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CN-122028916-A - Methods for treating cancer

CN122028916ACN 122028916 ACN122028916 ACN 122028916ACN-122028916-A

Abstract

A method of reducing resistance of a cancer to an anticancer drug in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, wherein the cancer overexpresses peroxiredoxin 1 (PRDX 1) and the compound is a triazole-linked flavonoid dimer. The anticancer drug may be doxorubicin, daunorubicin, vincristine, cisplatin, paclitaxel, mitoxantrone, and combinations thereof.

Inventors

  • ZHOU MINGXIANG
  • CHEN DEHENG
  • SUN GEGE
  • HUANG LIQIONG
  • CUI JIAHUA

Assignees

  • 香港理工大学

Dates

Publication Date
20260512
Application Date
20240913
Priority Date
20230914

Claims (20)

  1. 1. A method of reducing resistance of a cancer to an anticancer drug in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, wherein the cancer overexpresses peroxiredoxin 1 (PRDX 1) and the compound has formula 1: 1 or a pharmaceutically acceptable salt thereof, wherein: A is a bond or a moiety of formula 2: 2; m is an integer selected from 1-3; n is an integer selected from 1-3; p is an integer selected from 0 to 4; R 1 is a moiety of formula 3 or formula 4: 3; 4; r 2 is a moiety of formula 5: 5; R 3 is hydrogen, alkyl, - (CH 2 ) p PhR 9 or-C (O) PhR 9 ; R 4 、R 5 、R 6 、R 7 、R 9 and R 10 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, perhaloalkoxy, halogen, nitrile, nitro 、-OR、-SR、-N(R) 2 、-C(O)R、-C(O)OR、-OC(O)R、-N(R)C(O)R、-C(O)N(R) 2 、-N(R)C(O)OR、-OC(O)N(R)-、-OC(O)OR、-N(R)C(O)N(R) 2 、-S(O) 2 R、-S(O) 2 N(R) 2 、-N(R)S(O) 2 R、-C≡CH、-CH 2 OCH 2 C≡CH、-OCH 2 C≡CH、-N(CH 2 C≡CH) 2 、-C(O)OCH 2 C≡CH、-N 3 、-CH 2 N 3 、 And ; R 8 is hydrogen or a moiety of formula 6: 6; X is O or H 2 ; r 11 is hydrogen, -C (O) R, -C (O) OR, -OC (O) R, -N (R) C (O) R, -C (O) N (R) 2 , -N (R) C (O) OR OR-N 3 , and R is independently at each occurrence hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or aralkyl.
  2. 2. The method of claim 1, wherein m is 1 and n is 2, or m is 2 and n is 2.
  3. 3. The method of claim 1 or 2, wherein R 4 、R 5 、R 6 、R 7 、R 9 and R 10 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, halogen, nitrile, nitro 、-OR、-SR、-N(R) 2 、-C(O)R、-C(O)OR、-OC(O)R、-CH 2 OCH 2 C≡CH、-OCH 2 C≡CH、-N(CH 2 C≡CH) 2 、-C(O)OCH 2 C≡CH、-N 3 、-CH 2 N 3 , and 。
  4. 4. The method of claim 1 OR 2, wherein R 4 、R 5 、R 6 、R 7 、R 9 and R 10 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, halo, nitrile, nitro, -OR, -SR, -N (R) 2 , -C (O) R, -C (O) OR, and-OC (O) R, and R 11 is hydrogen, -C (O) R, -C (O) OR, -OC (O) R, -N (R) C (O) R, -C (O) N (R) 2 , OR-N (R) C (O) OR.
  5. 5. The method of claim 1, wherein the compound has formula 7: 7 or a pharmaceutically acceptable salt thereof, wherein: R 4 、R 5 、R 6 、R 7 and R 10 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, halo, nitrile, nitro, -OR, -SR, -N (R) 2 , -C (O) R, -C (O) OR, and-OC (O) R; r 11 is-C (O) OR, -N (R) C (O) R, -C (O) N (R) 2 OR-N (R) C (O) OR.
  6. 6. The method of claim 5, wherein R 4 、R 5 、R 6 、R 7 and R 10 are each independently selected from the group consisting of hydrogen, alkyl, halogen, nitrile, nitro, -OR, and-N (R) 2 , and R 11 is-C (O) OR.
  7. 7. The method of claim 1, wherein the compound has formula 8: 8 or a pharmaceutically acceptable salt thereof, wherein: R 4 、R 5 、R 6 、R 7 and R 9 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, halo, nitrile, nitro, -OR, -SR, -N (R) 2 , -C (O) R, -C (O) OR, and-OC (O) R.
  8. 8. The method of claim 7, wherein R 4 、R 5 、R 6 、R 7 and R 9 are each independently selected from the group consisting of hydrogen, alkyl, halogen, nitrile, nitro, -OR, and-N (R) 2 .
