초록

The present invention provides moenomycin-based probe compounds of Formula (I) for use in screening inhibitors of bacterial glycosyltransferases. The present invention also provides bacterial glycosyltransferase screening assays using compounds of Formula (I).

대표청구항 ▼

1. A compound of Formula (I): or a salt thereof, wherein R1 is -L-RP, —C(O)NH-L-RP, —CH2O-L-RP, or —C(O)O-L-RP;R2 and R3 are independently hydrogen, optionally substituted aliphatic, —OR9, —N(R8)2, or —C(O)NHR8;R4 is hydrogen or —WR4a;W is —O— or —NH—;R4a is hydrogen, a hydroxyl protecting group, o

1. A compound of Formula (I): or a salt thereof, wherein R1 is -L-RP, —C(O)NH-L-RP, —CH2O-L-RP, or —C(O)O-L-RP;R2 and R3 are independently hydrogen, optionally substituted aliphatic, —OR9, —N(R8)2, or —C(O)NHR8;R4 is hydrogen or —WR4a;W is —O— or —NH—;R4a is hydrogen, a hydroxyl protecting group, optionally substituted aliphatic, —C(O)R10, —C(O)NHR8, —C(═NR8)NHR8, or —C(O)OR9;R5 is hydrogen or —NHR8;R6 is hydrogen, —CH3, —CH2OR9, or —CH2ORCX; wherein RCX is a carbohydrate moiety;R7 is hydrogen, —OR9, or —N(R8)2;each R8 is independently hydrogen, an amino protecting group, —C(O)R10, optionally substituted aliphatic, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl, or two R8 groups on the same nitrogen may be taken together to form an optionally substituted heterocyclyl;each R9 is independently hydrogen, a hydroxyl protecting group, —C(O)R10, optionally substituted aliphatic, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;each R10 is independently optionally substituted aliphatic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl;Ra and Rb are independently hydrogen or a hydroxyl protecting group;G is an optionally substituted C1-16 aliphatic group, wherein 0 to 10 methylene units are optionally replaced with —O—, —NRx—, —S—, —C(O)—, —C(═NRx), —S(O)—, —SO2—, —N═N—, —C═N—, —N—O—, an optionally substituted arylene, an optionally substituted heterocyclylene, or an optionally substituted heteroarylene; wherein each instance of Rx is independently hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; orG is a group of Formula (a), (b), or (c): wherein a is 3, 4, or 5; wherein X1, X2, X3, X4, X5, X6, and X7 are each independently hydrogen or halogen;d is an integer between 1 and 25, inclusive; ande is an integer of between 2 and 25, inclusive;provided the sum of d and e is greater than 16; or wherein Y is —O—, —S—, —NRY—, or an optionally substituted methylene group, wherein RY is hydrogen, optionally substituted aliphatic, or an amino protecting group;each instance of Rc is independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —ORe, —SRe, —NHRe, or —N(Re)2, wherein each instance of Re is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two Re groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;each instance of Rd is independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —ORf, —SRf, —NHRf, or —N(Rf)2, wherein each instance of Rf is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two Rf groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;Rz is hydrogen, —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —ORg, —SRg, —NHRg, or —N(Rg)2, wherein each instance of Rg is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl or two Rg groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;each instance of n is, independently, 0, 1, 2, 3, or 4;each instance of m is, independently, 0, 1, 2, 3, or 4; andx is 1, 2, 3, 4, 5, or 6;RYY is hydrogen or —ORXX;RXX is hydrogen, a hydroxyl protecting group, or a group of formula: wherein R11 is hydrogen, optionally substituted aliphatic, —C(O)NHR8, —CH2OR9, or —C(O)OR9;R12 and R13 are independently hydrogen, optionally substituted aliphatic, —OR9, —N(R8)2, or —C(O)NHR8;R14 is hydrogen or —NHR8;R15 is hydrogen, —C(O)NHR8, —CH2OR9, or —C(O)OR9;R16 is hydrogen or —OR9;R17 is hydrogen or —OR9;R18 is hydrogen or —OR9;R19a is hydrogen or —OR9;R19b is hydrogen