WO2022258012A1 - Application d'une combinaison ou d'un complexe de pyridostatine ou d'un dérivé de celle-ci et d'un composé transplatine dans la préparation d'un médicament pour le traitement du cancer - Google Patents

Application d'une combinaison ou d'un complexe de pyridostatine ou d'un dérivé de celle-ci et d'un composé transplatine dans la préparation d'un médicament pour le traitement du cancer Download PDF

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WO2022258012A1
WO2022258012A1 PCT/CN2022/097856 CN2022097856W WO2022258012A1 WO 2022258012 A1 WO2022258012 A1 WO 2022258012A1 CN 2022097856 W CN2022097856 W CN 2022097856W WO 2022258012 A1 WO2022258012 A1 WO 2022258012A1
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formula
cancer
compound
complex
independently
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PCT/CN2022/097856
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English (en)
Chinese (zh)
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汪福意
侯垠竹
罗群
房田田
甘铁梁
赵耀
张燕燕
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中国科学院化学研究所
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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage

Definitions

  • pyridostatin mainly acts on nucleotide chains, and can maintain the twisting load generated by DNA and RNA polymerases when they melt. Therefore, DNA or RNA polymerases cannot open G4, resulting in DNA breaks. Furthermore, PDS induces functional telomere abnormalities, generates DNA damage at specific genomic targets, and exhibits antiproliferative activity. Due to the specific interaction between PDS and G4 structure, PDS has been applied to the study of G4 enrichment, G4 gene sequencing and G4 biological function.
  • trans-platinum compounds Unlike cisplatin with high anticancer activity, trans-platinum compounds have higher chemical reactivity and three-dimensional structure, and most trans-platinum compounds with different structures have no antitumor activity or their activity is very low.
  • a group such as thiazole
  • transplatinum compounds exhibit different degrees of inhibitory activity against a variety of solid tumor cells, including cisplatin-resistant cells, such as : trans-[PtCl 2 (NH 3 )(thiazole)](trans-PtTz) etc. But its activity is still weak compared with cisplatin. How to enhance the antitumor activity of trans-platinum compounds is still of interest to researchers.
  • PDS can significantly down-regulate PC4 protein (transcriptional coactivator), and can act as an inhibitor of PC4 protein expression. Since PC4 protein is the trans-PtTz responsive protein, it is speculated that PDS will affect the cytotoxicity of trans-PtTz. It was found through experiments that PDS pretreatment can significantly enhance the cytotoxicity of trans-PtTz to be similar to that of cisplatin. Under the same conditions, PDS does not significantly increase the cytotoxicity of cisplatin, so PDS can specifically increase the cytotoxicity of trans-platinum compounds, and PDS can be used in combination with trans-platinum compounds to achieve the purpose of treating cancer. Moreover, the literature shows that PDS derivatives such as Formula 15b and Formula 15c also have G4 stability, so it can be inferred that PDS derivatives also have similar properties of inhibiting PC4 protein expression and improving the cytotoxicity of trans-PtTz.
  • R has a structure shown in formula 2a, formula 2b, formula 2c or formula 2d or a salt or solvate thereof;
  • PDS can be obtained commercially, and the preparation method of the derivative can refer to CN104045629A, or it can be prepared according to a conventional preparation method in the art.
  • PDS and its derivatives can inhibit the expression of PC4 protein, and related diseases or adverse symptoms mediated by PC4 protein can be alleviated or treated by PDS and its derivatives.
  • the trans-platinum compound may be a common trans-platinum compound in the art, or a divalent trans-platinum compound.
  • Am 1 and Am 2 can be common compounds with coordination function (such as nitrogen-containing compounds).
  • Am 1 and Am 2 are each independently a monodentate ligand, more preferably, Am 1 and Am 2 are each independently ammonia, thiazole, piperidine, piperazine, 4-picoline, 2-methyl Butylamine, sec-butylamine, 1-adamantamine, piperidine-piperidine, diethylamine or 1-methyl-7-azaindole.
  • the trans-platinum compound may be trans-[PtCl 2 (NH 3 )(thiazole)].
  • the third aspect of the present invention provides the application of the combination of pyridostatin or its derivatives and a trans-platinum compound in the preparation of a drug for treating cancer. That is, a combination of pyridostatin or a derivative thereof and a trans-platinum compound may be used in the treatment of cancer.
