WATER-SOLUBLE ZINC IONOPHORES, ZINC CHELATORS, AND/OR ZINC COMPLEXES AND USE FOR TREATING CANCER

Abstract

Disclosed herein are novel zinc ionophores, zinc chelators and/or zinc complexes with enhanced aqueous solubility. Methods of treating cancer using at least one zinc ionophore and/or zinc chelator are also disclosed. Also disclosed herein are compositions and methods for treating cancer with combination therapy using at least one texaphyrin metal complex and at least one zinc ionophore or the respective pharmaceutically acceptable derivatives or salts thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 presents non-limiting examples of zinc ionophores.

FIG. 2 presents a non-limiting synthesis of 5-PEG-[3]-ZnHPT, also designated herein as PEGZnHPT.

FIG. 3 presents a non-limiting synthesis of 5-PEG-[3]-ZnHPT, also designated herein as PEGZnHPT, 5-PEG-[2]-ZnHPT, and 5-PEG-[1]-ZnHPT.

FIG. 4 presents a non-limiting synthesis of 3-O-PEG-ZnHPT.

FIG. 5 presents a non-limiting synthesis of 3-O-PEG-ZnHPT.

FIG. 6 presents a non-limiting synthesis of 5-CONHPEG-ZnHPT.

FIG. 7 presents a non-limiting synthesis of 6-OPEG-ZnHPT.

FIG. 8 presents a non-limiting synthesis of 5-OPEG-ZnHPT.

FIG. 9 presents a non-limiting synthesis of ZnHPT derivatives.

FIG. 10 presents a non-limiting synthesis of ZNHPT derivatives.

FIG. 11 presents a non-limiting synthesis of ZNHPT derivatives.

FIG. 12 presents a non-limiting synthesis of a ZNHPT derivative.

FIG. 13 presents a non-limiting synthesis of ZNHPT derivatives.

FIG. 14 presents non-limiting examples of zinc ionophores, zinc chelators, and/or zinc complexes.

FIG. 15 presents a single crystal X-ray diffraction structure of a complex of Formula I wherein R₀, R₂, R₃═H and R₁═CH₂OCH₂CH₂OCH₃.

FIG. 16 presents a non-limiting example of 24 h plateau phase cell culture studies with A549 cells in which MTT reduction is measured as a function of zinc concentration and 5-PEG-[2]-ZnHPT concentration.

FIG. 17 presents a non-limiting example of 24 h plateau phase cell culture studies with A549 cells in which MTT reduction is measured as a function of zinc concentration and 5-PEG-[3]-ZnHPT concentration.

FIG. 18 presents a non-limiting example of 24 h plateau phase cell culture studies with PC3 cells in which MTT reduction is measured as a function of zinc concentration and 5-PEG-[2]-ZnHPT concentration.

FIG. 19 presents a non-limiting example of 24 h plateau phase cell culture studies with PC3 cells in which MTT reduction is measured as a function of zinc concentration and 5-PEG-[3]-ZnHPT concentration.

FIG. 20 presents non-limiting examples of zinc chelators.

FIG. 21 presents a non-limiting example of 24 h exponential phase cell culture studies with A549 cells in which MTT reduction is measured as a function of zinc concentration and DPM 1 concentration.

FIG. 22 presents a non-limiting example of 24 h exponential phase cell culture studies with A549 cells in which MTT reduction is measured as a function of zinc concentration and DPM 3 concentration.

FIG. 23 presents a non-limiting example of 24 h plateau phase cell culture studies with A549 cells in which MTT reduction is measured as a function of MGd concentration and ZnHPT concentration, and in which all studies were done in the presence of 50 μM of Zn²⁺.

FIG. 24 presents a non-limiting example of 24 h plateau phase cell culture studies with PC3 cells in which MTT reduction is measured as a function of MGd concentration and ZNHPT concentration, and in which all studies were done in the presence of 50 μM of Zn²⁺.

FIG. 25 presents a non-limiting example of 24 h plateau phase cell culture studies with A549 cells in which MTT reduction is measured as a function of MGd concentration and PEGZnHPT concentration, and in which all studies were done in the presence of 50 μM of Zn²⁺.

FIG. 26 presents a non-limiting example of 24 h plateau phase cell culture studies with PC3 cells in which MTT reduction is measured as a function of MGd concentration and PEGZnHPT concentration, and in which all studies were done in the presence of 25 μM of Zn²⁺.

FIG. 27 presents a non-limiting example of the mean fluorescence of Fluozin-3 observed in 4 h plateau phase cell culture with A549 cells as a function of zinc concentration and PEGZnHPT concentration.

FIG. 28 presents a non-limiting example of the measured tumor volumes in a A549 tumor xenograft model as a function of time following the injection of certain agents.

FIG. 29 presents a non-limiting example of the measured tumor volumes in a PC3 tumor xenograft model as a function of time following the injection of certain agents.

FIG. 30 presents a non-limiting example of the measured tumor volumes in a PC3 tumor xenograft model as a function of time following the injection of certain agents.

FIG. 31 presents a non-limiting example of the measured tumor volumes in a DU-145 tumor xenograft model as a function of time following the injection of certain agents.

FIG. 32 presents a non-limiting example of 2 h plateau phase cell culture studies with A549 cells in which Lipoate reduction is measured as a function of zinc concentration and 5-PEG-[3]-ZnHPT concentration.

FIG. 33 presents a non-limiting example of 2 h plateau phase cell culture studies with A549 cells in which Lipoate reduction is measured as a function of zinc concentration and 5-PEG-[2]-ZnHPT concentration.

FIG. 34 presents a non-limiting example of 2 h plateau phase cell culture studies with A549 cells in which Lipoate reduction is measured as a function of zinc concentration and 5-PEG-[1]-ZnHPT concentration.

FIG. 35 presents a non-limiting example of 2 h plateau phase cell culture studies with A549 cells in which Lipoate reduction is measured as a function of zinc concentration and ZnHPT concentration.

FIG. 36 presents a non-limiting example of 3 day exponential phase cell culture studies with A549 cells in which Relative proliferation is measured as a function of zinc concentration and 5-PEG-[3]-ZnHPT concentration.

FIG. 37 presents a non-limiting example of 3 day exponential phase cell culture studies with A549 cells in which Relative proliferation is measured as a function of zinc concentration and 5-PEG-[2]-ZnHPT concentration.

FIG. 38 presents a non-limiting example of 3 day exponential phase cell culture studies with A549 cells in which Relative proliferation is measured as a function of zinc concentration and 5-PEG-[1]-ZnHPT concentration.

FIG. 39 presents a non-limiting example of 3 day exponential phase cell culture studies with A549 cells in which Relative proliferation is measured as a function of zinc concentration and ZnHPT concentration.

FIG. 40 presents a non-limiting example of 3 day exponential phase cell culture studies with A549 cells in which Relative proliferation is measured as a function of zinc concentration and 5-PEG-[3]-HPT concentration.

FIG. 41 presents a non-limiting example of 3 day exponential phase cell culture studies with A549 cells in which Relative proliferation is measured as a function of zinc concentration and 5-PEG-[2]-HPT concentration.

FIG. 42 presents a non-limiting example of 3 day exponential phase cell culture studies with A549 cells in which Relative proliferation is measured as a function of zinc concentration and 5-PEG-[1]-HPT concentration.

FIG. 43 presents a non-limiting example of 3 day exponential phase cell culture studies with A549 cells in which Relative proliferation is measured as a function of zinc concentration and HPT concentration.

FIG. 44 presents a non-limiting example of 24 h plateau phase cell culture studies with A549 cells in which MTT reduction is measured as a function of copper concentration and 5-PEG-[3]-HPT concentration.

FIG. 45 presents a non-limiting example of 24 h plateau phase cell culture studies with A549 cells in which MTT reduction is measured as a function of copper concentration and 5-PEG-[2]-HPT concentration.

FIG. 46 presents a single crystal X-ray diffraction structure of a complex of compound 33a wherein R₀, ═CH₃R₂, R₁═H and R₃═OCH₂CH₂OCH₃.

FIG. 47 presents a non-limiting example of 1 day plateau phase cell culture studies with A549 cells in which MTT reduction is measured as a function of zinc concentration and compound 33a concentration.

