Charged compounds comprising a nucleic acid binding moiety...

Details Charged compounds comprising a nucleic acid binding moiety... Charged compounds comprising a nucleic acid binding moiety...

2001-03-14

2003-04-29

Fredman, Jeffrey (Department: 1656)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C536S022100, C536S023100, C536S025300, C536S025330, C536S025600, C536S026100

Reexamination Certificate

active

06555693

ABSTRACT:

BACKGROUND OF THE INVENTION
Many compounds, either naturally occurring or synthetic, have been found to bind to double stranded nucleic acid, especially double stranded deoxyribonucleic acid (“dsDNA”). Depending on their structure, the compounds bind to different parts of the nucleic acid. Some bind to the major groove while others associate with the minor groove. Still others intercalate between adjacent base pairs. Combination binding modes are also known, in which a compound has binding interactions with more than one site in the nucleic acid.
Certain dsDNA binding compounds may be used to regulate the expression of genes for medical purposes. If a disease is characterized by the overexpression or the undesired expression of a gene (e.g., an oncogene), the disease may be treated by suppressing in toto or in part the expression of the gene by the binding of such compounds to the gene or a promoter site thereof. Infections by pathogens such fungi, bacteria, and viruses may be combated with compounds that affect the expression of genes essential for the proliferation of the pathogen.
Whatever the application, the compound must strongly bind to dsDNA, generally meaning that it binds with an association constant of at least 10
6
M
−1
, preferably at least about 10
9
M
−1
. However, binding strength alone is not determinative of efficacy. Many other factors come into play, including, for instance, cellular uptake, stability, toxicity, binding specificity, and the like. A compound that is acceptable or superior in one characteristic may be fatally deficient in another characteristic. Thus, there is a continuing need to develop new classes of nucleic acid binding compounds for use in such applications.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a new class of compounds, as well as compositions comprising such compounds, methods of synthesizing such compounds, methods of screening such compounds to identify those having anti-infective activity, and methods of using such compounds to prevent or inhibit infections.
In one aspect, the invention provides a class of charged compounds. The members of this class of compounds each comprise a nucleic acid binding moiety, and can be represented by formula (I):
W—Y—[Het]—L—[NABM]  (I)
or a salt thereof, preferably a pharmaceutically acceptable salt. Additionally, esters, amides, prodrugs, isomers, or metabolites of formula I are also within the scope of the present invention.
With respect to this invention, “NABM” refers to nucleic acid binding moiety, particularly nucleic acid binding moieties that bind to or associate with double-stranded nucleic acids, particularly dsDNA. NABMs include small molecules, proteins, and nucleic acids. Preferred small molecules include polyamides, particularly synthetic polyamides, and preferred nucleic acids include oligonucleotides. NABMs include intercalating moieties, minor groove binding moieties, major groove binding moieties, and those that include moieties that bind in a combination of such modes, e.g., an NABM that includes both minor and major groove binding moieties.
In formula I above, an NABM is linked to a heteroaromatic moiety (“Het”) via linker “L”. L represents a bond, preferably a covalent bond, or a linking group. Het represents a heteroaromatic moiety other than N-methyl or N-hydrogen pyrrole, selected from the group consisting of
wherein one of X
1
, X
2
, and X
3
is a ring vertex selected from the group consisting of —O—, —S—, and —NR
3
—, and the other two of X
1
, X
2
, and X
3
are ring vertices selected from the group consisting of ═N— and ═CR
4
—.
Covalently attached to the heteroaromatic moiety [Het] is a substituent having the formula:
wherein Y is selected from O, S, S(O), SO
2
, C(R
1
)
2
, N(R
3
)SO
2
, SO
2
N(R
3
) and NR
3
; and W is halogen or a group having the formula:
The various R groups in formula I have the following meanings: each R
1
is independently selected from H, F, substituted or unsubstituted (C
1
-C
6
)alkyl and a substituted or unsubstituted (C
1
-C
6
)heteroalkyl group; R
2
is a moiety bearing a polar group if Y is other than NR
3
and is a moiety bearing a polar group, a substituted or unsubstituted (C
1
-C
12
)alkyl group or a substituted or unsubstituted (C
1
-C
12
)heteroalkyl group if Y is NR
3
; each R
3
is independently selected from H, a substituted or unsubstituted (C
1
-C
12
) alkyl group and a substituted or unsubstituted (C
1
-C
12
)heteroalkyl group, provided that neither of R
2
(R
1
)
2
C and R
3
contains a 2-chloroethyl or 2-hydroxyethyl group when Y equals NR
3
; and each R
4
is independently selected from hydrogen, halogen, an amino group, a (C
1
-C
8
)alkylamino group, a di(C
1
-C
8
)alkylamino group, a tri(C
1
-C
8
)alkyl ammonium group, a hydroxyl group, a (C
1
-C
8
)alkoxy group, a thiol group, a (C
1
-C
8
)thioether group, a (C
1
-C
8
)sulfone group, a (C
1
-C
8
)sulfoxide group, a (C
1
-C
8
)sulfonamide group, a substituted or unsubstituted (C
1
-C
12
)alkyl group and a substituted or unsubstituted (C
1
-C
12
)heteroalkyl group.
Additionally, at least one of R
2
, [Het], or [NABM] has a positive charge.
In one group of preferred embodiments, the compounds of the invention can be represented by formula (Ia)
or a salt, preferably a pharmaceutically acceptable salt, or an ester, amide, prodrug, isomer, or metabolite thereof.
In formula Ia, the subscripts a, b, and d are each independently 0, 1, 2, 3, 4, or 5, with the proviso that at least one of a, b, or d is other than 0. The subscripts c, e and f are each independently 0 or 1.
In these embodiments, R
5
is selected from halogen, OR
7
and N(R
7
)
2
. R
6
is selected from hydrogen, halogen, a substituted or unsubstituted (C
1
-C
12
) alkyl group and a substituted or unsubstituted (C
1
-C
12
)heteroalkyl group. Each R
7
is independently selected from hydrogen, a substituted or unsubstituted (C
1
-C
12
) alkyl group and a substituted or unsubstituted (C
1
-C
12
)heteroalkyl group. Each Q is independently selected from —(CH
2
)
2
—, —(CH
2
)
3
—, and a heteroaromatic ring independently selected from the group consisting of substituted or unsubstituted imidazole, pyrrole, pyrazole, furan, isothiazole, oxazole, isoxazole, thiazole, furazan, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, and thiophene rings. Preferably, Q is a thiophene ring. Exemplary suitable substituents in a heteroaromatic ring Q include Cl, F, CH
3
, and hydroxy.
Compounds according to the invention can be in unpurified, substantially purified, and purified forms. The compounds can be present with any additional component(s) such as a solvent, reactant, or by-product that is present during compound synthesis or purification, and any additional component(s) that is present during the use or manufacture of a compound or that is added during formulation or compounding of a compound.
In another aspect, the present invention provides methods for synthesizing the compounds of the invention. Broadly, such methods comprise linking a NABM to R
2
(R
1
)
2
C—Y—[Het], either directly or through an optional linking group L. The various moieties of the invention can be synthetic or natural products. Synthetic moieties may be synthesized by solution or solid phase methods. Two or moieties may also be synthesized together.
In yet another aspect, the invention provides compositions comprising a compound according to the invention and one or more excipients, diluents, or carriers. Such compositions can be dry or liquid formulations. The particular composition employed will depend on the intended application for the compound. Compounds according to this invention have been found to be strongly bind dsDNA. Preferably, the association constant for a compound of the invention an dsDNA is at least about 10
6
M
−1
, more preferably at least about 10
9
M
−1
, and most preferably about 10
10
M
−1
, 10
11
M
&m

Affiliated with

Also associated with

Rating

Charged compounds comprising a nucleic acid binding moiety... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Charged compounds comprising a nucleic acid binding moiety..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Charged compounds comprising a nucleic acid binding moiety... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3093036