  • the administration sequence of the pyridostatin or its derivatives and the trans-platinum compound is preferably administered simultaneously or the sequence of administering the pyridostatin or its derivatives first and then the trans-platinum compound is administered, more preferably the pyridostatin is administered first or its derivatives followed by trans-platinum compounds.
  • R has the structure shown in formula 2a, formula 2b or formula 2c ;
  • the halogen may be one or more of Cl, Br or I, preferably Cl.
  • R 6 and R 7 are different; one has a structure shown in formula 4c, and the other has a structure shown in formula 5c:
  • X and Y are each independently halogen, each independently preferably Cl;
  • R 2 , R 3 , R 4 and R 5 are each independently selected from substituted or unsubstituted H or C1-C4 alkyl;
  • n, 1, m 1 and m 2 are each independently 1, 2, 3, 4 or 5.
  • the dosage ratio of acetone and pyridine can be selected in a wide range, preferably, the ratio of acetone and pyridine is 1:0.1-10 by volume.
  • the number of C atoms in the carbon chain portion of the azide aliphatic halohydrocarbon or haloalkyne is 1, 2, 3, 4 or 5.
  • the corresponding azido aliphatic halogenated hydrocarbon is azidochloromethane.
  • Am 1 and Am 2 are each independently a monodentate ligand, each independently preferably ammonia, thiazole, piperidine, piperazine, 4-picoline, 2-methylbutylamine, sec-butylamine, 1- Amantadine, piperidine-piperidine, diethylamine, or 1-methyl-7-azaindole;
  • step (3) the reaction of the compound shown in formula 12 with the compound shown in formula 13 can be carried out by conventional methods in the art.
  • the method for reacting the compound shown in formula 12 with the compound shown in formula 13 includes : reacting the compound shown in formula 12 with the compound shown in formula 13 in the presence of a catalyst.
  • the freeze dryer model LGJ-12 was purchased from Beijing Songyuan Huaxing Technology Development Co., Ltd.;
  • NanoLC-MS/MS mass spectrometer equipped with Orbitrap Fusion Lumos mass spectrometer and EASY-nLC 1200 nanoUPLC system were purchased from Thermo Fisher Scientific (China) Co., Ltd.
  • Figure 1 shows the proteins whose up- and down-regulation times are greater than 1.5 in the proteomic results. It can be seen that the PC4 protein expressed by the SUB1 gene was down-regulated by 4.76 times in the PDS group, indicating that the treatment of PDS severely inhibited the expression of PC4 protein.
  • HeLa cells were cultured in DMEM medium (containing 10% FBA, 1% penicillin and streptomycin), and the culture environment was 5% CO, 37°C. Cells were seeded into 96-well plates and cultured to a density of 80-90%. The cells were divided into three groups, and the culture medium was replaced with medium without PDS, 2 ⁇ M PDS and 10 ⁇ M PDS respectively. After culturing at 37°C for 24 hours, the cells were washed twice with PBS and added to each well. 200 ⁇ L of medium containing 0, 2, 8, 30, 50, 70, 100, 180, and 200 ⁇ M tran-PtTz.
  • This example is used to illustrate single-cell Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) imaging with or without PDS treatment in the present invention and the statistical method for the results.
  • TOF-SIMS Time-of-Flight Secondary Ion Mass Spectrometry

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le domaine des cancers. La divulgation concerne une application d'une combinaison ou d'un complexe de pyridostatine (PDS) ou d'un dérivé de celle-ci et d'un composé transplatine dans la préparation d'un médicament pour le traitement d'un cancer. Le prétraitement de PDS sur des cellules augmente l'accumulation de trans-[PtCl2(NH3)(thiazole)] (trans-PtTz) dans des cellules et améliore grandement la cytotoxicité du trans-PtTz. AU regard de l'activité biologique de la PDS, la PDS peut être utilisée en combinaison avec le composé transplatine pour atteindre l'objectif d'amélioration de la cytotoxicité du composé transplatine, ou un dérivé de PDS peut être lié au composé transplatine pour synthétiser un complexe, en vue d'obtenir un rendement élevé, une faible toxicité et des effets antitumoraux multi-cibles au moyen d'une thérapie photodynamique (PDT) et d'une chimiothérapie photoactivée (PACT). La présente invention présente une valeur d'application unique et importante dans la recherche et le développement d'un médicament antitumoral.
PCT/CN2022/097856 2021-06-11 2022-06-09 Application d'une combinaison ou d'un complexe de pyridostatine ou d'un dérivé de celle-ci et d'un composé transplatine dans la préparation d'un médicament pour le traitement du cancer WO2022258012A1 (fr)