FIG. 48 presents a non-limiting example of 1 day plateau phase cell culture studies with A549 cells in which MTT reduction is measured as a function of zinc concentration and compound 33b concentration.

FIG. 49 presents a non-limiting example of 1 day plateau phase cell culture studies with A549 cells in which MTT reduction is measured as a function of zinc concentration and compound 28 concentration.

FIG. 50 presents a non-limiting example of 3 day exponential phase cell culture studies with A549 cells in which Relative proliferation is measured as a function of zinc concentration and 11bi concentration.

FIG. 51 presents a non-limiting example of 3 day exponential phase cell culture studies with A549 in which Relative proliferation is measured as a function of zinc concentration and 11bii concentration.

Claims

1. A compound, comprising Formula (I):

2. The compound of claim 1, wherein each of R0, R1, R2, and R3 is the same on each side of Formula (I), independently lower alkyl, (CH2)v—ORy, ORy, NHRy, C(O)NHRy, wherein Ry is PEG or PPG; wherein PEG or PPG is —(O-alkylene or O-substituted alkylene)x-O—Rz or -(alkylene-O or substituted alkylene-O)x—Rz; wherein Rz is H or alkyl; v and x are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

3. The compound of claim 2, wherein each R0, R1, R2, and R3 are the same on each side of Formula (I).

4. The compound of claim 2, wherein R3 is OPEG; wherein x is 3; and R0, R1, and R2 are H.

5. The compound of claim 2, wherein R1 is C(O)NHPEG; wherein x is 3; and R0, R2, and R3 are H.

6. The compound of claim 2, wherein R1 is CH2—OPEG; wherein x is 3; and R0, R2, and R3 are H.

7. The compound of claim 2, wherein R1 is CH2—OPEG; wherein x is 2; and R0, R2, and R3 are H.

8. The compound of claim 2, wherein R1 is CH2—OPEG; wherein x is 1; and R0, R2, and R3 are H.

9. The compound of claim 2, wherein R0 is CH3 and R3 is OPEG; wherein x is 1; and R1 and R2 are H.

10. The compound of claim 2, wherein R0 is CH3 and R3 is OPEG; wherein x is 2; and R1 and R2 are H.

11. The compound of claim 2, wherein R0 is CH3 and R3 is OPEG; wherein x is 3; and R1 and R2 are H.

12. A compound, comprising Formula (Ib):

13. A compound, comprising Formula (II):

14. The compound of claim 13 wherein j is 0; L is a bond; and R0, R1, and R2 are H.

15. The compound of claim 13 wherein L is (CH2OCH2)m, wherein m is an integral number from 0-4; j is 1, and R0, R1, and R2 are H.

16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

17. A pharmaceutical composition comprising a compound of claim 12 and a pharmaceutically acceptable excipient.

18. A pharmaceutical composition comprising a compound of claim 13 and a pharmaceutically acceptable excipient.

19. A method of treating cancer comprising administering to a patient in need a therapeutically effective amount of at least one compound having the structure of Formula (I):

20. The method of claim 19 further comprising the step of administering to a patient in need a therapeutically effective amount of motexafin gadolinium or a pharmaceutically acceptable texaphyrin derivative.

21. The method of claim 19 wherein the cancer is selected from the group consisting of adrenal cortical cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, adult CNS brain tumors, pediatric CNS brain metastases, brain metastases, breast cancer, Castleman Disease, cervical cancer, childhood Non-Hodgkin's lymphoma, colon and rectum cancer, endometrial cancer, esophagus cancer, Ewing's family of tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic disease, hematological malignancies, Hodgkin's disease, Kaposi'sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, acute lymphocytic leukemia, acute myeloid leukemia, children's leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lung cancer, lung carcinoid tumors, Non-Hodgkin's lymphoma, male breast cancer, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cavity and paranasal cancer, nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (adult soft tissue cancer), melanoma skin cancer, nonmelanoma skin cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Waldenstrom's macroglobulinemia. In one embodiment, the cancers are selected from the group consisting of metastatic brain cancer, lung cancer, glioblastoma, lymphomas, leukemia, renal cell cancer (kidney cancer), head and neck cancer, breast cancer, prostrate cancer, and ovarian cancer.