Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-02-04
2003-03-04
McGarry, Sean (Department: 1635)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S224500, C514S253080
Reexamination Certificate
active
06528517
ABSTRACT:
1.0 BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to novel quinobenzoxazines, methods of synthesis, and uses thereof. More particularly, it concerns the synthesis of quinobenzoxazine compounds, pyridobenzophenoxazines, pyrridonaphthophenoxazines, and other related compounds that can stabilize the topoisomerase II-DNA complex and interact with G-quadruplex DNA and that, as a consequence, exhibit anticancer and antibiotic activity.
2. Description of Related Art
There remains a persistent need for new compounds with antibiotic properties. Over time bacterial agents evolve to develop resistance to existing classes of antibiotics, thus driving the continual need for new and effective antibiotics. The development of new classes of compounds with both narrow and broad spectrum antibacterial properties is therefore desired.
Similarly, there also has been a need for, and much research focused on, the treatment of cancer using chemotherapies. Resources continue to be directed toward the development of antineoplastic agents for the treatment of cancers, including solid tumors, leukemias, and other forms of cancer. Many antineoplastic agents developed are not ideal because of problems associated with their cytotoxicity and multidrug resistance of some cancers. What is needed are compositions for the treatment of cancers that are effective while minimizing their adverse effects.
The cytotoxicity of the fluoroquinolones is due to their ability to shift the cleavage-religation equilibrium required for topoisomerase action toward cleavage, thereby effectively trapping the enzyme on DNA to form the “cleaved complex” (Shen et al., 1989a; Shen et al., 1989b; Shen et al., 1989c; Willmott and Maxwell, 1993). The quinobenzoxazines are potent mammalian DNA topoisomerase II inhibitors. It has been proposed that the quinobenzoxazines inhibit DNA topoisomerase II reaction at a step prior to the formation of the “cleaved complex” intermediate (Permana et al., 1994).
The quinobenzoxazines are synthetic analogues of antibacterial fluoroquinolones (Chu and Maleczka, Jr., 1987; Chu et al., 1992; Chu et al., 1994). Studies have shown that some quinobenzoxazine derivatives have curative activity against solid tumors, murine tumors, and human xenographs (Clement et al., 1995). The antineoplastic effects of related compounds, the quinobenzothiazines, are detailed in U.S. Pat. No. 5,624,924, and is incorporated herin by reference. DNA binding studies reveal that antibacterial fluoroquinolones prefer to bind single-stranded DNA to duplex DNA or bind the DNA-gyrase complex in the presence of Mg
2+
(Willmott and Maxwell, 1993). In contrast, the quinobenzoxazines bind duplex DNA through intercalation. A drug self-assembly model has been proposed for the quinobenzoxazines based on results of biophysical and biochemical studies (Fan et al., 1995; Yu et al., 1996). In this model, a 2:2 drug:Mg
2+
dimer binds DNA with one drug molecule intercalating between DNA base pairs and the other drug molecule externally bound through two chelated Mg
2+
ions. The two magnesium cations link the two drug molecules in a head-to-tail fashion in which the &bgr;-ketoacid moiety is the bidentate ligand as a head and the primary amino group of the amino-pyrrolidine side chain is the tail. Each magnesium cation also binds with one phosphate oxygen of DNA backbone and two water molecules to form an octahedral complex.
