Replication protein A (RPA) is the major human ssDNA binding protein and is required for both nucleotide excision repair (NER) and homologous recombination (HR). The RPA heterotrimer consists of 70 kDa, 32 kDa and 14 kDa subunits with the 70-kDa subunit containing the two major high affinity DNA binding domains (DBD) DBD A and B, as well as DBD C and F. DBD D and E are in the 32-kDa and 14-kDa subunit, respectively. Binding to short stretches of ssDNA (˜8-10 nucleotides) is primarily mediated by DBD A and B, while intermediate length ssDNA (˜12-23 nucleotides) also involves DBD C. Longer length ssDNA (˜28-30 nucleotides) engages DBD D in addition to DBDs A, B and C. RPA plays essential and non-redundant roles in both NER and HR, apart from its role in replication and DNA damage checkpoint activation. Each of these roles requires binding of RPA to ssDNA, making RPA-DNA interaction a promising target for anti-cancer therapeutic activity in combination with Pt-containing cancer drugs, for example, cisplatin.
The ssDNA binding activity of RPA is required for several DNA metabolic pathways including DNA replication, recombination and repair. High affinity interactions with DNA are sustained by the numerous oligosaccharide/oligonucleotide binding (OB)-folds present on each of the three subunits. The DNA binding pocket of a single OB-fold accommodates 3-4 bases of ssDNA. The main OB-folds, DNA binding domains A and B (DBD-A and DBD-B) are present in the central region of the p70 subunit and contribute most of the binding energy for RPA-ssDNA interactions. Individual OB-folds are compact modular domains populated with hydrophobic and basic amino acids. These structural features make the OB-folds an attractive target for development of small molecule inhibitors (SMIs) of DNA binding activity. Given RPA's central role in cell growth and DNA repair, it is an attractive target for the development of compounds that can interfere with its activity. Some aspects of the instant invention include compounds that interact with RPA and methods of using the same to influence cell growth and death.
Platinum-based chemotherapeutics exert their therapeutic efficacy via the formation of DNA adducts which interfere with DNA replication, transcription and cell division and ultimately induce cell death. Repair and tolerance of these Pt-DNA lesions by NER and HR can substantially reduce the effectiveness of therapy. Inhibition of these repair pathways, therefore, holds the potential to sensitize cancer cells to Pt treatment and increase clinical efficacy. Replication Protein A (RPA) plays essential roles in both NER and HR, along with its role in DNA replication and DNA damage checkpoint activation. Each of these functions is, in part, mediated by RPA binding to single-stranded DNA (ssDNA).
In some embodiments of the present disclosure, the synthesis and characterization of derivatives of RPA small molecule inhibitors and their activity in models of epithelial ovarian cancer (EOC) and non-small cell lung cancer (NSCLC) are shown. In some embodiments, synthesized analogs of RPA inhibitor TDRL-505 are disclosed along with the structure activity relationships. Certain compounds, such as, for example, TDRL-551, exhibit a greater than 2-fold increase in in vitro activity. TDRL-551 showed synergy with Pt in tissue culture models of EOC and in vivo efficacy, as a single agent and in combination with platinum, in a NSCLC xenograft model. Data demonstrate the utility of RPA inhibition in EOC and NSCLC and the potential in developing anticancer therapeutics that target RPA-DNA interactions.
Platinum (Pt)-based combination chemotherapy has been the front-line treatment for a variety of malignancies including testicular, lung, and ovarian cancer. However, resistance to Pt-based regimens remains a major limitation in the successful treatment for many of these cancers including epithelial ovarian cancer (EOC) and non-small cell lung cancer (NSCLC). More than 80% of EOC patients relapse with Pt-resistant disease, where second line therapies are largely ineffective. Thus, ovarian cancer has been clinically designated as the most deadly gynecological cancer owing to extremely poor prognosis and overall low survival rates. The clinical efficacy of cisplatin is a function of its ability to cross-link DNA thereby blocking DNA replication, transcription and cell division. Ultimately Pt-treatment induces apoptosis, however, the balance between DNA damage and DNA repair dictates the extent of tumor death. While Pt-resistance is multifactorial, increased DNA repair is a major contributor. Hence, exploiting DNA repair as a target to sensitize cells to Pt-based chemotherapy holds immense potential for increasing the survival rates in cancer therapy.
