The State University of New York

University System of Maryland

Johns Hopkins University

Steven E Rokita

Cynthia J Burrows

Tianhu Li

Qingping Zeng

Kenneth D Karlin

Narasimha N Murthy

Lei Li

Xiaoying Chen

Moneesh Chatterjee

Kristi J Humphreys

Hyunmin Kang

The present invention is related to a novel method for oxidizing or splitting nucleic acids at specific points on a complementary nucleic acid segment using a dinuclear copper-based compound of Formula I. Additionally, the present invention is related to a novel treatment of cancer, tumors, and cancer cells using a dinuclear copper-based compound of formula I or a naked ligand of Formula II.

Dinuclear copper-based compound and ligand for nucleic acid scission and anticancer treatment

The invention relates to a compound comprising a labeled nickel complex (FIG.) that is used to detect and purify nucleic acid sequences by forming an adduct between a specific nucleic acid base and the labeled nickel complex. The adduct can also be purified through a separation process, such as affinity chromatography 

Nickel-based reagents for detecting DNA and DNA-protein contacts

The present invention is related to a novel method for splitting nucleic acids at specific points on a complementary nucleic acid segment using a dinuclear copper-based compound of Formula I. Additionally, the present invention is related to a novel treatment of cancer, tumors, and cancer cells using a dinuclear copper-based compound of Formula I or a naked ligand of formula II: (Formula I and II). 

A silyloxy aromatic derivative capable of alkylating a target biological molecule when activated by ionic strength. A sequence directed reagent may be constructed by conjugating a methyl silyloxy aromatic derivative to a hexamethylamino linker attached to either the 5' or 3' terminus of an oligonucleotide. Annealing this modified fragment of DNA to its complementary sequence allows for target modification subsequent to ionic activation. The product of this reaction is a covalent crosslink between the reagent and target strands resulting from an alkylation of DNA by the activated silyloxy aromatic derivative. In a preferred embodiment, a nitrophenyl or bromo group is attached to a methyl group of the silyloxy aromatic derivative. This reagent may be similarly linked to an oligonucleotide probe. Activation of the alkylating agent by an ionic signal (X) which may naturally occur, or may be introduced into the media containing the target molecule, such as by the introduction of a salt (MX).

Ion triggered alkylation of biological targets by silyloxy aromatic

Anthraquinone derivatives are constructed for alkylation of target molecules. The anthraquinone derivative includes an anthraquinone ring system which has been modified by the addition of inducibly reactive substituents at positions on the ring system. The anthraquinone ring system can be selectively activated for alkylation of a target molecule. The substituents may be from 1 to 4 methyl groups, whereupon activation is achieved by a photochemical signal. In an additional alternative embodiment, the inducible reactive substituents may include both methyl groups and substituted methylene groups. In this embodiment, the activation of the anthraquinone derivative is achieved by photochemical and/or reductive signals. Alternatively, the substituents may be from 1 to 8 methyl groups modified to include a reactive group, whereupon activation is achieved by a chemical or enzymatic reductive signal. The anthraquinone derivatives of the invention may be used for non-specific modification of target molecules. Alternatively, the anthraquinone derivative may be further derivatized to permit specific modification of target molecules. The further derivatization of the anthraquinone includes attaching a probe to the anthraquinone ring system by way of a linking group. The probe is chosen to selectively localize to a target molecule, whereupon the anthraquinone derivative may be activated to react with and aklylate the target molecule. Also the process of employing such anthraquinone derivatives for use in vitro or in vivo for alkylating, specifically or non-specifically alkylating, target molecules.

Reactive anthraquinone derivatives and conjugates thereof

A process is provided for oxidatively modifying nucleic acids containing a target nucleotide. The nucleic acid is contacted with a polyaza metal complex in the presence of an oxidizing agent so that the nucleic acid is modified at or near the target nucleotide. Also provided are a kit for carrying out the process and a method for treating neoplastic growth by administering to a subject having neoplastic growth, an effective amount of a polyaza metal complex which is capable of modifying DNA.

Modification of DNA and oligonucleotides using metal complexes of

A silyloxy aromatic derivative capable of alkylating a target biological molecule when activated by ionic strength. A sequence directed reagent may be constructed by conjugating a methyl silyloxy aromatic derivative to a hexamethyiamino linker attached to either the 5' or 3' terminus of an oligonucleotide. Annealing this modified fragment of DNA to its complementary sequence allows for target modification subsequent to ionic activation. The product of this reaction is a covalent crosslink between the reagent and target strands resulting from an alkylation of DNA by the activated silyloxy aromatic derivative. In a preferred embodiment, a nitrophenyl or bromo group is attached to a methyl group of the silyloxy aromatic derivative. This reagent may be similarly linked to an oligonucleotide probe. Activation of the alkylating agent by an ionic signal (X) which may naturally occur, or may be introduced into the media containing the target molecule, such as by the introduction of a salt (MX).

A sequence directed reagent is constructed by conjugating a methyl silyloxy aromatic derivative to a hexamethylamino linker attached to either the 5' or 3' terminus of an oligonucleotide. Annealing this modified fragment of DNA to its complementary sequence allows for target modification subsequent to ionic activation. The product of this reaction is a covalent crosslink between the reagent and target strands resulting from an alkylation of DNA by the activated silyloxy aromatic derivative. In a preferred embodiment, a nitrophenyl group is attached to the methyl group of the silyloxy aromatic derivative. This reagent is similarly linked to an oligonucleotide probe. Activation of this probe linked alkylating agent by an ionic signal, (X) which may naturally occur, or may be introduced into the media containing the target molecule, such as by the introduction of a salt (MX).

A sequence directed reagent is constructed by conjugating a methyl naphthoquinone derivative to a hexamethylamino linker attached to the 5' terminus of an oligonucleotide. Annealing this modified fragment of DNA to its complementary sequence allows for target modification subsequent to photochemical activation. The product of this reaction is a covalent crosslink between the reagent and target strands resulting from an alkylation of DNA by the photoexcited quinone. The modified sequence is not labile to acid, base or reductants, and blocks the exonuclease activity of the Klenow fragment of DNA polymerase I. In another embodiment, a highly reactive moiety, such as Br is attached to the methyl group of the naphthoquinone derivative. This reagent is similarly linked to an oligonucleotide probe. Activation of this probe linked alkylating agent is by a reductive signal which may either naturally occur within the cell, such as an enzyme, or introduced into the media containing the target molecule.

Growing community of inventors

Port Jefferson, NY, United States of America

Steven E Rokita