US2017313736A1PendingUtilityA1
Mutagenic nucleoside analogs and uses thereof
Assignee: MASSACHUSETTS INST TECHNOLOGYPriority: Jan 28, 2015Filed: Jul 6, 2017Published: Nov 2, 2017
Est. expiryJan 28, 2035(~8.5 yrs left)· nominal 20-yr term from priority
A61K 31/706C07H 19/23A61K 31/7052C07H 19/173A61P 31/18C07H 19/12A61K 31/7068A61K 31/7076A61P 31/12A61P 31/20C07H 19/04A61P 35/00A61K 45/06A61K 31/708C12Q 1/6811A61K 31/7064G01N 33/15G01N 21/3577
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Claims
Abstract
The present disclosure provides nucleoside analogs of Formula (I) or (II). The nucleoside analogs are expected to show multiple tautomerism and may increase the mutation of an RNA and/or DNA (be mutagenic) of a virus or cancer cell. The multiple tautomerism and mutagenesis of the nucleoside analogs may be adjusted by substituting the nucleoside analogs with one or more electron-donating groups and/or electron-withdrawing groups to increase or decrease the pK a (e.g., to a pK a between 5.5 or 8.5). The present disclosure also provides pharmaceutical compositions and kits including the nucleoside analogs and methods of treating a viral infection (e.g., influenza, HIV infection, or hepatitis) or cancer using the nucleoside analogs, pharmaceutical compositions, or kits.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula (I):
wherein:
R 1 is H or —OH;
X is of the formula:
Y is —O—, —NR 2 — or —C(R 2 ) 2 —;
U is —O—, —NR 2 — or —C(R 2 ) 2 —;
Z is —O—, —S—, —NH—, or —C(R 2 ) 2 —;
each instance of R 2 is independently H, an electron-withdrawing group, or an electron-donating group;
W is an anionic counterion; and
n is 1, 2, or 3;
wherein the pK a of the compound is between 5.5 and 8.5, inclusive, and the pK a is a pK a at 25° C.
2 . The compound of claim 1 , wherein the compound is of the formula:
3 . The compound of claim 1 , wherein the compound is of the formula:
4 . The compound of claim 1 , wherein the compound is of the formula:
5 . The compound of claim 1 , wherein R 1 is H.
6 . The compound of claim 1 , wherein R 1 is —OH.
7 . The compound of any one of claims 1 - 6 , wherein X is
8 . The compound of claim 7 , wherein X is
9 . The compound of claim 7 , wherein X is
10 . The compound of any one of claims 1 to 6 , wherein X is
11 . The compound of claim 10 , wherein X is
12 . The compound of claim 10 , wherein X is
13 . The compound of claim 10 , wherein X is
14 . The compound of claim 10 , wherein X is
15 . The compound of claim 10 , wherein X is
16 . The compound of claim 10 , wherein X is
17 . The compound of any one of claims 1 - 6 , wherein X is
18 . The compound of claim 17 , wherein X is
19 . The compound of claim 17 , wherein X is
20 . The compound of any one of claims 1 - 6 , wherein X is
21 . The compound of claim 20 , wherein X is
22 . The compound of claim 20 , wherein X is
23 . The compound of claim 20 , wherein X is
24 . The compound of claim 20 , wherein X is
25 . The compound of claim 20 , wherein X is
26 . The compound of claim 20 , wherein X is
27 . The compound of claim 20 , wherein X is
28 . The compound of claim 20 , wherein X is
29 . The compound of any one of claims 1 - 6 , wherein X is
30 . The compound of claim 29 , wherein X is
31 . The compound of any one of claims 1 - 6 , wherein X is
32 . The compound of claim 31 , wherein X is
33 . The compound of claim 31 , wherein X is
34 . The compound of any one of claims 1 - 6 , wherein X is
35 . The compound of claim 34 , wherein X is
36 . The compound of claim 34 , wherein X is
37 . The compound of any one of claims 1 - 6 , wherein X is
38 . The compound of claim 37 , wherein X is
39 . The compound of claim 37 , wherein X is
40 . The compound of any one of claims 1 - 6 , wherein X is
41 . The compound of claim 40 , wherein X is
42 . The compound of claim 40 , wherein X is
43 . The compound of any one of claims 1 - 6 , wherein X is
44 . The compound of claim 43 , wherein X is
45 . The compound of claim 43 , wherein X is
46 . The compound of any one of claims 1 - 6 , wherein X is
47 . The compound of claim 46 , wherein X is
48 . The compound of claim 46 , wherein X is
49 . The compound of any one of claims 1 - 48 , wherein Y is —O—.
