYSZWOLKUGE-UHFFFAOYSA-N 0.000 description 1
- MAGSSGQAJNNDLU-UHFFFAOYSA-N s-phenylthiohydroxylamine Chemical compound NSC1=CC=CC=C1 MAGSSGQAJNNDLU-UHFFFAOYSA-N 0.000 description 1
- PIDYQAYNSQSDQY-UHFFFAOYSA-N s-tritylthiohydroxylamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(SN)C1=CC=CC=C1 PIDYQAYNSQSDQY-UHFFFAOYSA-N 0.000 description 1
- BPELEZSCHIEMAE-UHFFFAOYSA-N salicylaldehyde imine Chemical compound OC1=CC=CC=C1C=N BPELEZSCHIEMAE-UHFFFAOYSA-N 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000013515 script Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 239000004054 semiconductor nanocrystal Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 201000001223 septic arthritis Diseases 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 125000005629 sialic acid group Chemical group 0.000 description 1
- 125000005630 sialyl group Chemical group 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- COIVODZMVVUETJ-UHFFFAOYSA-N sulforhodamine 101 Chemical compound OS(=O)(=O)C1=CC(S([O-])(=O)=O)=CC=C1C1=C(C=C2C3=C4CCCN3CCC2)C4=[O+]C2=C1C=C1CCCN3CCCC2=C13 COIVODZMVVUETJ-UHFFFAOYSA-N 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- SFZCNBIFKDRMGX-UHFFFAOYSA-N sulfur hexafluoride Chemical compound FS(F)(F)(F)(F)F SFZCNBIFKDRMGX-UHFFFAOYSA-N 0.000 description 1
- 229960000909 sulfur hexafluoride Drugs 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 201000010740 swine influenza Diseases 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- GZCRRIHWUXGPOV-UHFFFAOYSA-N terbium atom Chemical compound [Tb] GZCRRIHWUXGPOV-UHFFFAOYSA-N 0.000 description 1
- XKXIQBVKMABYQJ-UHFFFAOYSA-M tert-butyl carbonate Chemical compound CC(C)(C)OC([O-])=O XKXIQBVKMABYQJ-UHFFFAOYSA-M 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- NBAOBNBFGNQAEJ-UHFFFAOYSA-M tetramethylrhodamine ethyl ester perchlorate Chemical compound [O-]Cl(=O)(=O)=O.CCOC(=O)C1=CC=CC=C1C1=C2C=CC(=[N+](C)C)C=C2OC2=CC(N(C)C)=CC=C21 NBAOBNBFGNQAEJ-UHFFFAOYSA-M 0.000 description 1
- JGVWCANSWKRBCS-UHFFFAOYSA-N tetramethylrhodamine thiocyanate Chemical compound [Cl-].C=12C=CC(N(C)C)=CC2=[O+]C2=CC(N(C)C)=CC=C2C=1C1=CC=C(SC#N)C=C1C(O)=O JGVWCANSWKRBCS-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- UIERETOOQGIECD-ONEGZZNKSA-N tiglic acid Chemical compound C\C=C(/C)C(O)=O UIERETOOQGIECD-ONEGZZNKSA-N 0.000 description 1
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BZVJOYBTLHNRDW-UHFFFAOYSA-N triphenylmethanamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(N)C1=CC=CC=C1 BZVJOYBTLHNRDW-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
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- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
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- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/12—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
- C12N9/2402—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1)
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Description
本発明は、シアリダーゼの診断および画像化の分野に関する。具体的には、本発明は、ウイルス、細菌、および哺乳動物シアリダーゼに不可逆的に結合する標的特異的化合物に関する。より具体的には、本発明は、シアリダーゼの活性部位に共有結合的に結合し、診断および治療機能に有用である化合物に関する。
シアリダーゼは、ノイラミニダーゼ(NA)とも呼ばれ、複合糖質のオリゴサッカライド由来の末端シアル酸残基の加水分解を触媒するエキソグリコシダーゼである。シアリダーゼは、様々な機能に関して広く発現される(R. K. Y. M. Saito、Biochemistry and function of sialidases、Plenum Press:New York、1995年)。多くの病原体、例えば、ウイルス、細菌、および原生動物などが、浸潤、栄養、脱離、および免疫回避のためにシアリダーゼを産生する(E. Severiら、Microbiology、2007年、153巻、2817頁)。
