WO2018161741A1 - Inhibiteur d'ape1 et son application dans la préparation d'un médicament pour le traitement de tumeurs et de maladies liées à une angiogenèse anormale - Google Patents

Inhibiteur d'ape1 et son application dans la préparation d'un médicament pour le traitement de tumeurs et de maladies liées à une angiogenèse anormale Download PDF

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Publication number
WO2018161741A1
WO2018161741A1 PCT/CN2018/074656 CN2018074656W WO2018161741A1 WO 2018161741 A1 WO2018161741 A1 WO 2018161741A1 CN 2018074656 W CN2018074656 W CN 2018074656W WO 2018161741 A1 WO2018161741 A1 WO 2018161741A1
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WIPO (PCT)
Prior art keywords
ape1
compound
kshv
inhibitor
ring
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PCT/CN2018/074656
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English (en)
Chinese (zh)
Inventor
袁岩
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中山大学
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Application filed by 中山大学 filed Critical 中山大学
Publication of WO2018161741A1 publication Critical patent/WO2018161741A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine

Definitions

  • APE1 inhibitors are combined with clinically available anti-tumor drugs, such as cisplatin, artemisinin and other anti-tumor drugs through other mechanisms of action, these compounds mainly act by inhibiting APE1, such administration
  • anti-tumor drugs such as cisplatin, artemisinin and other anti-tumor drugs through other mechanisms of action
  • these compounds mainly act by inhibiting APE1, such administration
  • the method should fall within the scope of protection of the present invention.
  • vascular proliferation at the bottom of the retina can cause macular degeneration, which is the leading cause of blindness in the elderly.
  • the blood concentration of conventional oral administration or injection administration is often unable to maintain an effective onset concentration in the eye, resulting in poor drug efficacy.
  • a conventional VEGF antagonist is administered by injection, the therapeutic effect is poor or the therapeutic time is short, and the administration mode is not as varied as the small molecule inhibitor.
  • APE1 inhibitors are very effective in animal models of macular degeneration.
  • structural analogs of C10 and C10 can inhibit diseases of abnormal vascular proliferation such as macular degeneration by inhibiting the redox end function of APE1.
  • Figure 2 is a graph showing the inhibition of the redox end of APE1 by C10 and E3330:
  • the cDNAs of APE1 and c-fos were cloned into the N-terminal His-tagged pET-28a vector, and c-jun was cloned into the GST-tagged pGEX-4T-1 vector.
  • Each plasmid was transferred to Roseta E. coli and cultured in LB medium. When the bacterial density OD reached 0.6, it was induced with 1 mM IPTG.
  • E. coli transferred to APE-1 was incubated at 37 ° C for 4 h, and E. coli transfected with c-jun and c-fos was incubated at 25 ° C for 4 h. The bacterial solution was lysed with a lysate with PMSF.
  • KSHV-PDLSC was treated with the drug for 24 hours, and the drug-containing medium was removed.
  • the cells were cultured for 24 hours, and the supernatant was collected.
  • the ELISA kit was used to detect the cytokine secretion levels of cells treated with different drug concentrations. The change.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un inhibiteur d'APE1 et une application de ce dernier dans la préparation d'un médicament pour le traitement de tumeurs et de maladies liées à une angiogenèse anormale. L'inhibiteur d'APE1 possède la structure représentée par la formule 1 suivante, et inhibe sélectivement une extrémité redox de l'APE1.
PCT/CN2018/074656 2017-03-09 2018-01-31 Inhibiteur d'ape1 et son application dans la préparation d'un médicament pour le traitement de tumeurs et de maladies liées à une angiogenèse anormale WO2018161741A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710138466.1 2017-03-09
CN201710138466.1A CN107184572B (zh) 2017-03-09 2017-03-09 一种ape1抑制剂及其在制备用于治疗肿瘤和血管异常增生性疾病药物中的应用

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WO2018161741A1 true WO2018161741A1 (fr) 2018-09-13

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PCT/CN2018/074656 WO2018161741A1 (fr) 2017-03-09 2018-01-31 Inhibiteur d'ape1 et son application dans la préparation d'un médicament pour le traitement de tumeurs et de maladies liées à une angiogenèse anormale

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CN (1) CN107184572B (fr)
WO (1) WO2018161741A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11351130B2 (en) 2017-04-17 2022-06-07 Indiana University Research And Technology Corporation Prevention and reversal of inflammation induced DNA damage

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107184572B (zh) * 2017-03-09 2020-07-28 中山大学 一种ape1抑制剂及其在制备用于治疗肿瘤和血管异常增生性疾病药物中的应用
CN110917358A (zh) * 2019-12-26 2020-03-27 成都医学院第一附属医院 一种逆转肺腺癌顺铂耐药性的药物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102600115A (zh) * 2011-12-16 2012-07-25 西安交通大学 姜黄素c及其衍生物c3在防治视网膜黄斑变性药物中的应用
CN107184572A (zh) * 2017-03-09 2017-09-22 中山大学 一种ape1抑制剂及其在制备用于治疗肿瘤和血管异常增生性疾病药物中的应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102600115A (zh) * 2011-12-16 2012-07-25 西安交通大学 姜黄素c及其衍生物c3在防治视网膜黄斑变性药物中的应用
CN107184572A (zh) * 2017-03-09 2017-09-22 中山大学 一种ape1抑制剂及其在制备用于治疗肿瘤和血管异常增生性疾病药物中的应用

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AHMED, M.M.: "Synthesis of thiophene and NO -curcuminoids for antiinflammatory and anti-cancer activities", MOLECULES, vol. 18, no. 2, 25 January 2013 (2013-01-25), pages 1483 - 501, XP055605954, ISSN: 1420-3049 *
KHAN, M. A.: "Synthesis and anti-inflammatory properties of some aromatic and heterocyclic aromatic curcuminoids", BIOORGANIC CHEMISTRY, vol. 40, no. 1, 25 November 2011 (2011-11-25), pages 35 - 36, XP028443386, ISSN: 0045-2068, DOI: doi:10.1016/j.bioorg.2011.11.004 *
QIU, XU: "Synthesis and evaluation of curcumin analogues as potential thioredoxin reductase inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY, 24 July 2008 (2008-07-24), XP024524922, ISSN: 0968-0896 *
ZENG, HONGYAO: "Synthesis of Curcuminoids and Researches on related methods", MEDICINE AND HEALTH SCIENCES, vol. 4, 15 April 2008 (2008-04-15), pages E057 - 39 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11351130B2 (en) 2017-04-17 2022-06-07 Indiana University Research And Technology Corporation Prevention and reversal of inflammation induced DNA damage

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CN107184572A (zh) 2017-09-22
CN107184572B (zh) 2020-07-28

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