50 . The compound of any one of claims 1 - 48 , wherein Y is —NR 2 —.
51 . The compound of any one of claims 1 - 48 , wherein Y is —C(R 2 ) 2 —.
52 . The compound of any one of claims 1 - 51 , wherein U is —O—.
53 . The compound of any one of claims 1 - 51 , wherein U is —NR 2 —.
54 . The compound of any one of claims 1 - 51 , wherein U is —C(R 2 ) 2 —.
55 . The compound of any one of claims 1 - 54 , wherein Z is —O—or —S—.
56 . The compound of any one of claims 1 - 54 , wherein Z is —NH—.
57 . The compound of any one of claims 1 - 54 , wherein Z is —C(R 2 ) 2 —.
58 . The compound of any one of claims 1 - 57 , wherein W is F − , Cl − , Br − , I − , NO 3 − , ClO 4 − , OH − , H 2 PO 4 , HPO 4 2 , PO 4 3 , HSO 4 , SO 4 2- , OTf, OTs, OMs, OAc, OBz, BF 4 , PF 4 , PF 3 , AsF 6 , or SbF 6 − .
59 . The compound of any one of claims 1 - 58 , wherein n is 1.
60 . The compound of any one of claims 1 - 58 , wherein n is 2.
61 . The compound of any one of claims 1 - 58 , wherein n is 3.
62 . The compound of any one of claims 1 - 61 , wherein the pK a is between 6 and 8, inclusive.
63 . The compound of any one of claim 62 , wherein the pK a is between 6.5 and 7.5, inclusive.
64 . A pharmaceutical composition comprising a compound of any one of claims 1 - 63 and optionally a pharmaceutically acceptable excipient.
65 . The pharmaceutical composition of claim 64 further comprising an additional pharmaceutical agent.
66 . The pharmaceutical composition of claim 65 , wherein the additional pharmaceutical agent is an antiviral agent.
67 . The pharmaceutical composition of claim 65 , wherein the additional pharmaceutical agent is an anticancer agent.
68 . A method of increasing the mutagenicity of a first compound, the method comprising substituting the first compound with one or more electron donating groups and/or electron withdrawing groups to provide a second compound, wherein:
the first compound is a nucleobase, nucleoside, nucleotide, or an analog thereof; and
if the pK a of the first compound is higher than 7, then the pK a of the second compound is lower than the pK a of the first compound; or
if the pK a of the first compound is lower than 7, then the pK a of the second compound is higher than the pK a of the first compound;
wherein each pK a is independently a pK a at 25° C.
69 . The method of claim 68 , wherein the pK a of the second compound is between 5.5 and 8.5, inclusive.
70 . The method of claim 68 , wherein the pK a of the second compound is between 6 and 8, inclusive.
71 . The method of claim 68 , wherein the pK a of the second compound is between 6.5 and 7.5, inclusive.
72 . The compound of any one of claims 1 - 63 or the method of any one of claims 68 - 71 , wherein each of the electron-withdrawing group and electron-donating group is independently:
if attached to a carbon atom: halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —N(R a )C(═O)R a , —N(R a )C(═O)OR a , —N(R a )C(═O)N(R a ) 2 , —N(R a )S(═O)R a , —N(R a )S(═O)OR a , —N(R a )S(═O)N(R a ) 2 , —N(R a )S(═O) 2 R a , —N(R a )S(═O) 2 OR a , —N(R a )S(═O) 2 N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , —OC(═O)N(R a ) 2 , —SeR a , —N(R a ) 3 + , —O—OR a , —N═NR a , —N 3 , —S(═O)R a , —S(═O)OR a , —S(═O)N(R a ) 2 , —S(═O) 2 R a , —S(═O) 2 OR a , —S(═O) 2 N(R a ) 2 , —NO, or —C(═O)-halide, or two instances of R 2 on a same carbon atom are joined to form oxo or substituted or unsubstituted alkenyl; or
if attached to a nitrogen atom: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , or a nitrogen protecting group; and
each instance of R a is independently H, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R a are joined to form a substituted or unsubstituted, heterocyclic ring, or substituted or unsubstituted, heteroaryl ring.