(式中、
C3位のF原子は、アキシャルまたはエクアトリアルであり、
R1は、Hまたは任意選択で置換されたC1〜6アルキルであり、
R2は、OR2O、N3、N(R2N)2、またはグアニジンであり、
R2Oの各事例は独立に、水素、任意選択で置換されたC1〜6アルキル、任意選択で置換されたアシル、または酸素保護基であり、
R2Nの各事例は独立に、水素、任意選択で置換されたC1〜6アルキル、任意選択で置換されたアシル、または窒素保護基であり、
R3aおよびR3bの各事例は独立に、水素、−C(=O)−R3r、または酸素保護基であり、
R3rの各事例は、任意選択で置換されたC1〜6アルキル、任意選択で置換されたアリール、任意選択で置換されたヘテロアリール、または任意選択で置換された複素環、任意選択で置換されたアルキルアリール、任意選択で置換されたアルキルヘテロアリール、または任意選択で置換されたアルキル複素環であり、
Xは、−O−、−O(C=O)−、−NH−、−NH(C=O)−、−(C=O)NH−、−O(C=O)NH−、−O(C=S)NH−、−NH(C=O)NH−、および−NH(C=S)NH−からなる群から選択され、
R4は、H、任意選択で置換されたC1〜6アルキル、または−L−Zであり、
Yは、任意選択で置換されたC1〜6アルキルまたは−L−Zであり、
Lの各事例は独立に、−(CH2)n−、−(CH2)nC=O−、−(CH2)nNH−、−(C=O)(CH2)n−、−(CH2)nNH(C=O)−、−(C=O)(CH2)nNH(C=O)−、−(CH2)nSCH2(C=O)−、および−(CH2CH2O)n−からなる群から選択され、
nの各事例は、1〜8の整数であり、両端を含み、
Zの各事例は、さらなるライゲーションのための官能基であり、
ただし、化合物は、式
を提供する。
(式中、R3cは独立に、水素、任意選択で置換されたC1〜6アルキル、任意選択で置換されたアシル、または酸素保護基である)である。
(式中、Ry1は、水素または任意選択で置換されたC1〜6アルキルである)である。
(式中、Ry2は、水素または任意選択で置換されたC1〜6アルキルである)である。
特定の官能基および化学用語の定義を以下により詳細に説明する。化学元素は、the Periodic Table of the Elements, CAS version、Handbook of Chemistry and Physics、75版、内表紙に従って識別され、特定の官能基は一般に、その中に記載されているように定義される。さらに、有機化学の一般的原理、ならびに特定の機能性部分および反応性は、Organic Chemistry、Thomas Sorrell、University Science Books、Sausalito、1999年;SmithおよびMarch、March’s Advanced Organic Chemistry、5版、John Wiley & Sons, Inc.、New York、2001年;Larock、Comprehensive Organic Transformations、VCH Publishers, Inc.、New York、1989年;ならびにCarruthers、Some Modern Methods of Organic Synthesis、3版、Cambridge University Press、Cambridge、1987年に記載されている。
あるいは炭素原子上の2個のジェミナル水素は、基=O、=S、=NN(Rbb)2、=NNRbbC(=O)Raa、=NNRbbC(=O)ORaa、=NNRbbS(=O)2Raa、=NRbb、または=NORccで置き換えられており、
Raaの各事例は独立に、C1〜10アルキル、C1〜10ペルハロアルキル、C2〜10アルケニル、C2〜10アルキニル、C1〜10ヘテロアルキル、C2〜10ヘテロアルケニル、C2〜10ヘテロアルキニル、C3〜10カルボシクリル、3〜14員ヘテロシクリル、C6〜14アリール、および5〜14員ヘテロアリールから選択され、または2個のRaa基は、接合されて3〜14員ヘテロシクリルもしくは5〜14員ヘテロアリール環を形成し、各アルキル、アルケニル、アルキニル、ヘテロアルキル、ヘテロアルケニル、ヘテロアルキニル、カルボシクリル、ヘテロシクリル、アリール、およびヘテロアリールは独立に、0、1、2、3、4、もしくは5個のRdd基と置換されており、
Rbbの各事例は独立に、水素、−OH、−ORaa、−N(Rcc)2、−CN、−C(=O)Raa、−C(=O)N(Rcc)2、−CO2Raa、−SO2Raa、−C(=NRcc)ORaa、−C(=NRcc)N(Rcc)2、−SO2N(Rcc)2、−SO2Rcc、−SO2ORcc、−SORaa、−C(=S)N(Rcc)2、−C(=O)SRcc、−C(=S)SRcc、−P(=O)2Raa、−P(=O)(Raa)2、−P(=O)2N(Rcc)2、−P(=O)(NRcc)2、C1〜10アルキル、C1〜10ペルハロアルキル、C2〜10アルケニル、C2〜10アルキニル、C1〜10ヘテロアルキル、C2〜10ヘテロアルケニル、C2〜10ヘテロアルキニル、C3〜10カルボシクリル、3〜14員ヘテロシクリル、C6〜14アリール、および5〜14員ヘテロアリールから選択され、または2個のRbb基は、接合されて3〜14員ヘテロシクリルもしくは5〜14員ヘテロアリール環を形成し、各アルキル、アルケニル、アルキニル、ヘテロアルキル、ヘテロアルケニル、ヘテロアルキニル、カルボシクリル、ヘテロシクリル、アリール、およびヘテロアリールは独立に、0、1、2、3、4、もしくは5個のRdd基と置換されており、
Rccの各事例は独立に、水素、C1〜10アルキル、C1〜10ペルハロアルキル、C2〜10アルケニル、C2〜10アルキニル、C1〜10ヘテロアルキル、C2〜10ヘテロアルケニル、C2〜10ヘテロアルキニル、C3〜10カルボシクリル、3〜14員ヘテロシクリル、C6〜14アリール、および5〜14員ヘテロアリールから選択され、または2個のRcc基は、接合されて3〜14員ヘテロシクリルもしくは5〜14員ヘテロアリール環を形成し、各アルキル、アルケニル、アルキニル、ヘテロアルキル、ヘテロアルケニル、ヘテロアルキニル、カルボシクリル、ヘテロシクリル、アリール、およびヘテロアリールは独立に、0、1、2、3、4、もしくは5個のRdd基と置換されており、
Rddの各事例は独立に、ハロゲン、−CN、−NO2、−N3、−SO2H、−SO3H、−OH、−ORee、−ON(Rff)2、−N(Rff)2、−N(Rff)3 +X−、−N(ORee)Rff、−SH、−SRee、−SSRee、−C(=O)Ree、−CO2H、−CO2Ree、−OC(=O)Ree、−OCO2Ree、−C(=O)N(Rff)2、−OC(=O)N(Rff)2、−NRffC(=O)Ree、−NRffCO2Ree、−NRffC(=O)N(Rff)2、−C(=NRff)ORee、−OC(=NRff)Ree、−OC(=NRff)ORee、−C(=NRff)N(Rff)2、−OC(=NRff)N(Rff)2、−NRffC(=NRff)N(Rff)2、−NRffSO2Ree、−SO2N(Rff)2、−SO2Ree、−SO2ORee、−OSO2Ree、−S(=O)Ree、−Si(Ree)3、−OSi(Ree)3、−C(=S)N(Rff)2、−C(=O)SRee、−C(=S)SRee、−SC(=S)SRee、−P(=O)2Ree、−P(=O)(Ree)2、−OP(=O)(Ree)2、−OP(=O)(ORee)2、C1〜6アルキル、C1〜6ペルハロアルキル、C2〜6アルケニル、C2〜6アルキニル、C1〜6ヘテロアルキル、C2〜6ヘテロアルケニル、C2〜6ヘテロアルキニル、C3〜10カルボシクリル、3〜10員ヘテロシクリル、C6〜10アリール、5〜10員ヘテロアリールから選択され、各アルキル、アルケニル、アルキニル、ヘテロアルキル、ヘテロアルケニル、ヘテロアルキニル、カルボシクリル、ヘテロシクリル、アリール、およびヘテロアリールは独立に、0、1、2、3、4、もしくは5個のRgg基と置換されており、または2個のジェミナルRdd置換基は、接合されて=Oもしくは=Sを形成することができ、