or —OR9; wherein a hydrogen radical on the compound of Formula (I) is replaced with -L-RP; L is a covalent bond, —NRy—, —N(Ry)C(O)—, —N(Ry)C(O)N(Ry)—, —N(Ry)C(S)N(Ry)—, —C(O)N(Ry)—, —N(Ry)SO2—, —SO2N(Ry)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO2—, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or an optionally substituted aliphatic linker, wherein one or more methylene units of the aliphatic linker are optionally replaced by —NRy—, —N(Ry)C(O)—, —N(Ry)C(O)N(Ry)—, —N(Ry)C(S)N(Ry)—, —C(O)N(Ry)—, —N(Ry)SO2—, —SO2N(Ry)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO2—, cycloalkylene, heterocyclylene, arylene, or heteroarylene; wherein Ry is hydrogen, C1-6 alkyl, or —C(O)C1-6 alkyl; andRP is selected from the group consisting of ligands, radionuclides, fluorescent dyes, chemiluminescent agents, microparticles, enzymes, calorimetric labels, magnetic labels, and haptens. 2. A compound of Formula (I): or a salt thereof, wherein R1 is hydrogen, —C(O)NHR8, —CH2OR9, or —C(O)OR9;R2 and R3 are independently hydrogen, optionally substituted aliphatic, —OR9, —N(R8)2, or —C(O)NHR8;R4 is hydrogen or —WR4a;W is —O— or —NH—;R4a is hydrogen, a hydroxyl protecting group, optionally substituted aliphatic, —C(O)R10, —C(O)NHR8, —C(═NR8)NHR8, or —C(O)OR9;R5 is hydrogen or —NHR8;R6 is hydrogen, —CH3, —CH2OR9, or —CH2ORCX; wherein RCX is a carbohydrate moiety;R7 is hydrogen, —OR9, or —N(R8)2;each R8 is independently hydrogen, an amino protecting group, —C(O)R10, optionally substituted aliphatic, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl, or two R8 groups on the same nitrogen may be taken together to form an optionally substituted heterocyclyl;each R9 is independently hydrogen, a hydroxyl protecting group, —C(O)R10, optionally substituted aliphatic, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;each R10 is independently optionally substituted aliphatic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl;Ra and Rb are independently hydrogen or a hydroxyl protecting group;G is an optionally substituted C1-16 aliphatic group, wherein 0 to 10 methylene units are optionally replaced with —O—, —NRx—, —S—, —C(O)—, —C(═NRx), —S(O)—, —SO2—, —N═N—, —C═N—, —N—O—, an optionally substituted arylene, an optionally substituted heterocyclylene, or an optionally substituted heteroarylene; wherein each instance of Rx is independently hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; orG is a group of Formula (a), (b), or (c): wherein a is 3, 4, or 5; wherein X1, X2, X3, X4, X5, X6, and X7 are each independently hydrogen or halogen;d is an integer between 1 and 25, inclusive; ande is an integer of between 2 and 25, inclusive;provided the sum of d and e is greater than 16; or wherein Y is —O—, —S—, —NRY—, or an optionally substituted methylene group, wherein RY is hydrogen, optionally substituted aliphatic, or an amino protecting group;each instance of Rc is independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —ORe, —SRe, —NHRe, or —N(Re)2, wherein each instance of Re is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two Re groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;each instance of Rd is independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —ORf, —SRf, —NHRf, or —N(Rf)2, wherein each instance of Rf is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two Rf groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;Rz is hydrogen, —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —ORg, —SRg, —NHRg, or —N(Rg)2, wherein each instance of Rg is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl or two Rg groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;each instance of n is, independently, 0, 1, 2, 3, or 4;each instance of m is, independently, 0, 1, 2, 3, or 4; andx is 1, 2, 3, 4, 5, or 6;RYY is hydrogen or —ORXX;RXX is hydrogen, a hydroxyl protecting group, or a group of formula: wherein R11 is hydrogen, optionally substituted