73 . The compound or method of claim 72 , wherein each of the electron-withdrawing group and electron-donating group is independently:
if attached to a carbon atom: halogen, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —N(R a )C(═O)R a , —N(R a )C(═O)OR a , —N(R a )C(═O)N(R a ) 2 , —N(R a )S(═O)R a , —N(R a )S(═O)OR a , —N(R a )S(═O)N(R a ) 2 , —N(R a )S(═O) 2 R a , —N(R a )S(═O) 2 OR a , —N(R a )S(═O) 2 N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , —OC(═O)N(R a ) 2 , —SeR a , —N(R a ) 3 + , —O—OR a , —N═NR a , —N 3 , —S(═O)R a , —S(═O)OR a ,—S(═O)N(R a ) 2 , —S(═O) 2 R a , —S(═O) 2 OR a , —S(═O) 2 N(R a ) 2 , —NO,—C(═O)-halide, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted aryl; or if attached to a nitrogen atom: —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted aryl.
74 . The compound or method of claim 72 , wherein each of the electron-withdrawing group and electron-donating group, if attached to a carbon atom, is independently halogen, —OR a , —N(R a ) 2 , —SR a , —CN, —C(═O)R a , —C(═O)OR a , —NO 2 ,—SeR a , —N(R a ) 3 + , —O—OR a , —N═NR a , —N 3 , —S(═O) 2 R a , —S(═O) 2 OR a , —NO,—C(═O)-halide, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted aryl.
75 . The compound or method of claim 72 , wherein each of the electron-withdrawing group and electron-donating group, if attached to a carbon atom, is independently F, Cl, or —OH.
76 . The compound or method of any one of claims 72 - 74 , wherein each of the alkyl, alkenyl, and aryl independently is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —N(R a )C(═O)R a , —N(R a )C(═O)OR a , —N(R a )C(═O)N(R a ) 2 , —N(R a )S(═O)R a , —N(R a )S(═O)OR a , —N(R a )S(═O)N(R a ) 2 , —N(R a )S(═O) 2 R a , —N(R a )S(═O) 2 OR a , —N(R a )S(═O) 2 N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a ,—OC(═O)N(R a ) 2 , —SeR a , —N(R a ) 3 + , —O—OR a , —N═NR a , —N 3 , —S(═O)R a , —S(═O)OR a , —S(═O)N(R a ) 2 , —S(═O) 2 R a , —S(═O) 2 OR a , —S(═O) 2 N(R a ) 2 , —NO,—C(═O)-halide, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted aryl.
77 . The compound or method of claim 76 , wherein each of the alkyl, alkenyl, and aryl independently is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, —OR a , —N(R a ) 2 , —SR a , —CN, —C(═O)R a , —C(═O)OR a , —NO 2 ,—SeR a , —N(R a ) 3 + , —O—OR a , —N═NR a , —N 3 , —S(═O) 2 R a , —S(═O) 2 OR a , —NO,—C(═O)-halide, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted aryl.
78 . The compound or method of any one of claims 72 - 77 , wherein each instance of alkyl is independently C 1-6 alkyl.
79 . The compound or method of any one of claims 72 - 78 , wherein each instance of aryl is independently phenyl.
80 . A method of determining tautomeric forms of a compound, the method comprising:
providing the compound in physiological conditions; performing a variable temperature 1-dimensional infrared spectroscopy test or a variable temperature 2-dimensional infrared spectroscopy test on the compound; and performing a density functional theory calculation on the compound; wherein the compound is a nucleobase, nucleoside, nucleotide, or an analog thereof.
81 . The method of claim 80 further comprising detecting the presence of tautomeric forms of the compound.
82 . The method of claim 80 further comprising quantitating the relative amount of tautomeric forms of the compound.
83 . The method of any one of claims 80 - 82 , wherein in the step of providing the compound, the compound is provided in the absence of a polymer.
84 . The method of any one of claims 80 - 82 , wherein in the step of providing the compound, the compound is provided further in the presence of a polymer.
85 . The method of any one of claims 80 - 84 , wherein in the step of providing the compound, the compound is not part of a polymer.