Applications Claiming Priority (2)

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CN202110653608.4 2021-06-11
CN202110653608.4A CN115463131A (zh) 2021-06-11 2021-06-11 吡啶抑素或其衍生物和反式铂类化合物的组合或配合物在制备治疗癌症的药物中的应用

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104045629A (zh) * 2014-06-25 2014-09-17 中国科学院化学研究所 Pyridostatin类化合物及其制备方法与应用

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* Cited by examiner, † Cited by third party
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CA2862005A1 (fr) * 2012-01-20 2013-07-25 The Uab Research Foundation Dosage de telomeres extracellulaires
US10196372B2 (en) * 2015-01-05 2019-02-05 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services MYC G-quadruplex stabilizing small molecules and their use
EP3915549A1 (fr) * 2020-05-26 2021-12-01 Merck Patent GmbH Inducteurs de sénescence destinés à être utilisés dans le traitement et/ou la prévention de maladies induites par un virus

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104045629A (zh) * 2014-06-25 2014-09-17 中国科学院化学研究所 Pyridostatin类化合物及其制备方法与应用

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CONESA CHRISTINE, JOËL ACKER: "Landes Bioscience PoiNt-of-View PoiNt of View", RNA BIOLOGY, vol. 7, no. 3, 1 May 2010 (2010-05-01), pages 287 - 290, XP093014602, ISSN: 1547-6286 *
DU ZHIFENG, LUO QUN, YANG LIPING, BING TAO, LI XIANCHAN, GUO WEI, WU KUI, ZHAO YAO, XIONG SHAOXIANG, SHANGGUAN DIHUA, WANG FUYI: "Mass Spectrometric Proteomics Reveals that Nuclear Protein Positive Cofactor PC4 Selectively Binds to Cross-Linked DNA by a trans -Platinum Anticancer Complex", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 136, no. 8, 26 February 2014 (2014-02-26), pages 2948 - 2951, XP093014590, ISSN: 0002-7863, DOI: 10.1021/ja410678y *
HOU YINZHU, GAN TIELIANG, FANG TIANTIAN, ZHAO YAO, LUO QUN, LIU XINGKAI, QI LUYU, ZHANG YANYAN, JIA FEIFEI, HAN JUANJUAN, LI SHUMU: "G-quadruplex inducer/stabilizer pyridostatin targets SUB1 to promote cytotoxicity of a transplatinum complex", NUCLEIC ACIDS RESEARCH, vol. 50, no. 6, 8 April 2022 (2022-04-08), GB , pages 3070 - 3082, XP093014572, ISSN: 0305-1048, DOI: 10.1093/nar/gkac151 *
LEJAULT PAULINE, MORUNO-MANCHON JOSE F., VEMU SREE M., HONARPISHEH PEDRAM, ZHU LIANG, KIM NAYUN, URAYAMA AKIHIKO, MONCHAUD DAVID, : "Regulation of autophagy by DNA G-quadruplexes", AUTOPHAGY, vol. 16, no. 12, 1 December 2020 (2020-12-01), US , pages 2252 - 2259, XP093014583, ISSN: 1554-8627, DOI: 10.1080/15548627.2020.1769991 *
SHI, C. ; ZHU, Y. ; ZHAU, H.E. ; SU, Y. ; CHUNG, L.W.K. ; CHENG, T.: "PC4, a novel marker for stem cell transformation and cancer progression", JOURNAL OF BIOTECHNOLOGY, vol. 136, 1 October 2008 (2008-10-01), Amsterdam NL , pages S189, XP026830342, ISSN: 0168-1656 *

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