Adenosine analog and its use in regulating the circadian clock
The present invention provides a kind of nucleoside analogue compounds, and a composition comprising the compound and pentostatin, their use for modulating circadian rhythm, preferably, for shifting circadian phase, and methods for modulating circadian rhythm, preferably, for shifting circadian phase via the compound or the composition.
1 . A composition comprising an adenosine analogue compound of Formula I or a pharmaceutically acceptable salt thereof and pentostatin,
wherein:
R 1 is H;
R 2 is H, OH, O-Biotin, OAc, OTBS, F, Cl, Br, or I;
R 3 is OH, O-Biotin, OAc, or OTBS; or R 2 and R 3 are independently absent or ═O;
R 4 and R 5 are independently H, OH, F, Cl, Br, I, ═O, O-Biotin or N 3 ; or R 2 /R 3 and R 4 /R 5 form expoxy ethane together with the carbons they are connected to;
R 6 and R 7 are independently H, CH 2 —OH, CH 2 —N 3 , CH 2 —O-Biotin, CH 2 —AcO, CH 2 —OTBS, CO 2 Me, triphosphorylated methylene, 1,2-bishydroxyethane, tetrabutylammonium monophosphate, 1-hydroxyprop-2-yn-1-yl, or diazacymene;
R 8 is H, NH—CH 3 , F, Cl, Br, I, —O—CH 3 , or deuterium;
R 10 is H, —CH 3 , F, Cl, Br, I, NH 2 , NH—CH 3 , NH—NH 2 , ═O, NHBn, Biotinamide, m-hydroxyaniline, amino-cyclopropane, amino-cyclobutane, amino-cyclopentane, amino-cyclohexane, OMe or octamide; and
R 12 is H, NH 2 , F, Cl, Br, I, OMe, or 4-formamide-substituted pyrazole,
wherein the adenosine analogue compound does not include adenosine itself.
2 . The composition of claim 1 , wherein:
R 7 is CH 2 —OH, CH 2 —N 3 , CH 2 —O-Biotin, CH 2 —AcO, CH 2 —OTBS, CO 2 Me, triphosphorylated methylene, 1,2-bishydroxyethane, tetrabutylammonium monophosphate, 1-hydroxyprop-2-yn-1-yl, or diazacymene.
3 . The composition of claim 1 , wherein:
R 4 is H, and R 5 is H, OH, F, Cl, Br, I, O-Biotin or N 3 ; or
R 4 is H, OH, F, Cl, Br, I, O-Biotin or N 3 , and R 5 is H.
4 . The composition of claim 1 , wherein:
R 6 is H, and R 7 is CH 2 —OH, CH 2 —N 3 , CH 2 —O-Biotin, CH 2 —AcO, CH 2 —OTBS, CO 2 Me, triphosphorylated methylene, 1,2-bishydroxyethane, tetrabutylammonium monophosphate, 1-hydroxyprop-2-yn-1-yl, or diazacymene; or
R 6 is H, CH 2 —OH, CH 2 —N 3 , CH 2 —O-Biotin, CH 2 —AcO, CH 2 —OTBS, CO 2 Me, triphosphorylated methylene, 1,2-bishydroxyethane, tetrabutylammonium monophosphate, 1-hydroxyprop-2-yn-1-yl, or diazacymene, and R 7 is H.
5 . The composition of claim 1 , wherein:
R 8 is H or deuterium;
R 10 is NH 2 , NH—CH 3 , NH—NH 2 , amino-cyclopropane, amino-cyclobutane, amino-cyclopentane, or amino-cyclohexane; and
R 12 is H.
6 . The composition of claim 1 , wherein the compound is cordycepin, or the compound is selected from:
7 . The composition of claim 6 , wherein the compound is:
8 . A composition comprising a compound, or a pharmaceutically acceptable salt thereof and pentostatin, wherein the compound is selected from:
Name
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
NQZ-067
25
NQZ-068
26
NQZ-069
27
Abacavir NQZ-078
28
Vidaradine NQZ-071
29
NQZ-082
30
NQZ-081
31
NQZ-083
32
NQZ-084
33
NQZ-089
34
NQZ-091
35
NQZ-106
36
NQZ-107
37
NQZ-117
38
NQZ-125
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+get,574
61
+get,575
62
+get,576
63
64
65
66
67
68
9 . A method for modulating circadian rhythm, for shifting circadian phase, for increasing circadian amplitude, for regulating RUVBL helicase, for treating jet lag, shift-work, age-related sleep disturbances, or circadian clock-related sleep disturbances, which comprises administrating to a subject a therapeutically effective amount of a substance, wherein the substance is the composition of claim 1 .
10 . The method of claim 9 , wherein the substance is administrated at the time of Per2-dLuc peak, but not at the trough.
11 . The method of claim 9 , wherein the target of the substance is RUVBL helicase, which mediate cordycepin-mediated induction of Per2-dLuc and the clock phase shift, is the direct target of cordycepin, or is the target of the compound of Formula I,
wherein:
R 1 is H;
R 2 is H, OH, O-Biotin, OAc, OTBS, F, Cl, Br, or I; R 3 is OH, O-Biotin, OAc, or OTBS; or R 2 and R 3 are independently absent or ═O;
R 4 and R 5 are independently H, OH, F, Cl, Br, I, ═O, O-Biotin or N 3 ; or R 2 /R 3 and R 4 /R 5 form expoxy ethane together with the carbons they are connected to;
R 6 and R 7 are independently H, CH 2 —OH, CH 2 —N 3 , CH 2 —OBiotin, CO 2 Me, triphosphorylated methylene, 1,2-bishydroxyethane, tetrabutylammonium monophosphate, 1-hydroxyprop-2-yn-1-yl, or diazacymene;
R 8 is H, NH—CH 3 , F, Cl, Br, I, —O—CH 3 , or deuterium;
R 10 is H, —CH 3 , F, Cl, Br, I, NH 2 , NH—NH 2 , ═O, NHBn, Biotinamide, m-hydroxyaniline, amino-cyclopropane, or octamide; and
R 12 is H, NH 2 , F, Cl, Br, I, OMe, or 4-formamide-substituted pyrazole.
12 . The method of claim 11 , wherein the RUVBL helicase is RUVBL1 helicase or RUVBL2 helicase.
13 . The method of claim 9 , wherein the substance is formulated for enteral administration, intravenous administration, oral administration, or sublingual administration.
14 . A method for increasing circadian amplitude, for regulating RUVBL helicase, for treating jet lag, shift-work, age-related sleep disturbances, or circadian clock-related sleep disturbances, which comprises administrating to a subject a therapeutically effective amount of substance, wherein the substance is a compound, or a pharmaceutically acceptable salt thereof, and the subject is a human, wherein the compound is: