Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-28
2003-10-07
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S297000, C546S070000, C546S103000, C546S104000
Reexamination Certificate
active
06630481
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to viologen linked acridine based molecule of the general formula 1 (1a, 1b, 1c, and 1d)
1a. wherein
Y=—(CH
2
)
n
—; n=1-11
R=—MV
2+
—(CH
2
)
m
—CH
3
2X
⊖
or -Pyr
2+
—(CH
2
)
m
—CH
3
2X
⊖
; m=1-13
1b. wherein
Y=—(CH
2
)
n
—; n=1-11
R=—MV
2+
—(CH
2
)
m
-Acr 2X
↓
or -Pyr
2+
-(CH
2
)
m
-Acr 2X
⊖
; m=1-11
1c. wherein
Y=ortho or para tolyl
R=MV
2+
—(CH
2
)
m
—CH
3
2X
⊖
or -Pyr
2−
-(CH
2
)
m
—CH
3
2X
⊖
; m=1-13
1d. wherein
Y=—(CH
2
)
n
—; n=1-10
R=—Acr
+
-R
1
X
⊖
/2X
wherein
N in the arcridine main ring is also quaternised by alkyl group
R
1
=—(CH
2
)
m
—CH
3
and —(CH
2
)
m
—C
6
H
4
—(CH
2
)
m
—CH
3
(para), m=0-13,
and wherein
and/or pharmaceutically acceptable derivative thereof, useful as phototherapeutical and catalytic photoactivated DNA cleaving agents. The present invention also relates to a process for the preparation of the novel molecule of formula 1. The novel molecules of the invention are useful for the stabilization of DNA including duplex, triplex and quadruplex structures through intercalation and/or bisintercalation and groove binding interactions. The novel molecules of the invention are also for the catalytic photoactivated cleavage of DNA purely through cosensitization with selectivity at guanine (G) sites in duplex and AG two base bulge containing sequences.
The present invention also relates to a series of bifunctional molecules of the general formula 1 (1a, 1b, and 1c) and derivatives thereof, are also useful as photocatalysts for the oxidation of water to generate hydrogen in industrial applications.
BACKGROUND OF THE INVENTION
Design of functional molecules that bind selectively to nucleic acids (DNA or RNA) and are capable of cleaving duplex or single stranded nucleic acids is an active area of research that has important biochemical and biomedical applications. Some of these effective agents have been extremely useful in the treatment of various diseases and also as probes for understanding DNA structures and DNA-protein interactions. While natural restriction enzymes have been very useful in many of these applications, their large size and/or limited range of sequence recognition capabilities prevent their general use. Hence, synthetic functional molecules that cause site-selective or sequence specific modifications of DNA and offer a clean and efficient way of cutting DNA at sites that are not recognized by conventional restriction enzymes are highly required.
In this context, a large number of synthetic ligands have been developed, which have it ability to recognize and bind to specific sequences or structural domains in DNA and exhibit nucleolytic activity under physiological conditions (chemical nucleases) or upon photoactivation (photonucleases). Some of these include, 1,10-phenanthroline-copper, ferrous-EDTA, bleomycin, enediyene antibiotics and anthraquinones. For examples, references may be made to U.S. Pat. No. 5,985,557; No. 6,090,543; No. 5,739,022; No. 5,556,949; No. 5,552,278; No. 5,504,075; No. 4,942,227; Nielsen, P. E.
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1982, 104, 313; Hecht, S. M.;
Bleomycin: Chemical, Biochemical and Biological aspects,
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1978, 17, 2740. However, synthetic ligands that are versatile and mimic the conventional restriction enzymes are yet to be developed.
Of the several classes of DNA cleaving systems reported, the photoactivated cleaving agents have been found to posses significant practical advantages over the reagents that cleave DNA under thermal conditions. An interesting aspect of the photoactivated DNA cleaving agent is that it allows the reaction to be controlled spatially and temporally by combining all of the components of the reaction mixture before the irradiation. Excitation of the reaction mixture with an appropriate light source initiates the reaction, which continues until the light is shut off The ability to control light, in both spatial and temporal sense would be advantageous for applications ranging from the time resolved probing of various biochemical processes such as transcription and translation to genomic analysis and therapeutic agents. For selected examples, reference may be made to U.S. Pat. No. 5,994,410; No. 5,734,032; No. 5,650,399; No. 5,607,924; No. 6,087,493; No. 6,057,096; 5,767,288: No. 5,439,794; Armitage, B.
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These photoactivated cleaving agents found to cleave DNA (i) by generation of diffusible (singlet oxygen) and non-diffusible (hydroxyl radicals) reactive intermediates, (ii) hydrogen atom abstraction and (iii) electron transfer. Most of the systems reported so far, initiate photocleavage by more than one mechanism. Though the damage induced by all these mechanisms lead to the initial modification of either sugar or nucleobase, which then results in phosphodiester cleavage, serious efforts are in progress to develop reagents which cleave DNA purely by one mechanism and also to target these cleaving agents to specific sequences or domains in DNA. References may be made to Cadet, J.; Teoule, R.
Photochem. Photobiol.
1978, 28, 661; Croke, D. T.; Perrouault, L.; Sari, M. A.; Battioni, J. P.; Mansuy, D.; Magda, D.; Wright, M. M.; Miller, R. A.; Sessler, J. L.; Sansom, P. L.
J. Am. Chem. Soc.
1995, 117, 3629; Theodorakis, E.; Wilcoxen, K. M.
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DNA and RNA Cleavers and Chemotherapy of Cancer and ViraL Diseases;
Meunier, B., Ed.; Kluwer: Netherlands, 1996, pp 163-176.
Recently, there has been growing interest in designing molecules, which cleave DNA effectively through photoinduced electron transfer mechanism involving purely by the oxidation of nucleobases. A unique feature of this mechanism is that one can have reasonable control over the cleavage. It has been observed that DNA cleavage by this mechanism occurs at guanine (G), since guanine is the most easily oxidizable base of the nucleic acids because of its low ionization potential. A large number of organic as well as inorganic systems have been reported which cause DNA cleavage by photoinduced electron transfer mechanism. However, m
Danaboyina Ramaiah
Joshy Joseph
Nadukkudy Varghese Eldho
Council of Scientific and Industrial Research of India
Darby & Darby
Huang Evelyn Mei
LandOfFree
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