Reeの各事例は独立に、C1〜6アルキル、C1〜6ペルハロアルキル、C2〜6アルケニル、C2〜6アルキニル、C1〜6ヘテロアルキル、C2〜6ヘテロアルケニル、C2〜6ヘテロアルキニル、C3〜10カルボシクリル、C6〜10アリール、3〜10員ヘテロシクリル、および3〜10員ヘテロアリールから選択され、各アルキル、アルケニル、アルキニル、ヘテロアルキル、ヘテロアルケニル、ヘテロアルキニル、カルボシクリル、ヘテロシクリル、アリール、およびヘテロアリールは独立に、0、1、2、3、4、もしくは5個のRgg基と置換されており、
Rffの各事例は独立に、水素、C1〜6アルキル、C1〜6ペルハロアルキル、C2〜6アルケニル、C2〜6アルキニル、C1〜6ヘテロアルキル、C2〜6ヘテロアルケニル、C2〜6ヘテロアルキニル、C3〜10カルボシクリル、3〜10員ヘテロシクリル、C6〜10アリール、および5〜10員ヘテロアリールから選択され、または2個のRff基は、接合されて3〜14員ヘテロシクリルもしくは5〜14員ヘテロアリール環を形成し、各アルキル、アルケニル、アルキニル、ヘテロアルキル、ヘテロアルケニル、ヘテロアルキニル、カルボシクリル、ヘテロシクリル、アリール、およびヘテロアリールは独立に、0、1、2、3、4、もしくは5個のRgg基と置換されており、
Rggの各事例は独立に、ハロゲン、−CN、−NO2、−N3、−SO2H、−SO3H、−OH、−OC1〜6アルキル、−ON(C1〜6アルキル)2、−N(C1〜6アルキル)2、−N(C1〜6アルキル)3 +X−、−NH(C1〜6アルキル)2 +X−、−NH2(C1〜6アルキル)+X−、−NH3 +X−、−N(OC1〜6アルキル)(C1〜6アルキル)、−N(OH)(C1〜6アルキル)、−NH(OH)、−SH、−SC1〜6アルキル、−SS(C1〜6アルキル)、−C(=O)(C1〜6アルキル)、−CO2H、−CO2(C1〜6アルキル)、−OC(=O)(C1〜6アルキル)、−OCO2(C1〜6アルキル)、−C(=O)NH2、−C(=O)N(C1〜6アルキル)2、−OC(=O)NH(C1〜6アルキル)、−NHC(=O)(C1〜6アルキル)、−N(C1〜6アルキル)C(=O)(C1〜6アルキル)、−NHCO2(C1〜6アルキル)、−NHC(=O)N(C1〜6アルキル)2、−NHC(=O)NH(C1〜6アルキル)、−NHC(=O)NH2、−C(=NH)O(C1〜6アルキル)、−OC(=NH)(C1〜6アルキル)、−OC(=NH)OC1〜6アルキル、−C(=NH)N(C1〜6アルキル)2、−C(=NH)NH(C1〜6アルキル)、−C(=NH)NH2、−OC(=NH)N(C1〜6アルキル)2、−OC(NH)NH(C1〜6アルキル)、−OC(NH)NH2、−NHC(NH)N(C1〜6アルキル)2、−NHC(=NH)NH2、−NHSO2(C1〜6アルキル)、−SO2N(C1〜6アルキル)2、−SO2NH(C1〜6アルキル)、−SO2NH2、−SO2C1〜6アルキル、−SO2OC1〜6アルキル、−OSO2C1〜6アルキル、−SOC1〜6アルキル、−Si(C1〜6アルキル)3、−OSi(C1〜6アルキル)3−C(=S)N(C1〜6アルキル)2、C(=S)NH(C1〜6アルキル)、C(=S)NH2、−C(=O)S(C1〜6アルキル)、−C(=S)SC1〜6アルキル、−SC(=S)SC1〜6アルキル、−P(=O)2(C1〜6アルキル)、−P(=O)(C1〜6アルキル)2、−OP(=O)(C1〜6アルキル)2、−OP(=O)(OC1〜6アルキル)2、C1〜6アルキル、C1〜6ペルハロアルキル、C2〜6アルケニル、C2〜6アルキニル、C1〜6ヘテロアルキル、C2〜6ヘテロアルケニル、C2〜6ヘテロアルキニル、C3〜10カルボシクリル、C6〜10アリール、3〜10員ヘテロシクリル、5〜10員ヘテロアリールから選択され、または2個のジェミナルRgg置換基は、接合されて=Oもしくは=Sを形成することができ、X−は、対イオンである。
例えば、本発明は以下を提供する。
(項目1)
式(I):
の化合物、またはその塩
(式中、
C3位のF原子は、アキシャルまたはエクアトリアルであり、
R 1 は、Hまたは任意選択で置換されたC 1〜6 アルキルであり、
R 2 は、OR 2O 、N 3 、N(R 2N ) 2 、またはグアニジンであり、
R 2O の各事例は独立に、水素、任意選択で置換されたC 1〜6 アルキル、任意選択で置換されたアシル、または酸素保護基であり、
R 2N の各事例は独立に、水素、任意選択で置換されたC 1〜6 アルキル、任意選択で置換されたアシル、または窒素保護基であり、
R 3a およびR 3b の各事例は独立に、水素、−C(=O)−R 3r 、または酸素保護基であり、
R 3r の各事例は、任意選択で置換されたC 1〜6 アルキル、任意選択で置換されたアリール、任意選択で置換されたヘテロアリール、または任意選択で置換された複素環、任意選択で置換されたアルキルアリール、任意選択で置換されたアルキルヘテロアリール、または任意選択で置換されたアルキル複素環であり、
Xは、−O−、−O(C=O)−、−NH−、−NH(C=O)−、−(C=O)NH−、−O(C=O)NH−、−O(C=S)NH−、−NH(C=O)NH−、および−NH(C=S)NH−からなる群から選択され、
R 4 は、H、任意選択で置換されたC 1〜6 アルキル、または−L−Zであり、
Yは、任意選択で置換されたC 1〜6 アルキルまたは−L−Zであり、
Lの各事例は独立に、−(CH 2 ) n −、−(CH 2 ) n C=O−、−(CH 2 ) n NH−、−(C=O)(CH 2 ) n −、−(CH 2 ) n NH(C=O)−、−(C=O)(CH 2 ) n NH(C=O)−、−(CH 2 ) n SCH 2 (C=O)−、および−(CH 2 CH 2 O) n −からなる群から選択され、
nの各事例は、1〜8の整数であり、両端を含み、
Zの各事例は、さらなるライゲーションのための官能基であり、
ただし、該化合物は、式
のものではない)。
(項目2)
Zが、任意選択で置換されたアルキン、任意選択で置換されたアルケン、ハロゲン、−N 3 、N(R N ) 2 、OR O 、SR S 、またはCO 2 R O であり、
R N の各事例が独立に、水素、任意選択で置換されたC 1〜6 アルキル、任意選択で置換されたアシル、または窒素保護基であり、
R O の各事例が独立に、水素、任意選択で置換されたC 1〜6 アルキル、任意選択で置換されたアシル、または酸素保護基であり、
R S の各事例が独立に、水素、任意選択で置換されたC 1〜6 アルキル、または硫黄保護基である、項目1に記載の化合物。
(項目3)
式(II−a):
の項目1に記載の化合物、またはその塩
(式中、R 3c は独立に、水素、任意選択で置換されたC 1〜6 アルキル、任意選択で置換されたアシル、または酸素保護基である)。
(項目4)
式(II−b):
の項目3に記載の化合物、またはその塩。
(項目5)
式(II−b1):
の項目3に記載の化合物、またはその塩。
(項目6)
式(II−b2):
の項目3に記載の化合物、またはその塩
(式中、R y1 は、水素、ハロゲン、または任意選択で置換されたC 1〜6 アルキルである)。
(項目7)
式(II−b3):