Repair and tolerance of cisplatin-DNA adducts occur primarily via nucleotide excision repair (NER) and homologous recombination (HR). Approximately 95% of Pt-DNA lesions formed by cisplatin are intrastrand crosslinks with the remaining ˜5% being interstrand crosslinks and a small number of mono-lesions. There is evidence for and against each lesion type being the cytotoxic lesion caused by cisplatin. Interstrand lesions are less abundant and repaired more efficiently than intrastrand lesions, and involve the HR pathway in conjunction with the FANC protein complex (a group of proteins associated with Fanconi anemia). Interstand adducts are more cytotoxic with estimates to as few as 20 interstrand crosslinks causing cell death if left unrepaired. While more abundant and repaired slower, intrastrand lesions are better tolerated via HR and bypass polymerases. Repair of intrastrand crosslinks occurs via the NER pathway. Therefore, while the exact lesion responsible for clinical efficacy remains to be determined, what is clear is that both NER and HR have differential and contributory roles in the cellular sensitivity to cisplatin.
Structural analysis of RPA reveals unique protein-DNA interactions that would facilitate the design of potent and selective small molecule inhibitors (SMIs). It has been also shown that genetic mutants of RPA display defects in DNA repair without impacting DNA replication and vice versa. This separation of function can be exploited by using chemical probes that exclusively interfere with the DNA repair pathway and that, in conjunction with DNA-damaging agents, would offer a new possibility for cancer treatment. Both reversible and irreversible chemical inhibitors of RPA have been reported. The reversible inhibitor TDRL-505 exhibits synergistic effects with DNA damaging agents in a lung cancer cell model. This small molecule hinders the binding of DBD A and B of RPA to ssDNA, which according to in silico docking analysis occurs as a consequence of its interaction with DBD B and the DBD A-B interdomain. In the present disclosure, a series of analogs of TDRL-505 have been screened in vitro and their activity in an EOC cell culture model has been evaluated. Structure activity relationship (SAR) data led to at least one enhanced compound, TDRL-551. Herein disclosed is in vitro, cellular and in vivo activity of RPA inhibitor TDRL-551 in models of lung and ovarian cancer.
A first set of embodiments of the present disclosure, includes at least one compound of Formula I or a pharmaceutically acceptable salt thereof, or a metabolite thereof:

In a first embodiment of the first set of embodiments: R1 is
or phenyl optionally substituted with 1 to 3 R5;
R2 is
or phenyl optionally substituted with —C(═O)OH or —SO2NH2;
n is 1, 2, or 3;
R3 is C1-C6 alkyl, or alternatively R3 forms a dioxolane ring sharing two carbon atoms with the quinolone ring of R1;
R4 is hydroxyl, C1-C6 alkoxy, —O—CH2-phenyl, morpholinyl, 1-methylpiperazinyl, 1-amino-cyclopropyl, amino-methyl-cyclopropyl;
R5 is C1-C6 alkyl or C1-C6 alkoxy;
X is halogen; and
Y1 and Y2 are independently selected from H, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, —NH2, —NO2, —OC(═O)C(H)═CH2, carboxyl, or tetrazolyl; alternatively, Y1 and Y2 are taken together to form a dioxolane ring sharing two carbons with the phenyl ring of Formula I;
A second embodiment includes the compound of the first embodiment, wherein R1 is
and X is chlorine. In an even more particular embodiment, R3 is C1-C6 alkyl, and even more particularly, R3 is ethyl.
A third embodiment includes the compound of the first embodiment, wherein R1 is phenyl optionally substituted with 1 to 3 R5. In an even more particular embodiment, R1 is unsubstituted phenyl. In another more particular embodiment, R1 is phenyl substituted with 1-2 C1-C6 alkoxy, and more particularly, 1-2 methoxy.