  9. 9. The method of claim 1, wherein the compound is selected from the group consisting of: 、 、 、 、 、 and pharmaceutically acceptable salts thereof.
  10. 10. The method of claim 1, wherein the compound is selected from the group consisting of: 、 and pharmaceutically acceptable salts thereof.
  11. 11. The method of any one of claims 1-10, wherein the anticancer drug is selected from the group consisting of doxorubicin, daunorubicin, vincristine, cisplatin, paclitaxel, mitoxantrone, and combinations thereof.
  12. 12. The method of any one of claims 1-11, further comprising co-administering an anticancer drug selected from the group consisting of doxorubicin, daunorubicin, vincristine, cisplatin, paclitaxel, mitoxantrone, and combinations thereof.
  13. 13. The method of any one of claims 1-12, wherein the cancer is head and neck squamous cell carcinoma, non-small cell lung cancer, breast cancer, esophageal cancer, pancreatic adenocarcinoma, ovarian cancer, cervical cancer, liver cancer, myeloma, hodgkin's lymphoma, non-hodgkin's lymphoma, and bladder cancer.
  14. 14. The method of any one of claims 1-12, wherein the cancer is breast cancer.
  15. 15. A method of treating cancer in a subject in need thereof, the method comprising co-administering to the subject a therapeutically effective amount of a compound and a therapeutically effective amount of an anti-cancer drug, wherein the cancer overexpresses peroxiredoxin 1 (PRDX 1), and the compound has formula 1: 1 or a pharmaceutically acceptable salt thereof, wherein: A is a bond or a moiety of formula 2: 2; m is an integer selected from 1-3; n is an integer selected from 1-3; p is an integer selected from 0 to 4; R 1 is a moiety of formula 3 or formula 4: 3; 4; r 2 is a moiety of formula 5: 5; R 3 is hydrogen, alkyl, - (CH 2 ) p PhR 9 or-C (O) PhR 9 ; R 4 、R 5 、R 6 、R 7 、R 9 and R 10 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, perhaloalkoxy, halogen, nitrile, nitro 、-OR、-SR、-N(R) 2 、-C(O)R、-C(O)OR、-OC(O)R、-N(R)C(O)R、-C(O)N(R) 2 、-N(R)C(O)OR、-OC(O)N(R)-、-OC(O)OR、-N(R)C(O)N(R) 2 、-S(O) 2 R、-S(O) 2 N(R) 2 , and-N (R) S (O) 2 R; R 8 is hydrogen or a moiety of formula 6: 6; X is O or H 2 ; R 11 is hydrogen, -C (O) R, -C (O) OR, -OC (O) R, -N (R) C (O) R, -C (O) N (R) 2 OR-N (R) C (O) OR, and R is independently at each occurrence hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or aralkyl.
  16. 16. The method of claim 15, wherein m is 1 and n is 2, or m is 2 and n is 2.
  17. 17. The method of claim 15 OR 16, wherein R 4 、R 5 、R 6 、R 7 、R 9 and R 10 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, halo, nitrile, nitro, -OR, -SR, -N (R) 2 , -C (O) R, -C (O) OR, and-OC (O) R, and R 11 is hydrogen, -C (O) R, -C (O) OR, -OC (O) R, -N (R) C (O) R, -C (O) N (R) 2 , OR-N (R) C (O) OR.
  18. 18. The method of claim 15, wherein the compound has formula 7: 7 Or a pharmaceutically acceptable salt thereof, wherein: R 4 、R 5 、R 6 、R 7 and R 10 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, halo, nitrile, nitro, -OR, -SR, -N (R) 2 , -C (O) R, -C (O) OR, and-OC (O) R; r 11 is-C (O) OR, -N (R) C (O) R, -C (O) N (R) 2 OR-N (R) C (O) OR.
  19. 19. The method of claim 18 wherein R 4 、R 5 、R 6 、R 7 and R 10 are each independently selected from the group consisting of hydrogen, alkyl, halogen, nitrile, nitro, -OR, and-N (R) 2 , and R 11 is-C (O) OR.
  20. 20. The method of claim 15, wherein the compound has formula 8: 8 or a pharmaceutically acceptable salt thereof, wherein: R 4 、R 5 、R 6 、R 7 and R 9 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, halo, nitrile, nitro, -OR, -SR, -N (R) 2 , -C (O) R, -C (O) OR, and-OC (O) R.