の項目3に記載の化合物、またはその塩。
(項目8)
式(II−c):
の項目1に記載の化合物、またはその塩。
(項目9)
式(II−c1):
の項目8に記載の化合物、またはその塩。
(項目10)
式(II−c2):
の項目8に記載の化合物、またはその塩
(式中、R y2 は、水素または任意選択で置換されたC 1〜6 アルキルである)。
(項目11)
式(II−c3):
の項目8に記載の化合物、またはその塩。
(項目12)
Yが任意選択で置換されたC 1〜6 アルキルである、項目8から11のいずれか一項に記載の化合物。
(項目13)
Yがメチルである、項目11に記載の化合物。
(項目14)
YがCF 3 である、項目11に記載の化合物。
(項目15)
R 1 がHまたはメチルである、前記項目のいずれか一項に記載の化合物。
(項目16)
前記C3位の前記F原子がアキシャルである、前記項目のいずれか一項に記載の化合物。
(項目17)
前記C3位の前記F原子がエクアトリアルである、項目1から15のいずれか一項に記載の化合物。
(項目18)
R 3a が−C(=O)−R 3r であり、R 3r が任意選択でアルキルアリールである、前記項目のいずれか一項に記載の化合物。
(項目19)
R 3a が任意選択で置換されたベンゾイルである、前記項目のいずれか一項に記載の化合物。
(項目20)
R 3a が−C(=O)−R 3r であり、R 3r が任意選択で置換されたアリールである、項目1から18のいずれか一項に記載の化合物。
(項目21)
R 3a が−C(=O)−Phである、項目20に記載の化合物。
(項目22)
R 3a が、CH 3 CO−、C 2 H 5 CO−、C 3 H 7 CO−、t−BuCO−、CF 3 CO−、PhCH 2 CO−、またはC 6 H 5 CO−である、項目1から18に記載の化合物。
(項目23)
前記化合物が以下の式:
の1つである、項目1に記載の化合物。
(項目24)
項目1から23のいずれか一項に記載の化合物を含むシアリダーゼタンパク質付加体であって、前記シアリダーゼタンパク質が前記化合物に共有結合的にコンジュゲートされている、シアリダーゼタンパク質付加体。
(項目25)
式
の項目24に記載のシアリダーゼタンパク質付加体。
(項目26)
前記シアリダーゼが、ヒト、ウイルス、または細菌シアリダーゼである、項目25に記載のシアリダーゼタンパク質付加体
(項目27)
前記シアリダーゼが、nanA、nanB、nanC、nanJ、nanI、およびnanHからなる群から選択される細菌シアリダーゼである、項目26に記載のシアリダーゼタンパク質付加体。
(項目28)
前記化合物がDFSA−5−インまたはDFSA−7−インである、項目24から27のいずれか一項に記載のシアリダーゼタンパク質付加体。
(項目29)
前記化合物が、配列番号1〜6の任意のペプチド内の1つまたは複数のチロシン(Y)残基と共有結合的に連結しており、前記ペプチドが、nanA、nanB、nanC、nanJ、nanI、またはnanHのフラグメントである、項目24から28のいずれか一項に記載のシアリダーゼタンパク質付加体。
(項目30)
前記シアリダーゼが、インフルエンザウイルスノイラミニダーゼ(NA)である、項目26に記載のシアリダーゼタンパク質付加体。
(項目31)
前記シアリダーゼが、Neu1、Neu2、Neu3、およびNeu4からなる群から選択されるヒトシアリダーゼである、項目26に記載のシアリダーゼタンパク質付加体。
(項目32)
前記項目1から23のいずれか一項に記載の化合物を含む検出可能なコンジュゲートであって、前記化合物が検出可能なタグ付け部分に共有結合的にコンジュゲートされている、検出可能なコンジュゲート。
(項目33)
項目24から30のいずれか一項に記載のシアリダーゼタンパク質付加体を含む検出可能なシアリダーゼタンパク質コンジュゲートであって、前記シアリダーゼタンパク質付加体が、検出可能なタグ付け部分に共有結合的にコンジュゲートされている、検出可能なシアリダーゼタンパク質コンジュゲート。
(項目34)
前記タグ付け部分が標識を含む、項目32に記載の検出可能なコンジュゲート、または項目33に記載の検出可能なシアリダーゼコンジュゲート。
(項目35)
以下の式:
のいずれか1つの項目34に記載の検出可能なコンジュゲートもしくは検出可能なシアリダーゼコンジュゲート、またはその塩
(式中、
C3位のF原子は、アキシャルまたはエクアトリアルであり、
R K は、H、任意選択で置換されたC 1〜6 アルキル、またはシアリダーゼタンパク質であり、
R 2 は、OR 2O 、N 3 、N(R 2N ) 2 、またはグアニジンであり、
R 2O の各事例は独立に、水素、任意選択で置換されたC 1〜6 アルキル、任意選択で置換されたアシル、または酸素保護基であり、
R 2N の各事例は独立に、水素、任意選択で置換されたC 1〜6 アルキル、または窒素保護基であり、
R 3a およびR 3b の各事例は独立に、水素、−C(=O)−R 3r 、または酸素保護基であり、
R 3r の各事例は、任意選択で置換されたC 1〜6 アルキル、任意選択で置換されたアリール、任意選択で置換されたヘテロアリール、または任意選択で置換された複素環、任意選択で置換されたアルキルアリール、任意選択で置換されたアルキルヘテロアリール、または任意選択で置換されたアルキル複素環であり、
Xは、−O−、−O(C=O)−、−NH−、−NH(C=O)−、−(C=O)NH−、−O(C=O)NH−、−O(C=S)NH−、−NH(C=O)NH−、および−NH(C=S)NH−からなる群から選択され、
R 4a は、H、任意選択で置換されたC 1〜6 アルキル、または任意選択で置換されたアシルであり、
Y a は、Hまたは任意選択で置換されたC 1〜6 アルキルであり、
Lの各事例は独立に、−(CH 2 ) n −、−(CH 2 ) n C=O−、−(CH 2 ) n NH−、−(C=O)(CH 2 ) n −、−(CH 2 ) n NH(C=O)−、−(C=O)(CH 2 ) n NH(C=O)−、−(CH 2 ) n SCH 2 (C=O)−、または−(CH 2 CH 2 O) n −からなる群から選択され、
nの各事例は、1〜8の整数であり、両端を含み、
R p およびR q の各事例は独立に、水素、任意選択で置換された脂肪族;任意選択で置換されたヘテロ脂肪族;置換または非置換アリール;任意選択で置換されたヘテロアリール;任意選択で置換されたアシル;樹脂;タンパク質;レポーター;リンカーL a によって任意選択で接合された標識(該リンカーL a は任意選択で置換されたアルキレンである);任意選択で置換されたアルケニレン;任意選択で置換されたアルキニレン;任意選択で置換されたヘテロアルキレン;任意選択で置換されたヘテロアルケニレン;任意選択で置換されたヘテロアルキニレン;任意選択で置換されたアリーレン;任意選択で置換されたヘテロアリーレン;または任意選択で置換されたアシレンである)。
(項目36)
前記標識がフルオロフォアである、項目34から35のいずれか一項に記載の検出可能なコンジュゲートまたは検出可能なタンパク質コンジュゲート。
(項目37)
前記標識が、
である、項目34から35のいずれか一項に記載の検出可能なコンジュゲートまたは検出可能なタンパク質コンジュゲート。
(項目38)
シアリダーゼの存在を検出するための方法であって、該方法は、
(a)シアリダーゼを含む疑いのある試料を項目1から23のいずれか一項に記載の化合物と接触させるステップと、
(b)レポーターを添加するステップと、
(c)シグナルを検出するステップと
を含み、シグナルの存在は、前記試料中の前記シアリダーゼの存在を示す、方法。
(項目39)
前記シアリダーゼが細胞内にある、項目38に記載の方法。
