Organometallic complex

Details Organometallic complex Organometallic complex

2001-11-20

2002-10-01

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heavy metal containing doai

C514S184000, C514S186000, C514S188000, C546S006000, C546S008000, C546S009000, C546S010000, C546S114000

Reexamination Certificate

active

06458833

ABSTRACT:

BACKGROUND
Transition metal complexes that can cleave DNA are widely known as “chemical nucleases.” See, e.g., Pyle & Barton (1990)
Prog. Inorg. Chem
. 38: 413; Sigman et al. (1987)
Acc. Chem. Res
. 26: 98; and Stubbe & Kozarich (1987)
Chem. Rev
. 87: 1107. These complexes strongly bind to DNA and then cleave it under various conditions. For example, a transition metal complex can cleave DNA upon linking to a DNA-cleaving motif, e.g., acridine orange (Lippard et al. (1984)
J Am. Chem. Soc
. 106: 6102); upon X-ray irradiation (Grokhovsky & Zubarev (1991)
Nucl. Acids Res
. 19: 257); or under photolytic conditions (Rudnicki et al. (1991)
Bioorg. Med Chem. Lett
. 1: 451; or Thorp et al. (1995)
J Am. Chem. Soc
. 117:11673).
In addition, the just-described transition metal complexes may possess anticancer activity. See, e.g., Bruhn et al. (1987)
Prog. Inorg. Chem
. 38: 477; and Sherman & Lippard (1987)
Chem. Rev
. 87: 1153. For example, cisplatin and carboplatin (i.e., platinum complexes) have been routinely used for treating testicular and ovarian cancers (Christian (1992)
Semin. Oncol
. 19: 720; and Barnard (1989)
J Plat. Met. Rev
. 33: 162). In addition, many cisplatin derivatives have been developed as new anticancer reagents with less toxic side effect and reduced resistance. See Reedijk (1996)
J Chem. Soc., Chem. Commun
. 801; and Hambley (1997)
Coord. Chem. Rev
. 166: 181.
SUMMARY
This invention relates to a transition metal complex useful as a nucleic acid binding or cleaving agent.
In one aspect, this invention features a metal complex of the formula:
M is Pt, Pd, Ni, Co, or Cu; X (including atoms A
1
and A
2
) is aryl, heteroaryl, cyclyl, or heterocyclyl; Y is halogen, tosylate, mesylate, triflate, pyrophosphate, or carboxylate; each of A
1
and A
2
, independently, is N or C; each of A
3
and A
4
, independently, is N, S, or O, wherein A
1
, A
2
, A
3
, and A
4
taken together have one positive charge (a charge carried by one of the four atoms, e.g., N
+
); and each of R
1
and R
2
, independently, is alkyl, aryl, heteroaryl, alkoxyl, aryloxyl, heteroaryloxyl, alkoxylcarbonyl, aryloxylcarbonyl, or heteroaryloxylcarbonyl.
A subset of the metal complexes encompassed by the formula (I) is featured by that M is Pt. In these compounds, X is pyridinyl, one of A
1
and A
2
is N; Y is halogen; and each of R
1
and R
2
, independently, is alkyl. One exemplary metal complex of this invention is PtCl(DMSO) [&eegr;
2
-C
5
H
4
SN(O)]:
Alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, alkoxyl, aryloxyl, heteroaryloxyl, alkoxylcarbonyl, aryloxylcarbonyl, or heteroaryloxylcarbonyl mentioned above refers to both substituted and unsubstituted moieties. As used herein, alkyl is a straight or branched hydrocarbon chain containing 1 to 6 carbon atoms. The term “substituted” refers to one or more substituents (which may be the same or different), each in replace of a hydrogen atom. Examples of substituents include, but are not limited to, halogen, hydroxyl, amino, cyano, nitro, C
1
~C
6
alkyl, C
1
~C
6
alkenyl, C
1
~C
6
alkoxyl, aryl, heteroaryl, or heterocyclyl, wherein alkyl, alkenyl, alkoxyl, aryl, heteroaryl and heterocyclyl are optionally substituted with C
1
~C
6
alkyl, aryl, heteroaryl, halogen, hydroxyl, amino, alkylamino, arylamino, dialkylamino, diarylamino, cyano, or nitro. The term “aryl” refers to a hydrocarbon ring system having at least one aromatic ring. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, and pyrenyl. The term “heteroaryl” refers to a hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as O, N, or S. Examples of heteroaryl moieties include, but are not limited to, pyridinyl, carbazolyl, and indolyl.
A salt of a metal complex of formula (I) is also within the scope of this invention. Such a salt, for example, can be formed between a positively charged substituent (e.g., sulfoxide) on the complex and an anion. Examples of an anion include fluoride, chloride, bromide, iodide, sulfate, sulfite, phosphate, acetate, oxalate, and succinate. Likewise, a negatively charged substituent can form a salt with a cation. Suitable cations include, but are not limited to, sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as teteramethylammonium ion.
This invention also features a method for binding or cleaving a nucleic acid. The method includes contacting the nucleic acid with one or more metal complexes described above. Cleavage of the nucleic acid can be achieved by UV irradiation of the metal complex-bound nucleic acid. The nucleic acid described herein refers to a purine-containing DNA or RNA. It can be single-stranded, double-stranded, or partially single-stranded and partially double-stranded. In some embodiments, the method of this invention is performed in an aqueous buffer having a pH value which ranges from 5 to 8. A cleavage can be carried out by using UV light having a wavelength>300 nm.
Other features, objects, and advantages of the invention will be apparent from the description and from the claims.


REFERENCES:
Davidson JL et al. J. Chem. Soc., Dalton Trans. (1983), (4), 783-6.*
Rudnicki et al.Nicking Of Supercoiled DNA Via Metal Radicals Generated From Photolysis Of Species Containing Metal-Metal Bonds. Bioorganic & Medicinal Chemistry Letters, vol. 1, No. 9, pp. 451-454, 1991.
Sherman et al.Structural Aspects Of Platinum Anticancer Drug Interactions With DNA. Chemical Reviews, vol. 87, No. 5, pp. 1153-1181, 1987.
Reedijk.Improved Understanding in Platinum Antitumour Chemistry. Chem. Commun., 1996, pp. 801-806.
Neenhold et al.Major Groove Opening at the HIV-1 TAT-Binding Site of Tar RNA Evidenced By A Rhodium Probe. Abstract Only. (Full Source: BioChemistry, vol. 34, No. 19, pp. 6303-6309, 1995.).
Reedijk.The Relevance Of Hydrogen Bonding In The Mechanism Of Action Or Platinum Antitumor Compounds. Inorganica Chemica Acta, 198-200 (1992), pp, 873-881.
Wong et al.Current Status of Platinum-Based Antitumor Drugs. Chemical Reviews, vol. 99, No. 9, pp. 2451-2466, 1999.

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