The model interacts with DNA as follows: the polyaromatic ring of one moiety intercalates into DNA base pairs and anchors the whole assembly on DNA; and the &bgr;-ketoacid functionality and the 3-amino-pyrrolidine substituent of the second moiety chelate Mg
2+
through which the external molecule is bound in the DNA minor groove. In this manner, one quinobenzoxazine molecule serves as a DNA intercalator and the other quinobenzoxazine molecule binds externally, held to the first drug molecule by two Mg
2+
ions (Fan et al., 1995). On the basis of this model, new combinations of antibacterials and anticancer agents can be designed that target the bacterial gyrase-DNA and topoisomerase II-DNA complexes, respectively. In each case, one molecule designed to optimally interact with the DNA by intercalation, and the other designed to interact with the enzyme by external interaction with the DNA, are predicted to produce greater efficacy than the same molecule serving both roles in a suboptimum manner. G-quadruplexes also have been proposed as molecular targets for anticancer agents (Mergny and Hèléne, 1998). Drug interaction with G-quadruplexes leads to inhibition of telomerase (Sun et al., 1997; Wheelhouse et al., 1998; Fedoroff et al., 1998). Inhibition of telomerase has been proposed as a selective way to kill cancer cells because in large part only cancer cells depend upon telomerase for survival (Morin, 1995; Parkinson, 1996; Raymond et al., 1996).
Single agents that have dual mechanisms of action are proposed to have an advantage over agents that only have one defined mechanism of action. For example, studies have shown that Taxol not only targets tubulin, but also interacts with bcl-2 (Rodi, 1999). This may account for some of the efficacy of Taxol in its anticancer activity.
2.0 SUMMARY OF THE INVENTION
The present invention provides a new and novel solid- and solution-state parallel synthesis method for quinobenzoxazine analogues, a novel model of quinobenzoxazine self-assembling on DNA, and use of this model to design a series of new quinobenzoxazines, pyridobenzophenoxazines, pyrridonaphthophenoxazines and other related compounds that exhibit anticancer or antibiotic activity. The anticancer activity of these novel compounds is thought to operate via stabilization of the topoisomerase II-DNA complex and/or interaction with G-quadruplexes. The antibiotic activity of these compounds derives from their ability to interact with the gyrase-DNA complex, which is the bacterial type II topoisomerase.
The present invention therefore seeks to overcome deficiencies in the prior art by providing a new model for design and a new method for the synthesis, of a new series of quinobenzoxazines that display increased anticancer and antibiotic activities. One aspect of the invention includes a novel dimer model compound for use in developing quinobenzoxazines with potentiated anticancer and antibiotic activity. Further provided is a solid-state parallel synthesis method of producing these antineoplastic quinobenzoxazines and quinobenzoxazine derivatives.
The present invention contemplates a 2:2 quinobenzoxazine:Mg
2+
dimer model. This dimer binds DNA with one drug molecule intercalating between DNA base pairs and the other drug molecule externally binds through two chelated Mg
2+
ions. The magnesium cations link two drug molecules in a head-to-tail fashion in which the &bgr;-ketoacid moiety is the bidentate ligand as a head and the primary amino group of the amino pyrrolidine side chain is the tail. Each magnesium cation also binds with a single phosphate oxygen of the DNA backbone and two water molecules to form an octahedral complex. In this manner, one quinobenzoxazine molecule of the dimer serves as a DNA intercalator and the other quinobenzoxazine molecule binds externally, held to the first drug molecule by two Mg
2+
ions.
Alternatively, the 2:2 quinobenzoxazine:Mg
2+
dimer model utilizes a heterodimer. Based on the fact that fluoroquinolones, parent compounds to quinobenzoxazines, in the presence of quinobenzoxazines, can cooperatively interact with DNA in the presence of magnesium and have a cooperative effect on the lengthening of the DNA helix, a heterodimer model was made. The heterodimer is constructed by removal of the externally bound quinobenzoxazine molecule and substituting the nonintercalating fluoroquinolone parent molecule. The intercalating aspect of the dimer model remains a quinobenzoxazine. Upon addition of the nonintercalating fluoroquinolone to the quinobenzoxazine, a cooperative effect on DNA lengthening is observe
Gam Jongsik
Hurley Laurence H.
Kerwin Sean M.
Kwok Yan
Zeng Qingping
Board of Regents , The University of Texas System
Epps Janet
Fulbright & Jaworski L.L.P.
McGarry Sean
LandOfFree
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