A fourth embodiment includes the compound of any of the first to the third embodiments, wherein R2 is
In an even more particular embodiment, n is 2. In another more particular embodiment, n is 2. In another more particular embodiment, R4 is hydroxyl. In another more particular embodiment, R4 is C1-C6 alkoxy, and even more particularly ethoxy. In another more particular embodiment, R4 is —O—CH2-phenyl. In another more particular embodiment, R4 is morpholinyl. In another more particular embodiment, R4 is 1-methylpiperazinyl. In another more particular embodiment, R4 is 1-amino-cyclopropyl. In another more particular embodiment, R4 is amino-methyl-cyclopropyl
A fifth embodiment includes the compound of any of the first to the third embodiments, wherein R2 is

A sixth embodiment includes the compound of any of the first to the third embodiments, wherein R2 is or phenyl optionally substituted with —C(═O)OH or —SO2NH2. In a more particular embodiment, R2 is phenyl substituted with —C(═O)OH or —SO2NH2. In another more particular embodiment, R2 is phenyl substituted with —C(═O)OH. In yet another more particular embodiment, R2 is phenyl substituted with —SO2NH2.
A seventh embodiment includes the compound of any of the first to sixth embodiments, wherein Y1 and Y2 are independently selected from H, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, —NH2, —NO2, —OC(═O)C(H)═CH2, carboxyl, or tetrazolyl. In a more particular embodiment, Y1 is H and Y2 is a halogen, and even more particularly, Y1 is H and Y2 is iodine, or Y1 is H and Y2 is chlorine, or Y1 is H and Y2 is bromine. In another more particular embodiment, Y1 is H and Y2 is C1-C6 alkyl, and even more particularly, Y1 is H and Y2 is methyl. In another more particular embodiment, Y1 is H and Y2 is C1-C6 alkoxy, and even more particularly, Y1 is H and Y2 is methoxy. In another more particular embodiment, Y1 and Y2 are each independently C1-C6 alkoxy, and even more particularly, Y1 and Y2 are each methoxy. In another more particular embodiment, Y1 is H and Y2 is —OC(═O)C(H)═CH2. In another more particular embodiment, Y1 is H and Y2 is tetrazolyl. In another more particular embodiment, Y1 is H and Y2 is —NO2. In another more particular embodiment, Y1 is H and Y2 is NH2. In another more particular embodiment, Y1 is H and Y2 is —OH.
An eighth embodiment includes the compound of any of the first to sixth embodiments, wherein Y1 and Y2 are taken together to form a dioxolane ring sharing two carbons with the phenyl ring of Formula I.
A second set of embodiments of the present disclosure, includes at least one compound according to Formula II or a pharmaceutically acceptable salt thereof, or a metabolite thereof:

In a first embodiment of the second set of embodiments, R is C1-C6 alkyl; Y is a substituent selected from the group consisting of: fluorine, iodine, chlorine, and —OCF3; and n is 1, 2, or 3;
A second embodiment of the second set of embodiments includes the compound of the first embodiment, wherein R is methyl or ethyl.
A third embodiment of the second set of embodiments includes the compound of the first or second embodiment, wherein Y is selected from fluorine, iodine, and chlorine. In a more particular embodiment, Y is fluorine. In another more particular embodiment, Y is iodine. In another more particular embodiment, Y is chlorine.
A fourth embodiment of the second set of embodiments includes the compound of the first or second embodiment, wherein Y is —OCF3.
A fifth embodiment of the second set of embodiments includes the compound of any of the first through fourth embodiments, wherein n is 2.
A third set embodiments of the present disclosure, includes the compound according to any of the first and/or second sets of embodiments, wherein the compound is a compound selected from the group consisting of: TDRL-540, TDRL-539, TDRL-551, TDRL-557, and TDRL-652, NG-01-04, NG-01-02, NG-01-24, NG-01-25, or a pharmaceutically acceptable salt thereof, or a metabolite thereof.