Description

Methods for treating cancer Cross Reference to Related Applications The present application claims priority from U.S. provisional patent application No. 63/582,539 filed on 9/14 of 2023, which is incorporated herein by reference in its entirety. Technical Field The present disclosure relates to a method of sensitizing cancer cells to anticancer drugs and a method of treating cancer. Background Multidrug resistance is a major impediment to effective cancer treatment. Much research has been directed to developing improved methods for treating multi-drug resistant cancers. However, it is still difficult to find an effective treatment at the time of application. Cancer Stem Cells (CSCs) are believed to promote chemotherapy resistance and relapse. Accordingly, there remains a need to develop improved methods to reduce the resistance of cancer and to improve methods for treating resistant cancers. Disclosure of Invention A novel class of triazole-linked flavonoid dimers, exemplified by Ac13Az9 and Ac15 (Az 2) 2, were identified as being effective in reversing the resistance of cancer (e.g., CD44 +CD24-/low MCF-7 mammary CSC) at an effective concentration of 32 nM. Co-administration of Ac15 (Az 2) 2 and Doxorubicin (DOX) significantly inhibited tumor growth rate in animal models compared to the DOX-only group. To investigate the mechanism of action of triazole-linked flavonoid dimers described herein, photoactivatable derivatives were designed and synthesized and used to identify peroxiredoxin 1 (PRDX 1) as a target protein for Ac13Az 9. PRDX1 is a Reactive Oxygen Species (ROS) scavenger that protects cells from oxidative stress by detoxifying dangerous oxidants, including hydrogen peroxide and superoxide. CSCs overexpress PRDX1, and ectopic expression of PRDX1 confers DOX resistance to MCF-7 cells. Ac13Az9 and Ac15 (Az 2) 2 can reverse DOX resistance by increasing DOX-induced ROS damage, but are not interesting in their monomeric form. This suggests that the dimer structure is critical. The results described herein suggest that Ac13Az9 and Ac15 (Az 2) 2 disrupt monomer dimer homeostasis and cause ROS to accumulate in CSCs, which can lead to reversal of drug resistance. This study provides new insights into the mechanisms of cancer cell resistance and provides new strategies to reverse CSC resistance. By targeting PRDX1, the synthetic flavonoid dimers described herein can lead to up-regulation of cellular ROS levels and reverse chemical resistance of breast CSCs to anticancer drugs (e.g., DOX). In a first aspect, provided herein is a method of reducing resistance of a cancer to an anticancer drug in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, wherein the cancer overexpresses peroxiredoxin 1 (PRDX 1), and the compound has formula 1: 1 or a pharmaceutically acceptable salt thereof, wherein: A is a bond or a moiety of formula 2: 2; m is an integer selected from 1-3; n is an integer selected from 1-3; p is an integer selected from 0 to 4; R 1 is a moiety of formula 3 or formula 4: 3 4; r 2 is a moiety of formula 5: 5; R 3 is hydrogen, alkyl, - (CH 2)pPhR9 or-C (O) PhR 9; R 4、R5、R6、R7、R9 and R 10 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, perhaloalkoxy, halogen, nitrile, nitro 、-OR、-SR、-N(R)2、-C(O)R、-C(O)OR、-OC(O)R、-N(R)C(O)R、-C(O)N(R)2、-N(R)C(O)OR、-OC(O)N(R)-、-OC(O)OR、-N(R)C(O)N(R)2、-S(O)2R、-S(O)2N(R)2、-N(R)S(O)2R、-C≡CH、-CH2OCH2C≡CH、-OCH2C≡CH、-N(CH2C≡CH)2、-C(O)OCH2C≡CH、-N3、-CH2N3、 And; R 8 is hydrogen or a moiety of formula 6: 6; X is O or H 2; r 11 is hydrogen, -C (O) R, -C (O) OR, -OC (O) R, -N (R) C (O) R, -C (O) N (R) 2, -N (R) C (O) OR OR-N 3, and R is independently at each occurrence hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or aralkyl. In certain embodiments, m is 1 and n is 2, or m is 2 and n is 2. In certain embodiments, R 4、R5、R6、R7、R9 and R 10 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, halogen, nitrile, nitro 、-OR、-SR、-N(R)2、-C(O)R、-C(O)OR、-OC(O)R、-CH2OCH2C≡CH、-OCH2C≡CH、-N(CH2C≡CH)2、-C(O)OCH2C≡CH、-N3、-CH2N3, and。 In certain embodiments, R 4、R5、R6、R7、R9 and R 10 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, halo, nitrile, nitro, -OR, -SR, -N (R) 2, -C (O) R, -C (O) OR, and-OC (O) R, and R 11 is hydrogen, -C (O) R, -C (O) OR, -OC (O) R, -N (R) C (O) R, -C (O) N (R) 2, OR-N (R) C (O) OR. In certain embodiments, the compound has formula 7: 7 or a pharmaceutically acceptable salt thereof, wherein: R 4、R5、R6、R7 and R 10 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, halo, nitrile, nitro, -OR, -SR, -N (R) 2, -C (O) R, -C (O) OR, and-OC (O) R; r 11 is-C (O) OR, -N (R) C (O) R, -C (O) N