(項目40)
前記化合物が、PDFSA−5−イン(IV)もしくはPDFSA−7−イン(VII):
またはその誘導体、コンジュゲート、もしくはエステルである、項目38に記載の方法。
(項目41)
前記試料が、哺乳動物、家禽、または魚由来である、項目38から40のいずれか一項に記載の方法。
(項目42)
前記哺乳動物がヒトである、項目41に記載の方法。
(項目43)
前記試料が、病原体を含有する疑いがある、項目38から42のいずれか一項に記載の方法。
(項目44)
前記病原体が、細菌、ウイルス、原生動物、または真菌である、項目43に記載の方法。
(項目45)
細胞中のシアリダーゼの細胞内位置を画像化するステップをさらに含む、項目38から44のいずれか一項に記載の方法。
(項目46)
シアリダーゼの存在を検出するための方法であって、
(a)シアリダーゼを含む疑いのある試料を項目32に記載の検出可能なコンジュゲートと接触させるステップと、
(b)シグナルを検出するステップと
を含み、シグナルの存在は、前記試料中の前記シアリダーゼの存在を示す、方法。
(項目47)
前記シアリダーゼが細胞外にある、項目46に記載の方法。
(項目48)
前記検出可能なコンジュゲートが、PDFSA−5−イン(IV)もしくはPDFSA−7−イン(VII):
、またはその誘導体、コンジュゲート、もしくはエステルを含む、項目46に記載の方法。
(項目49)
前記試料が、哺乳動物、家禽、または魚由来である、項目46から48のいずれか一項に記載の方法。
(項目50)
前記哺乳動物がヒトである、項目49に記載の方法。
(項目51)
前記試料が、病原体を含有する疑いがある、項目46から50のいずれか一項に記載の方法。
(項目52)
前記病原体が、細菌、ウイルス、原生動物、または真菌である、項目51に記載の方法。
(項目53)
細胞中のシアリダーゼの細胞内位置を画像化するステップをさらに含む、項目46から52のいずれか一項に記載の方法。
(項目54)
(d)細胞をPDFSA−5−イン(IV)、PDFSA−7−イン(VII)の化合物、またはその誘導体もしくはエステルと接触させるステップと、
(e)細胞内エステラーゼに前記化合物をそれぞれDFSA−5−イン(III)またはDFSA−7−イン(VI)に変換させるステップと、
(f)DFSA−5−イン(III)またはDFSA−7−イン(VI)を前記細胞中の細胞内位置で1つまたは複数のシアリダーゼに共有結合的にコンジュゲートさせるステップと、
(g)レポーターを添加するステップと、
(h)細胞内シアリダーゼ分布の画像を得るステップと
をさらに含む、項目38に記載の方法。
(項目55)
シアリドーシスを診断するための方法であって、該方法は、
(a)シアリドーシスの疑いのある対象からの検査試料を項目1から23のいずれか一項に記載の化合物と接触させるステップと、
(b)レポーターを添加するステップと、
(c)シグナルを検出するステップと、
(d)前記シグナルを健康な対象からのシグナルと比較するステップと
を含み、前記検査試料中のシグナルの相対的な低減は、シアリドーシスを示す、方法。
(項目56)
シアリドーシスを診断するための方法であって、該方法は、
(a)シアリドーシスの疑いのある対象からの検査試料を項目32に記載の検出可能なコンジュゲートと接触させるステップと、
(b)シグナルを検出するステップと、
(c)前記シグナルを健康な対象からのシグナルと比較するステップと
を含み、前記検査試料中のシグナルの相対的な低減の存在は、シアリドーシスを示す、方法。
(項目57)
前記検査試料が線維芽細胞を含有する、項目55または56に記載の方法。
(項目58)
インフルエンザウイルスによる感染を診断するための方法であって、該方法は、
(a)インフルエンザウイルス感染の疑いのある対象からの検査試料を項目1から23のいずれか一項に記載の化合物と接触させるステップと、
(b)レポーターを添加するステップと、
(c)シグナルを検出するステップと
を含み、シグナルの存在は、インフルエンザウイルスによる感染の可能性を示す、方法。
(項目59)
インフルエンザウイルスによる感染を診断するための方法であって、該方法は、
(a)インフルエンザウイルス感染の疑いのある対象からの検査試料を項目32に記載の検出可能なコンジュゲートと接触させるステップと、
(b)シグナルを検出するステップと
を含み、シグナルの存在は、インフルエンザウイルスによる感染の可能性を示す、方法。
(項目60)
前記インフルエンザウイルスが細胞外にある、項目58または59に記載の方法。
(項目61)
前記化合物が、DFSA−5−イン(II)もしくはDFSA−7−イン(VI)、またはその誘導体もしくはエステルである、項目58に記載の方法。
(項目62)
前記検出可能なコンジュゲートが、DFSA−5−イン(II)もしくはDFSA−7−イン(VI)、またはその誘導体もしくはエステルを含む、項目59に記載の方法。
(項目63)
前記インフルエンザウイルスが細胞内にある、項目58または59に記載の方法。
(項目64)
前記インフルエンザウイルスが、オセルタミビルに耐性でない、項目58または59に記載の方法。
(項目65)
前記インフルエンザウイルスが、オセルタミビルに感受性である、項目58または59に記載の方法。
(項目66)
前記インフルエンザウイルスが、オセルタミビルに耐性である、項目58または59に記載の方法。
(項目67)
前記オセルタミビル耐性インフルエンザウイルスがH1N1である、項目58または59に記載の方法。
(項目68)
前記インフルエンザウイルスが、10 4 または10 4 より大きい力価で存在する、項目58から67のいずれかに記載の方法。
(項目69)
シアリダーゼ含有ウイルスを伴った感染を診断するための、項目1から23のいずれか一項に記載の化合物または項目32に記載の検出可能なコンジュゲートの使用。
(項目70)
哺乳動物、家禽、または魚由来の生物中のシアリダーゼを検出するための、項目1から23のいずれか一項に記載の化合物または項目32に記載の検出可能なコンジュゲートの使用。
(項目71)
前記生物がヒト由来である、化合物または項目32に記載の検出可能なコンジュゲートの使用。
(項目72)
前記生物が病原体を含有する、前記化合物または項目32に記載の検出可能なコンジュゲートの使用。
(項目73)
生細胞内のシアリダーゼ活性を画像化するための、項目1から23のいずれか一項に記載の化合物または項目32に記載の検出可能なコンジュゲートの使用。
(項目74)
前記画像化するステップが、細胞内シアリダーゼをプロファイリングすることをさらに含む、化合物または項目32に記載の検出可能なコンジュゲートの使用。
(項目75)
シアリドーシスを診断、予防、または処置するための、項目1から23のいずれか一項に記載の化合物または項目32に記載の検出可能なコンジュゲートの使用。
(項目76)
シアリダーゼ含有ウイルスを伴った感染を診断するための、項目1から23のいずれか一項に記載の化合物、または項目32に記載の検出可能なコンジュゲート。
(項目77)
哺乳動物、家禽、または魚由来の生物中のシアリダーゼを検出するための、項目1から23のいずれか一項に記載の化合物、または項目32に記載の検出可能なコンジュゲート。
(項目78)
生細胞内のシアリダーゼ活性を画像化するための、項目1から23のいずれか一項に記載の化合物、または項目32に記載の検出可能なコンジュゲート。
(項目79)
シアリドーシスを診断、予防、または処置するための、項目1から23のいずれか一項に記載の化合物、または項目32に記載の検出可能なコンジュゲート。
(式中、
C3位のF原子は、アキシャルまたはエクアトリアルであり、
R1は、Hまたは任意選択で置換されたC1〜6アルキルであり、