A fourth set embodiments of the present disclosure, includes the compound according to any of the first, second, and/or third sets of embodiments, wherein said compound is compound TDRL-551, or a pharmaceutically acceptable salt thereof or a metabolite thereof.
A fifth set of embodiments of the present disclosure includes the compound according to any of the first, second, third, and/or fourth sets of embodiments, wherein the compound at least partially inhibits Replication Protein A.
A sixth set of embodiments of the present disclosure includes at least one method of reducing the activity of a protein, comprising the steps of: providing a compound of any one of the first, second, third, and/or fourth sets of embodiments, or a pharmaceutically acceptable salt or metabolite thereof, wherein the compound binds to Replication Protein A or is metabolized into a chemical that binds to Replication Protein A; and contacting said compound with at least one isoform of Replication Protein A.
A seventh set of embodiments of the present disclosure includes at least one of the methods according to any of the sixth set of embodiments, wherein the contacting step between either the compound of any one of the first, second, third, and fourth embodiment, or a pharmaceutically acceptable salt or metabolite thereof, and the at least one isoform of Replication Protein A occurs in vivo or in vitro.
An eighth set of embodiments of the present disclosure includes at least one method of altering eukaryotic cell cycle-progression, comprising the steps of: providing a compound of any one of the first, second, third, and/or fourth sets of embodiments, or a pharmaceutically acceptable salt or metabolite thereof, wherein the compound interferes with eukaryotic cell cycle-progression or is metabolized into a chemical that interferes with eukaryotic cell cycle-progression; and contacting the compound with at least one eukaryotic cell.
A ninth set of embodiments of the present disclosure includes at least one method according to any of the eighth set of embodiments, wherein the contacting step between said compound of any one of the first, second, third, and/or fourth sets of embodiments, or a pharmaceutically acceptable salt or metabolite thereof, and the eukaryotic cell occurs in vivo or in vitro.
A tenth set of embodiments of the present disclosure includes at least one method of treating cancer, comprising the steps of: providing a compound of any of the first, second, third, and/or fourth sets of embodiments, or a pharmaceutically acceptable salt or metabolite thereof, wherein the compound interferes with the cell cycle of a cancer cell or is metabolized into a chemical that interferes with the cell cycle of a cancer cell; and contacting the compound with at least one cancer cell.
An eleventh set of embodiments of the present disclosure includes at least one method according to any of the tenth set of embodiments, wherein the contacting step between said compound of any of the first, second, third, and/or fourth sets of embodiments, or a pharmaceutically acceptable salt or metabolite thereof, and the cancer cell occurs in vivo in in vitro.
A twelfth set of embodiments of the present disclosure includes at least one set of methods according to any of the tenth and/or eleventh sets of embodiments, wherein the cancer cell is an epithelial ovarian cancer cell or a non-small cell lung cancer cell.
A thirteenth set of embodiments of the present disclosure includes at least one method of treating a disease, comprising the steps of: providing at least one compound of any of the first, second, third, and/or fourth sets of embodiments, or a pharmaceutically acceptable salt or metabolite thereof, wherein the compound is effective for the treatment of at least one disease; and administering at least one therapeutically effective dose of the compound to a patent diagnosed with a specific disease.
A fourteenth set of embodiments of the present disclosure includes at least one of the methods according to any of the thirteenth set of embodiments, wherein the compound is suitable for administration to a patient.
A fifteenth set of embodiments of the present disclosure includes at least one method according to any of the thirteenth set of embodiments, wherein the compound is suitable for administration to a patient orally.
A sixteenth set of embodiments of the present disclosure includes at least one method according to any of the thirteenth set of embodiments, wherein the compound is suitable for administration to a patient intraperitoneally.
A seventeenth set of embodiments of the present disclosure includes at least one method according to any one of the thirteenth, fourteenth, and/or sixteenth sets of embodiments, wherein the compound is in a formulation, and wherein said formulation includes methylcellulose.
An eighteenth set of embodiments of the present disclosure includes at least one method according to any one of the thirteenth, fourteenth, and/or sixteenth sets of embodiments, wherein the compound is in a formulation, and wherein said formulation includes Tween-80.