86 . The method of any one of claims 80 - 84 , wherein in the step of providing the compound, the compound is part of a polymer.
87 . The method of any one of claims 80 - 86 , wherein the 1-dimensional infrared spectroscopy test is a 1-dimensional Fourier transform infrared spectroscopy test.
88 . The method of any one of claims 80 - 87 , wherein the 2-dimensional infrared spectroscopy test is a 2-dimensional Fourier transform infrared spectroscopy test.
89 . A method of determining tautomeric forms of a compound, the method comprising:
providing the compound in physiological conditions; and performing a density functional theory calculation on the compound to determine the binding isotope effect for each of the tautomeric forms; wherein the compound is a nucleobase, nucleoside, nucleotide, or an analog thereof, and interacts non-covalently with a nucleic acid, aptamer, or protein.
90 . The method of claim 89 further comprising detecting the presence of tautomeric forms of the compound.
91 . The method of claim 89 further comprising quantitating the relative amount of tautomeric forms of the compound.
92 . A method of evaluating the mutagenicity of a compound in different pH conditions, the method comprising:
a primer extension reaction on a template strand comprising at a defined site a compound to provide a synthesized strand, wherein the primer extension reaction is performed in a solution buffered at pH between 5.0 and 9.0, inclusive, using a recombinant polymerase and a custom designed primer; specifically polymerase chain reaction (PCR) amplifying the synthesized strand to provide a PCR product; and analyzing the PCR product using a restriction endonuclease and postlabeling (REAP) assay to quantitate the mutagenicity of the compound present in the template strand; wherein the compound is a nucleobase, nucleoside, nucleotide, or an analog thereof.
93 . The method of claims 68 - 92 , wherein the compound is a compound of any one of claims 1 - 63 .
94 . A method of treating a viral infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 - 63 or a pharmaceutical composition of any one of claims 64 - 67 .
95 . The method of claim 94 , wherein the viral infection is an influenza virus infection, human immunodeficiency virus (HIV) infection, or hepatitis.
96 . A method of increase the mutation rate of a RNA or DNA of a virus, the method comprising contacting the virus with an effective amount of a compound of any one of claims 1 - 63 or a pharmaceutical composition of any one of claims 64 - 67 .
97 . A method of killing a virus, the method comprising contacting the virus with an effective amount of a compound of any one of claims 1 - 63 or a pharmaceutical composition of any one of claims 64 - 67 .
98 . A method of inhibiting the replication of a virus, the method comprising contacting the virus with an effective amount of a compound of any one of claims 1 - 63 or a pharmaceutical composition of any one of claims 64 - 67 .
99 . The method of any one of claims 96 - 98 , wherein the virus is influenza virus, human immunodeficiency virus (HIV), hepatitis virus, or Dengue virus.
100 . The method of any one of claims 96 - 99 , wherein the virus is in vitro.
101 . The method of any one of claims 96 - 99 , wherein the virus is in vivo.
102 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 - 63 or a pharmaceutical composition of any one of claims 64 - 67 .
103 . The method of claim 102 , wherein the cancer is a cancer with a mutator phenotype.
104 . A method of increasing the mutation rate of a RNA and/or DNA of a cancer cell, the method comprising contacting the cancer cell with an effective amount of a compound of any one of claims 1 - 63 or a pharmaceutical composition of any one of claims 64 - 67 .
105 . A method of inducing apoptosis of a cancer cell, the method comprising contacting the cancer cell with an effective amount of a compound of any one of claims 1 - 63 or a pharmaceutical composition of any one of claims 64 - 67 .
106 . A method of decreasing DNA methylation in a cancer cell, the method comprising contacting the cancer cell with an effective amount of a compound of any one of claims 1 - 63 or a pharmaceutical composition of any one of claims 64 - 67 .
107 . The method of any one of claims 104 - 106 , wherein the cancer cell is in vitro.
108 . The method of any one of claims 104 - 106 , wherein the cancer cell is in vivo.
109 . The method of any one of claims 104 - 108 , wherein the cancer cell is a cancer cell with a mutator phenotype.
110 . A kit comprising:
a compound of any one of claims 1 - 63 or a pharmaceutical composition of any one of claims 64 - 67 ; and instructions for using the compound or pharmaceutical composition.Join the waitlist — get patent alerts
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