R2は、OR2O、N3、N(R2N)2、またはグアニジンであり、
R2Oの各事例は独立に、水素、任意選択で置換されたC1〜6アルキル、任意選択で置換されたアシル、または酸素保護基であり、
R2Nの各事例は独立に、水素、任意選択で置換されたC1〜6アルキル、任意選択で置換されたアシル、または窒素保護基であり、
R3aおよびR3bの各事例は独立に、水素、−C(=O)−R3r、または酸素保護基であり、
R3rの各事例は、任意選択で置換されたC1〜6アルキル、任意選択で置換されたアリール、任意選択で置換されたヘテロアリール、または任意選択で置換された複素環、任意選択で置換されたアルキルアリール、任意選択で置換されたアルキルヘテロアリール、または任意選択で置換されたアルキル複素環であり、
Xは、−O−、−O(C=O)−、−NH−、−NH(C=O)−、−(C=O)NH−、−O(C=O)NH−、−O(C=S)NH−、−NH(C=O)NH−、および−NH(C=S)NH−からなる群から選択され、
R4は、H、任意選択で置換されたC1〜6アルキル、または−L−Zであり、
Yは、任意選択で置換されたC1〜6アルキルまたは−L−Zであり、
Lの各事例は独立に、−(CH2)n−、−(CH2)nC=O−、−(CH2)nNH−、−(C=O)(CH2)n−、−(CH2)nNH(C=O)−、−(C=O)(CH2)nNH(C=O)−、−(CH2)nSCH2(C=O)−、および−(CH2CH2O)n−からなる群から選択され、
nの各事例は、1〜8の整数であり、両端を含み、
Zの各事例は、さらなるライゲーションのための官能基であり、
ただし、化合物は、式
を提供する。
(式中、R3cは独立に、水素、任意選択で置換されたC1〜6アルキル、任意選択で置換されたアシル、または酸素保護基である)である。
(式中、Ry1は、水素、ハロゲンまたは任意選択で置換されたC1〜6アルキルである)である。
(式中、Ry2は、水素、ハロゲンまたは任意選択で置換されたC1〜6アルキルである)である。
Laは、本明細書で定義されており、
Rtの各事例は、水素、ハロゲン、任意選択で置換されたC1〜6アルキル、任意選択で置換されたC1〜6アルキル、任意選択で置換されたアリール、任意選択で置換されたヘテロアリール、または任意選択で置換された複素環である。
式中、
C3位のF原子は、アキシャルまたはエクアトリアルであり、
RKは、H、任意選択で置換されたC1〜6アルキル、またはシアリダーゼタンパク質であり、
R2、R3a、R3b、およびXは、本明細書で定義した通りであり、
R4aは、H、任意選択で置換されたC1〜6アルキル、または任意選択で置換されたアシルであり、
Yaは、Hまたは任意選択で置換されたC1〜6アルキルであり、
RpおよびRqの各事例は独立に、水素、任意選択で置換された脂肪族;任意選択で置換されたヘテロ脂肪族;置換または非置換アリール;任意選択で置換されたヘテロアリール;任意選択で置換されたアシル;樹脂;タンパク質;レポーター;任意選択で置換されたアルキレンであるリンカーLaによって任意選択で接合された標識;任意選択で置換されたアルケニレン;任意選択で置換されたアルキニレン;任意選択で置換されたヘテロアルキレン;任意選択で置換されたヘテロアルケニレン;任意選択で置換されたヘテロアルキニレン;任意選択で置換されたアリーレン;任意選択で置換されたヘテロアリーレン;または任意選択で置換されたアシレンである。
(a)シアリダーゼを含む疑いのある試料を本明細書に記載の化合物と接触させるステップと、
(b)レポーターを添加するステップと、
(c)シグナルを検出するステップと
を含み、シグナルの存在は、試料中のシアリダーゼの存在を示す、方法を提供する。
(a)シアリダーゼを含む疑いのある試料を検出可能なコンジュゲートと接触させるステップと、
(b)レポーターを添加するステップと、
(c)シグナルを検出するステップと
を含み、シグナルの存在は、試料中のシアリダーゼの存在を示す、方法を提供する。
(d)細胞をPDFSA−5−イン(IV)、PDFSA−7−イン(VII)の化合物、またはその誘導体もしくはエステルと接触させるステップと、
(e)細胞内エステラーゼにこの化合物をそれぞれDFSA−5−イン(III)またはDFSA−7−イン(VI)に変換させるステップと、
(f)DFSA−5−イン(III)またはDFSA−7−イン(VI)を細胞中の細胞内位置で1つまたは複数のシアリダーゼに共有結合的にコンジュゲートさせるステップと、
(g)レポーターを添加するステップと、
(h)細胞内シアリダーゼ分布の画像を得るステップと
をさらに含む。
(a)シアリドーシスの疑いのある対象からの検査試料を本明細書に記載の化合物と接触させるステップと、
(b)レポーターを添加するステップと、
(c)シグナルを検出するステップと、
(d)このシグナルを健康な対象からのシグナルと比較するステップと
を含み、検査試料中のシグナルの相対的な低減は、シアリドーシスを示す、方法を提供する。
(a)シアリドーシスの疑いのある対象からの検査試料を本明細書に記載の検出可能なコンジュゲートと接触させるステップと、
(b)シグナルを検出するステップと、
(d)このシグナルを健康な対象からのシグナルと比較するステップと、
を含み、検査試料中のシグナルの相対的な低減は、シアリドーシスを示す、方法を提供する。
(a)インフルエンザウイルス感染の疑いのある対象からの検査試料を請求項1から23のいずれか一項に記載の化合物と接触させるステップと、
(b)レポーターを添加するステップと、
(c)シグナルを検出するステップと
を含み、シグナルの存在は、インフルエンザウイルスによる感染の可能性を示す、方法を提供する。
(a)インフルエンザウイルス感染の疑いのある対象からの検査試料を請求項32に記載の検出可能なコンジュゲートと接触させるステップと、
(b)シグナルを検出するステップと
を含み、シグナルの存在は、インフルエンザウイルスによる感染の可能性を示す、方法を提供する。
シアリダーゼを含有する生細胞を本明細書に記載の任意の化合物とともに、化合物をシアリダーゼにコンジュゲートさせる条件下でインキュベートするステップと、
シアリダーゼ−化合物コンジュゲートをレポーターと、レポーターの化合物へのコンジュゲーションを可能にする条件下で接触させるステップと、
化合物にコンジュゲートされているレポーターから放出されるシグナルを検出するステップと
を含む方法を提供する。
(a)N−(ペンタ−4−イノイル)−マンノサミン(1)(T. L. Hsuら、Proc. Natl. Acad. Sci. USA、2007年、104巻、2614頁)を、3−フルオロピルビン酸(ナトリウム塩として)と、N−アセチルノイラミン酸アルドラーゼ(Neu5Acアルドラーゼ、EC4.1.3.3)の触媒作用によって反応させて付加体2を得るステップと、
(f)アルカリ性条件下でPDFSA−5−インを脱保護し、その後、逆相カラムで精製してDFSA−5−インを得るステップと
を含む。
(g)D−マンノサミンを3−フルオロピルビン酸(ナトリウム塩として)と、N−アセチルノイラミン酸アルドラーゼ(Neu5Acアルドラーゼ、EC4.1.3.3)の触媒作用によって反応させて付加体6を得るステップと、
をさらに含む。
(実施例1)
方法および材料。
(実施例2)
メチル5−(ペンタ−4−インアミド)−2,4,7,8,9−ペンタ−O−アセチル−3,5−ジデオキシ−3−フルオロ−D−エリスロ−α−L−マンノ−ノナ−2−ウロピラノソネート(ulopyranosonate)(4)。
(実施例3)
メチル5−(ペンタ−4−インアミド)−4,7,8,9−テトラ−O−アセチル−3,5−ジデオキシ−3−フルオロ−D−エリスロ−α−L−マンノ−2−ノナ−2−ウロピラノソネート(5)。
(実施例4)