A nineteenth set of embodiments of the present disclosure includes at least one method of treating a patient, comprising the steps of: providing at least one compound of any of the first, second, third, and/or fourth sets of embodiments, or a pharmaceutically acceptable salt or metabolite thereof, wherein said compound is formulated for treatment of a human or an animal patient; and administering at least one therapeutic dose of the compound to the human or animal patient.
A twentieth set of embodiments of the present disclosure includes at least one of the methods according to any of the nineteenth set of embodiments, wherein the patient is also treated with a therapeutically effective dose of at least one compound of any of the first, second, third, and fourth embodiment, or a pharmaceutically acceptable salt or metabolite thereof, wherein said compound damages DNA directly or that inhibits topoisomerase II.
A twenty-first set of embodiments of the present disclosure includes at least one method according to any of the nineteenth and/or twentieth sets of embodiments, wherein the patient is also treated with a therapeutically effective dose of at least one compound selected from the group consisting of: Cisplatin, Etoposide, Busulfan, Bendamustine, Carboplatin, Carmustine, Chlorambucil, Cyclophosphamide, Dacarbazine, Daunorubicin, Decitabine, Doxorubicin, Epirubicin, Etoposide, Idarubicin, Ifosfamide, Irinotecan, Lomustine, Mechlorethamine, Melphalan, Mitomycin C, Mitoxantrone, Oxaliplatin, Temozolomide, and Topotecan.
A twenty-second e set of embodiments of the present disclosure includes at least one method according to any one of the nineteenth, twentieth, and/or twenty first set of embodiments, wherein said therapeutically effective dose is in the ranges selected from the group consisting of: about 10 mg of said compound per kg−1 to about 1000 mg of said compound per kg−1 of the patient's body weight, about 10 mg of said compound per kg−1 to about 500 mg of said compound per kg−1 of the patient's body weight, about 20 mg of said compound per kg−1 to about 450 mg of said compound per kg−1 of the patient's body weight, about 30 mg of said compound per kg−1 to about 400 mg of said compound per kg−1 of the patient's body weight, about 40 mg of said compound per kg−1 to about 350 mg of said compound per kg−1 of the patient's body weight, and about 50 mg of said compound per kg−1 to about 300 mg of said compound per kg−1 of the patient's body weight.
A twenty-third set of embodiments of the present disclosure includes at least one method according to any one of the nineteenth, twentieth, twenty first, and/or twenty second set of embodiments, wherein said therapeutically effective dose is in the ranges selected from the group consisting of: about 10 mg of said compound per kg−1 to about 100 mg of said compound per kg−1 of the patient's body weight, about 50 mg of said compound per kg−1 to about 100 mg of said compound per kg−1 of the patient's body weight, about 100 mg of said compound per kg−1 to about 200 mg of said compound per kg−1 of the patient's body weight, about 150 mg of said compound per kg−1 to about 200 mg of said compound per kg−1 of the patient's body weight, about 200 mg of said compound per kg−1 to about 300 mg of said compound per kg−1 of the patient's body weight, about 250 mg of said compound per kg−1 to about 300 mg of said compound per kg−1 of the patient's body weight, about 300 mg of said compound per kg−1 to about 400 mg of said compound per kg−1 of the patient's body weight, about 350 mg of said compound per kg−1 to about 400 mg of said compound per kg−1 of the patient's body weight, about 400 mg of said compound per kg−1 to about 500 mg of said compound per kg−1 of the patient's body weight, about 450 mg of said compound per kg−1 to about 500 mg of said compound per kg−1 of the patient's body weight, about 500 mg of said compound per kg−1 to about 1000 mg of said compound per kg−1 of the patient's body weight, about 500 mg of said compound per kg−1 to about 9000 mg of said compound per kg−1 of the patient's body weight, about 500 mg of said compound per kg−1 to about 800 mg of said compound per kg−1 of the patient's body weight, about 500 mg of said compound per kg−1 to about 700 mg of said compound per kg−1 of the patient's body weight, about 500 mg of said compound per kg−1 to about 600 mg of said compound per kg−1 of the patient's body weight, about 600 mg of said compound per kg−1 to about 900 mg of said compound per kg−1 of the patient's body weight, about 700 mg of said compound per kg−1 to about 800 mg of said compound per kg−1 of the patient's body weight, about 800 mg of said compound per kg−1 to about 1000 mg of said compound per kg−1 of the patient's body weight, about 900 mg of said compound per kg−1 to about 1000 mg of said compound per kg−1 of the patient's body weight.
A twenty-fourth set of embodiments of the invention present disclosure at least one method according to any one of the nineteenth, twentieth, twenty first, twenty second, and/or twenty third sets of embodiments, wherein said dose is selected from the group consisting of: about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, and 1000 mg of said compound per kg−1 of the patient's body weight.
A twenty fifth set of embodiments of the invention present disclosure at least one method according to any one of the nineteenth, twentieth, twenty first, twenty second, and/or twenty third sets of embodiments, wherein said dose is about 50 mg of said compound per kg4 of the patient's body weight. In other embodiment, the dose is about 100 mg of said compound per kg−1 of the patient's body weight. In other embodiment, the dose is about 200 mg of said compound per kg−1 of the patient's body weight. Still in other embodiment, the dose is about 300 mg of said compound per kg−1 of the patient's body weight.
Some of the embodiments, disclosed herein include at least one method for reducing the activity of a protein, comprising the steps of: providing a compound of Formula II or a pharmaceutically acceptable salt or metabolite thereof, wherein said compound of Formula II binds to Replication Protein A or is metabolized into a chemical that binds to Replication Protein A, said compound having the following Formula:
wherein, R is C1-C6 alkyl, Y is a substituent selected from the group consisting of: fluorine, iodine, chlorine, and F3CO, and n is 1, 2, or 3; and contacting said compound of Formula II with at least one isoform of Replication Protein A. In some embodiments, the compound that binds to Replication Protein A is a compound selected from the group consisting of: TDRL-540, TDRL-539, TDRL-551, TDRL-557, TDRL-652, and pharmaceutically acceptable salts and metabolites thereof.
In other embodiments, the compound that binds to Replication Protein A is compound TDLR-551 or a pharmaceutically acceptable salt thereof or a metabolite thereof. In still other embodiments, the contacting step between either said compound of Formula II, or a pharmaceutically acceptable salt or metabolite thereof, and the at least one isoform of Replication Protein A occurs in vivo. In yet still other embodiments, the contacting step between either said compound of Formula II, or a pharmaceutically acceptable salt or metabolite thereof, and the at least one isoform of Replication Protein A occurs in vitro.
Also disclosed is a method of altering eukaryotic cell cycle-progression, comprising the steps of: providing a compound of Formula II, or a pharmaceutically acceptable salt or metabolite thereof, that interferes with eukaryotic cell cycle-progression or that is metabolized into a chemical that interferes with eukaryotic cell cycle-progression, said compound of Formula II having the following Formula:
wherein, R is C1-C6 alkyl, Y is a substituent selected from the group consisting of: fluorine, iodine, chlorine, and F3CO, and n is 1, 2, or 3; and contacting said compound of Formula II with at least one eukaryotic cell. In some embodiments, said compound that interferes with eukaryotic cell cycle-progression is a compound selected from the group consisting of: TDRL-540, TDRL-539, TDRL-551, TDRL-557, TDRL-652 and pharmaceutically acceptable salts and metabolites thereof.
In other embodiments, said compound that interferes with eukaryotic cell cycle-progression is compound TDLR-551 or a pharmaceutically acceptable salt thereof or a metabolite thereof. Still in other embodiments, the contacting step between said compound of Formula II, or a pharmaceutically acceptable salt or metabolite thereof, and the eukaryotic cell occurs in vivo. In still other embodiments, the contacting step between said compound of Formula II, or a pharmaceutically acceptable salt or metabolite thereof, and the eukaryotic cell occurs in vitro.