aliphatic, —C(O)NHR8, —CH2OR9, or —C(O)OR9;R12 and R13 are independently hydrogen, optionally substituted aliphatic, —OR9, —N(R8)2, or —C(O)NHR8;R14 is hydrogen or —NHR8;R15 is hydrogen, —C(O)NHR8, —CH2OR9, or —C(O)OR9;R16 is hydrogen or —OR9;R17 is hydrogen or —OR9;R18 is hydrogen or —OR9;R19a is hydrogen or —OR9;R19b is hydrogen or —OR9; wherein a hydrogen radical on the compound of Formula (I) is replaced with -L-RP: L is —NHC(S)NH—, —C(O)CH2—NHC(S)NH—, and RP is selected from the group consisting of ligands, radionuclides, fluorescent dyes, chemiluminescent agents, microparticles, enzymes, calorimetric labels, magnetic labels, and haptens. 3. The compound of claim 2, wherein RYY is —OH or —ORXX, and RXX is a group of formula: 4. The compound of claim 2, wherein RXX is a group of formula: 5. The compound of claim 2, wherein R6 is —CH2OH or —CH2ORCX; wherein RCX is a carbohydrate moiety. 6. The compound of claim 2, wherein G is 7. The compound of claim 2, wherein RP is selected from the group consisting of Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680, AMCA, AMCA-S, BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 493/503, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY 650/665, aminomethylcoumarin, carbocyanine, carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, coumarin, coumarin 343, cyanine dyes, dansyl, dapoxyl, dialkylaminocoumarin, 4′,5′-dichloro-2′,7′-dimethoxyfluorescein, DM-NERF, eosin, erythrosin, fluorescein, FAM, hydroxycoumarin, IRD40, IRD 700, IRD 800, 6-carboxy-4′,5′-dichloro-2′,7′-dimethoxyfluorescein (6-JOE), lissamine rhodamine B, Marina Blue, merocyanine, methoxycoumarin, naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, oxonol dyes, Pacific Blue, phycoerythrin, PyMPO, pyrene, rhodamine B, rhodamine 6G, rhodamine green, rhodamine red, rhodol green, styryl dyes, 2′,4′,5′,7′-tetrabromosulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X, 5(6)-carboxyfluorescein, 2,7-dichlorofluorescein, N,N-bis(2,4,6-trimethylphenyl)-3,4,9,10-perylenebis(dicarboximide), HPTS, ethyl eosin, DY-490XL MegaStokes, DY-485XL MegaStokes, Adirondack Green 520, ATTO 465, ATTO 488, ATTO 495, Y0Y0-1,5-FAM, BCECF, dichlorofluorescein, rhodamine 110, rhodamine 123, YO-PRO-I, SYTOX Green, Sodium Green, SYBR Green I, Alexa Fluor 500, FITC, Fluo-3, Fluo-4, fluoro-emerald, YoYo-I ssDNA, YoYo-I dsDNA, YoYo-I, SYTO RNASelect, Diversa Green-FP, Dragon Green, EvaGreen, Surf Green EX, Spectrum Green, Spectrum Red, NeuroTrace 500525, NBD-X, MitoTracker Green FM, LysoTracker Green DND-26, CBQCA, PA-GFP (post-activation), WEGFP (post-activation), FLASH-CCXXCC, Azami Green monomeric, Azami Green, green fluorescent protein (GFP), EGFP, Kaede Green, 7-benzylamino-4-nitrobenz-2-oxa-1,3-diazole, Bexl, doxorubicin, Lumio Green, and SuperGlo GFP. 8. The compound of claim 2 of formula: 9. The compound of claim 2, wherein: R1 is —C(O)NHR8, —CH2OR9, or —C(O)OR9;one of R2 and R3 is hydrogen, and the other is —OR9;R4 is —W—R4a;R5 is —NHR8;R6 is —CH3, —CH2OR9, or —CH2ORCX;R7 is —OR9 or —N(R8)2;R11 is —CH3, —C(O)NHR8, —CH2OR9, or —C(O)OR9;one of R12 and R13 is hydrogen, and the other is —OR9;R14 is —NHR8; andone of R19a and R19b is hydrogen, and the other is —OR9. 10. The compound of claim 3, wherein R11 is —CH2OH. 11. The compound of claim 2, wherein RP is selected from the group consisting of fluorescein, naphthofluorescein, 4′,5′-dichloro-2′,7′-dimethoxy-fluorescein, 2′,4′,5′,7′-tetrabromosulfone-fluorescein, 2,7-dichlorofluorescein, 6-carboxy-4′,5′-dichloro-2′,7′-dimethoxyfluorescein, and 5(6)-carboxyfluorescein. 12. The compound of claim 11, wherein RP is fluorescein. 13. The compound of claim 3, wherein R11 is —CH3. 14. The compound of claim 2, wherein R12 is hydrogen; and R13 is —OH. 15. The compound of claim 2, wherein G is of Formula (a). 16. The compound of claim 2, wherein G is of Formula (b). 