メチル5−(ペンタ−4−インアミド)−4,7,8,9−テトラ−O−アセチル−2,3,5−トリデオキシ−3−フルオロ−D−エリスロ−β−L−マンノ−ノナ−2−ウロピラノシルオネート(ulopyranosylonate)フルオリド(PDFSA−5−イン)。
(実施例5)
5−(ペンタ−4−インアミド)−2,3,5−トリデオキシ−3−フルオロ−D−エリスロ−β−L−マンノ−ノナ−2−ウロピラノシロニック(ulopyranosylonic)フルオリド(DFSA−5−イン)。
(実施例6)
細菌シアリダーゼのクローニング。
(実施例7)
E.coli内でのシアリダーゼの発現および組換えシアリダーゼの精製。
(実施例8)
ヒトシアリダーゼのクローニング。
(実施例9)
DFSAおよびPDFSAのIC50の判定
(実施例10)
膜クリック反応。
(実施例11)
細菌シアリダーゼ、インフルエンザノイラミニダーゼ、および組換えヒトシアリダーゼの標識。
(実施例12)
PDFSAを用いたシアリダーゼ発現細胞のin situ標識。
(実施例13)
シアリダーゼ活性アッセイ。
(実施例14)
DFSAを使用するインフルエンザ感染細胞の可視化。
(実施例15)
膜上のインフルエンザウイルスのOS感受性の迅速検出。
(実施例16)
DFSA標識シアリダーゼのトリプシンペプチドの質量分析。
請求項において、冠詞、例えば、「a」、「an」、および「the」などは、それとは反対に示されていない限り、または文脈から別段に明白でない限り、1つまたは1つを超えるを意味し得る。群の1つまたは複数の項の間に「または」を含む請求項または記載は、それとは反対に示されていない限り、または文脈から別段に明白でない限り、群の項の1つ、1つより多くのもの、またはすべてが、所与の生成物またはプロセス内に存在し、これらの中で使用され、またはこれらと別段に関連している場合、満たされていると見なされる。本発明は、群の正確に1つの項が所与の生成物またはプロセス内に存在し、これらの中で使用され、またはこれらと別段に関連している実施形態を含む。本発明は、群の項の1つ超またはすべてが所与の生成物またはプロセス内に存在し、これらの中で使用され、またはこれらと別段に関連している実施形態を含む。
(参考文献)
Claims (45)
- 式(I):
の化合物、またはその塩
(式中、
C3位のF原子は、アキシャルまたはエクアトリアルであり、
R1は、Hまたは任意選択で置換されたC1〜6アルキルであり、
R2は、OR2O、N3、N(R2N)2、またはグアニジンであり、
各R2Oは独立に、水素、任意選択で置換されたC1〜6アルキル、任意選択で置換されたアシル、または酸素保護基であり、
各R2Nは独立に、水素、任意選択で置換されたC1〜6アルキル、任意選択で置換されたアシル、または窒素保護基であり、
各R3aおよびR3bは独立に、水素、−C(=O)−R3r、または酸素保護基であり、
各R3rは、任意選択で置換されたC1〜6アルキル、任意選択で置換されたアリール、任意選択で置換されたヘテロアリール、または任意選択で置換された複素環、任意選択で置換されたアルキルアリール、任意選択で置換されたアルキルヘテロアリール、または任意選択で置換されたアルキル複素環であり、
Xは、−O−、−O(C=O)−、−NH−、−NH(C=O)−、−(C=O)NH−、−O(C=O)NH−、−O(C=S)NH−、−NH(C=O)NH−、および−NH(C=S)NH−からなる群から選択され、
R4は、H、任意選択で置換されたC1〜6アルキルであり、そしてYは、−L−Zであるか、または
R4は、−L−Zであり、そしてYは、任意選択で置換されたC1〜6アルキルであり、
各Lは独立に、−(CH2)n−、−(CH2)nC=O−、−(CH2)nNH−、−(C=O)(CH2)n−、−(CH2)nNH(C=O)−、−(C=O)(CH2)nNH(C=O)−、−(CH2)nSCH2(C=O)−、および−(CH2CH2O)n−からなる群から選択され、
各nは、1〜8の整数であり、両端を含み、
各Zは、さらなるライゲーションのための官能基である)。 - Zが、任意選択で置換されたアルキン、任意選択で置換されたアルケン、ハロゲン、−N3、N(RN)2、ORO、SRS、またはCO2ROであり、
各RNが独立に、水素、任意選択で置換されたC1〜6アルキル、任意選択で置換されたアシル、または窒素保護基であり、
各ROが独立に、水素、任意選択で置換されたC1〜6アルキル、任意選択で置換されたアシル、または酸素保護基であり、
各RSが独立に、水素、任意選択で置換されたC1〜6アルキル、または硫黄保護基である、請求項1に記載の化合物。 - 式(II−a):
の請求項1に記載の化合物、またはその塩
(式中、R3cは独立に、水素、任意選択で置換されたC1〜6アルキル、任意選択で置換されたアシル、または酸素保護基である)。 - 式(II−b):
の請求項3に記載の化合物、またはその塩。 - 式(II−b1):
- 式(II−b2):
(式中、Ry1は、水素、ハロゲン、または任意選択で置換されたC1〜6アルキルである)および
式(II−b3):
から選択される式を有する、請求項5に記載の化合物、またはその塩。 - 式(II−c):
の請求項1に記載の化合物、またはその塩。 - 式(II−c1):
、式(II−c2):
(式中、Ry2は、水素または任意選択で置換されたC1〜6アルキルである)および
式(II−c3):
から選択される式を有する、請求項7に記載の化合物、またはその塩。 - R4が−L−Zであり、そしてYが任意選択で置換されたC1〜6アルキルである、請求項7に記載の化合物。
- R4が−L−Zであり、そしてYがメチルまたはCF3である、請求項9に記載の化合物。
- R1がHまたはメチルである、請求項1に記載の化合物。
- 前記C3位の前記F原子がアキシャルである、請求項1に記載の化合物。
- 前記C3位の前記F原子がエクアトリアルである、請求項1に記載の化合物。
- R3aが−C(=O)−R3rであり、R3rが任意選択で置換されたアルキルまたは任意選択で置換されたアリールである、請求項1に記載の化合物。
- R3aが任意選択で置換されたベンゾイルである、請求項1に記載の化合物。
- R3aが、CH3CO−、C2H5CO−、C3H7CO−、t−BuCO−、CF3CO−、PhCH2CO−、またはC6H5CO−である、請求項1に記載の化合物。
- 前記化合物が以下の式:
の1つである、請求項1に記載の化合物。 - 請求項1に記載の化合物を含むシアリダーゼタンパク質付加体であって、シアリダーゼタンパク質が該化合物に共有結合的にコンジュゲートされている、シアリダーゼタンパク質付加体。
- 式
を有する、請求項18に記載のシアリダーゼタンパク質付加体。 - 前記シアリダーゼが、ヒト、ウイルス、または細菌シアリダーゼである、請求項19に記載のシアリダーゼタンパク質付加体。
- 前記シアリダーゼが、nanA、nanB、nanC、nanJ、nanI、およびnanHからなる群から選択される細菌シアリダーゼである、請求項19に記載のシアリダーゼタンパク質付加体。
- 前記化合物がDFSA−5−インまたはDFSA−7−インである、請求項19に記載のシアリダーゼタンパク質付加体。
- 前記化合物が、配列番号1〜6の任意のペプチド内の1つまたは複数のチロシン残基と共有結合的に連結しており、該ペプチドが、nanA、nanB、nanC、nanJ、nanI、またはnanHのフラグメントである、請求項19に記載のシアリダーゼタンパク質付加体。
- 前記シアリダーゼが、インフルエンザウイルスノイラミニダーゼ(NA)である、請求項19に記載のシアリダーゼタンパク質付加体。
- 前記シアリダーゼが、Neu1、Neu2、Neu3、およびNeu4からなる群から選択されるヒトシアリダーゼである、請求項19に記載のシアリダーゼタンパク質付加体。