Further disclosed is a method of treating cancer, comprising the steps of: providing a compound of Formula II, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula II interferes with the cell cycle of a cancer cell or is metabolized into a chemical that interferes with the cell cycle of a cancer cell, said compound of Formula II having the following Formula:
wherein, R is C1-C6 alkyl, Y is a substituent selected from the group consisting of: fluorine, iodine, chlorine, and F3CO, and n is 1, 2, or 3; and contacting said compound of Formula II with at least one cancer cell. In some embodiments, said compound that interferes with the cell cycle of a cancer cell is a compound selected from the group consisting of: TDRL-540, TDRL-539, TDRL-551, TDRL-557, TDRL-652, and pharmaceutically acceptable salts and metabolites thereof.
In other embodiments, said compound that interferes with the cell cycle of a cancer cell is compound TDLR-551 or a pharmaceutically acceptable salt thereof or a metabolite thereof. In still other embodiments, the contacting step between said compound of Formula II, or a pharmaceutically acceptable salt or metabolite thereof, and the cancer cell occurs in vivo. In some embodiments, the contacting step between said compound of Formula II, or a pharmaceutically acceptable salt or metabolite thereof, and the cancer cell occurs in vitro. In still yet some embodiments, the cancer cell is an epithelial ovarian cancer cell or a non-small cell lung cancer cell.
Additionally disclosed is a compound, comprising a compound of Formula:
wherein, R is C1-C6 alkyl, Y is a substituent selected from the group consisting of: fluorine, iodine, chlorine, and F3CO, and n is 1, 2, or 3, or a pharmaceutically acceptable salt thereof, or a metabolite thereof. In some embodiments, said compound is a compound selected from the group consisting of: TDRL-540, TDRL-539, TDRL-551, TDRL-557, and TDRL-652 or a pharmaceutically acceptable salt thereof, or a metabolite thereof. In other embodiments, said compound is compound TDLR-551, or a pharmaceutically acceptable salt thereof or a metabolite thereof.
Additionally disclosed is a method of treating a disease, comprising the steps of: supplying at least one compound according to Formula II above or a pharmaceutically acceptable salt or metabolite thereof, wherein said compound is effective for the treatment of at least one disease. In some embodiments, the compound is suitable for administration to a patient. In other embodiments, the compound is suitable for administration to a patient orally. In some exemplary embodiments, the compound is in a formulation and wherein said formulation includes methylcellulose. In yet other embodiments, the compound is suitable for administration to a patient intraperitoneally. In still other embodiments, the compound is in a formulation and wherein said formulation includes Tween-80.
Further disclosed is a method of treating a patient, comprising the steps of: providing at least one compound according to claim 17 or a pharmaceutically acceptable salt or metabolite thereof, wherein said compound is formulated for treatment of a human or an animal patient. In some embodiments, the method further comprises the step of administering at least one dose of the therapeutically effective amount of said compound to a patient. In other embodiments, the patient is also treated with a therapeutically effective dose of at least one compound that damages DNA directly or that inhibits topoisomerase II. Still in some other embodiments, the patient is also treated with a therapeutically effective dose of at least one compound selected from the group consisting of: Cisplatin, Etoposide, Busulfan, Bendamustine, Carboplatin, Carmustine, Chlorambucil, Cisplatin, Cyclophosphamide, Dacarbazine, Daunorubicin, Decitabine, Doxorubicin, Epirubicin, Etoposide, Idarubicin, Ifosfamide, Irinotecan, Lomustine, Mechlorethamine, Melphalan, Mitomycin C, Mitoxantrone, Oxaliplatin, Temozolomide, and Topotecan.
In some embodiments, said dose of Formula II is about 50 mg of said compound per kg−1 of the patient's body weight. In other embodiments, said dose of Formula II is about 100 mg of said compound per kg−1 of the patient's body weight. Still in other embodiments, said dose of Formula II is about 200 mg of said compound per kg−1 of the patient's body weight.