17. A compound of Formula (I): or a salt thereof, wherein R1 is hydrogen, —C(O)NHR8, —CH2OR9, or —C(O)OR9;R2 and R3 are independently hydrogen, optionally substituted aliphatic, —OR9, —N(R8)2, or —C(O)NHR8;R4 is hydrogen or —WR4a;W is —O— or —NH—;R4a is hydrogen, a hydroxyl protecting group, optionally substituted aliphatic, —C(O)R10, —C(O)NHR8, —C(═NR8)NHR8, or —C(O)OR9;R5 is hydrogen or —NHR8;R6 is hydrogen, —CH3, —CH2OR9, or —CH2ORCX; wherein RCX is a carbohydrate moiety;R7 is hydrogen, —OR9, or —N(R8)2;each R8 is independently hydrogen, an amino protecting group, —C(O)R10, optionally substituted aliphatic, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl, or two R8 groups on the same nitrogen may be taken together to form an optionally substituted heterocyclyl;each R9 is independently hydrogen, a hydroxyl protecting group, —C(O)R10, optionally substituted aliphatic, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;each R10 is independently optionally substituted aliphatic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl;Ra and Rb are independently hydrogen or a hydroxyl protecting group;G is an optionally substituted C1-16 aliphatic group, wherein 0 to 10 methylene units are optionally replaced with —O—, —NRx—, —S—, —C(O)—, —C(═NRx), —S(O)—, —SO2—, —N═N—, —C═N—, —N—O—, an optionally substituted arylene, an optionally substituted heterocyclylene, or an optionally substituted heteroarylene; wherein each instance of Rx is independently hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; orG is a group of Formula (a), (b), or (c): wherein a is 3, 4, or 5; wherein X1, X2, X3, X4, X5, X6, and X7 are each independently hydrogen or halogen;d is an integer between 1 and 25, inclusive; ande is an integer of between 2 and 25, inclusive;provided the sum of d and e is greater than 16; or wherein Y is —O—, —S—, —NRY—, or an optionally substituted methylene group, wherein RY is hydrogen, optionally substituted aliphatic, or an amino protecting group;each instance of Rc is independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —ORe, —SRe, —NHRe, or —N(Re)2, wherein each instance of Re is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two Re groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;each instance of Rd is independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —ORf, —SRf, —NHRf, or —N(Rf)2, wherein each instance of Rf is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two Rf groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;Rz is hydrogen, —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —ORg, —SRg, —NHRg, or —N(Rg)2, wherein each instance of Rg is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl or two Rg groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;each instance of n is, independently, 0, 1, 2, 3, or 4;each instance of m is, independently, 0, 1, 2, 3, or 4; andx is 1, 2, 3, 4, 5, or 6;RYY is hydrogen or —ORXX;RXX is hydrogen, a hydroxyl protecting group, or a group of formula: wherein R11 is hydrogen, optionally substituted aliphatic, —C(O)NHR8, —CH2OR9, or —C(O)OR9;R12 and R13 are independently hydrogen, optionally substituted aliphatic, —OR9, —N(R8)2, or —C(O)NHR8;R14 is hydrogen or —NHR8;R15 is hydrogen, —C(O)NHR8, —CH2OR9, or —C(O)OR9;R16 is hydrogen or —OR9;R17 is hydrogen or —OR9;R18 is hydrogen or —OR9;R19a is hydrogen or —OR9;R19b is hydrogen or —OR9; wherein a hydrogen radical on the compound of Formula (I) is replaced with -L-RP; L is an optionally substituted aliphatic linker wherein one methylene unit is replaced by tetrazolyl or NHC(S)NH—; and one or more additional methylene units are optionally replaced by —NRy—, —N(Ry)C(O)—, —N(Ry)C(O)N(Ry)—, —N(Ry)C(S)N(Ry)—, —C(O)N(Ry)—, —N(Ry)SO2—, —SO2N(Ry)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, or —SO2—; wherein Ry is hydrogen, C1-6 alkyl, or —C(O)C1-6 alkyl; andRP is selected from the group consisting of ligands, radionuclides, fluorescent dyes, chemiluminescent agents, microparticles, enzymes, calorimetric labels, magnetic labels, and haptens.