- 請求項1に記載の化合物を含む検出可能なコンジュゲートであって、該化合物が検出可能なタグ付け部分に共有結合的にコンジュゲートされている、検出可能なコンジュゲート。
- 請求項19に記載のシアリダーゼタンパク質付加体を含む検出可能なシアリダーゼタンパク質コンジュゲートであって、該シアリダーゼタンパク質付加体が、検出可能なタグ付け部分に共有結合的にコンジュゲートされている、検出可能なシアリダーゼタンパク質コンジュゲート。
- 前記タグ付け部分が標識を含む、請求項26に記載の検出可能なコンジュゲート、または請求項27に記載の検出可能なシアリダーゼコンジュゲート。
- 以下の式:
から選択される式を有する、請求項28に記載の検出可能なコンジュゲートもしくは検出可能なシアリダーゼコンジュゲート、またはその塩
(式中、
C3位のF原子は、アキシャルまたはエクアトリアルであり、
RKは、H、任意選択で置換されたC1〜6アルキル、またはタンパク質であり、
R2は、OR2O、N3、N(R2N)2、またはグアニジンであり、
各R2Oは独立に、水素、任意選択で置換されたC1〜6アルキル、任意選択で置換されたアシル、または酸素保護基であり、
各R2Nは独立に、水素、任意選択で置換されたC1〜6アルキル、または窒素保護基であり、
各R3aおよびR3bは独立に、水素、−C(=O)−R3r、または酸素保護基であり、
各R3rは、任意選択で置換されたC1〜6アルキル、任意選択で置換されたアリール、任意選択で置換されたヘテロアリール、または任意選択で置換された複素環、任意選択で置換されたアルキルアリール、任意選択で置換されたアルキルヘテロアリール、または任意選択で置換されたアルキル複素環であり、
Xは、−O−、−O(C=O)−、−NH−、−NH(C=O)−、−(C=O)NH−、−O(C=O)NH−、−O(C=S)NH−、−NH(C=O)NH−、および−NH(C=S)NH−からなる群から選択され、
R4aは、H、任意選択で置換されたC1〜6アルキル、または任意選択で置換されたアシルであり、
Yaは、Hまたは任意選択で置換されたC1〜6アルキルであり、
各Lは、独立に、−(CH2)n−、−(CH2)nC=O−、−(CH2)nNH−、−(C=O)(CH2)n−、−(CH2)nNH(C=O)−、−(C=O)(CH2)nNH(C=O)−、−(CH2)nSCH2(C=O)−、または−(CH2CH2O)n−からなる群から選択され、
各nは、1〜8の整数であり、両端を含み、
各RpおよびRqは独立に、水素、任意選択で置換された脂肪族;任意選択で置換されたヘテロ脂肪族;置換または非置換アリール;任意選択で置換されたヘテロアリール;任意選択で置換されたアシル;樹脂;タンパク質;レポーター;リンカーLaによって任意選択で接合された標識(該リンカーLaは任意選択で置換されたアルキレンである);任意選択で置換されたアルケニレン;任意選択で置換されたアルキニレン;任意選択で置換されたヘテロアルキレン;任意選択で置換されたヘテロアルケニレン;任意選択で置換されたヘテロアルキニレン;任意選択で置換されたアリーレン;任意選択で置換されたヘテロアリーレン;または任意選択で置換されたアシレンである)。 - 前記標識がフルオロフォアである、請求項28に記載の検出可能なコンジュゲートまたは検出可能なシアリダーゼコンジュゲート。
- 前記標識が、
である、請求項28に記載の検出可能なコンジュゲートまたは検出可能なシアリダーゼコンジュゲート。 - シアリダーゼの存在を検出するための方法であって、該方法は、
(a)シアリダーゼを含む疑いのある試料を請求項1に記載の化合物と接触させるステップと、
(b)レポーターを添加するステップと、
(c)シグナルを検出するステップと
を含み、シグナルの存在は、該試料中の該シアリダーゼの存在を示す、方法。 - 前記シアリダーゼが細胞内にある、請求項32に記載の方法。
- 前記化合物が、PDFSA−5−イン(IV)またはPDFSA−7−イン(VII):
- 前記試料が、哺乳動物、家禽、または魚由来である、請求項32に記載の方法。
- 前記哺乳動物がヒトである、請求項35に記載の方法。
- 前記試料が、病原体を含有する疑いがある、請求項32に記載の方法。
- 前記病原体が、細菌、ウイルス、原生動物、または真菌である、請求項37に記載の方法。
- 細胞中のシアリダーゼの位置を画像化するステップをさらに含む、請求項32に記載の方法。
- (a)細胞をPDFSA−5−イン(IV)、PDFSA−7−イン(VII)の化合物、またはその誘導体もしくはエステルと接触させるステップと、
(b)細胞内エステラーゼに前記化合物をそれぞれDFSA−5−イン(III)またはDFSA−7−イン(VI)に変換させるステップと、
(c)DFSA−5−イン(III)またはDFSA−7−イン(VI)を前記細胞中の細胞内位置で1つまたは複数のシアリダーゼに共有結合的にコンジュゲートさせるステップと、
(d)レポーターを添加するステップと、
(e)細胞内シアリダーゼ分布の画像を得るステップと
をさらに含む、請求項32に記載の方法。 - インフルエンザウイルスによる感染を決定する方法における使用のための、請求項1に記載の化合物を含む組成物であって、該方法は、
(a)インフルエンザウイルス感染の疑いのある対象からの検査試料を該組成物と接触させるステップと、
(b)レポーターを添加するステップと、
(c)シグナルを検出するステップと
を含み、シグナルの存在は、インフルエンザウイルスによる感染の可能性を示す、組成物。 - 前記化合物が、DFSA−5−イン(III)
もしくはDFSA−7−イン(VI)
、またはそのエステルである、請求項41に記載の組成物。 - 前記インフルエンザウイルスが、オセルタミビルに耐性でない、請求項41に記載の組成物。
- 前記インフルエンザウイルスが、オセルタミビルに感受性である、請求項41に記載の組成物。
- 前記インフルエンザウイルスが、オセルタミビルに耐性である、請求項41に記載の組成物。
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US9975965B2 (en) | 2015-01-16 | 2018-05-22 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
US10495645B2 (en) | 2015-01-16 | 2019-12-03 | Academia Sinica | Cancer markers and methods of use thereof |
WO2016118090A1 (en) | 2015-01-23 | 2016-07-28 | Agency For Science, Technology And Research | Cancer specific antigen-binding proteins |
US20170283878A1 (en) | 2015-12-11 | 2017-10-05 | Academia Sinica | Modulation of globoseries glycosphingolipid synthesis and cancer biomarkers |
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AU2013306098A1 (en) | 2015-02-12 |
JP2015531765A (ja) | 2015-11-05 |
US9914956B2 (en) | 2018-03-13 |
CA2880701A1 (en) | 2014-02-27 |
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