WO2024023197A1 - Analogue de cisplatine ayant un puissant effet anti-cancereux et de ciblage de cellules souches cancéreuses et synthèse de celui-ci - Google Patents

Analogue de cisplatine ayant un puissant effet anti-cancereux et de ciblage de cellules souches cancéreuses et synthèse de celui-ci Download PDF

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Publication number
WO2024023197A1
WO2024023197A1 PCT/EP2023/070805 EP2023070805W WO2024023197A1 WO 2024023197 A1 WO2024023197 A1 WO 2024023197A1 EP 2023070805 W EP2023070805 W EP 2023070805W WO 2024023197 A1 WO2024023197 A1 WO 2024023197A1
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Prior art keywords
compound
cancer
cisplatin
eugenoplatin
present
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PCT/EP2023/070805
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English (en)
Inventor
Abdelilah Aboussekhra
Ibrahim Al-Jammaz
Basem Al-Otaibi
Noura N. Alraouji
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King Faisal Specialist Hospital & Research Centre
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Publication date
Priority claimed from US17/877,339 external-priority patent/US20240033360A1/en
Priority claimed from EP22187899.4A external-priority patent/EP4311830A1/fr
Application filed by King Faisal Specialist Hospital & Research Centre filed Critical King Faisal Specialist Hospital & Research Centre
Publication of WO2024023197A1 publication Critical patent/WO2024023197A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a compound comprising a cisplatin component and a eugenol component.
  • the present invention further relates to a synthesis method of said compound, pharmaceutical compositions comprising the compound and its medical uses.
  • the present invention further relates to a method of treatment of cancer.
  • Cisplatin cis-diamminedichloroplatinum II
  • Cisplatin is a well-known metal-based DNA damaging chemotherapeutic drug, which has been used for the treatment of different types of cancer. Indeed, cisplatin is effective against various types of tumors, including carcinomas, lymphomas, and sarcomas (Tchounwou et al., 2021). Unfortunately, even low and non-toxic concentrations of cisplatin in the serum could be toxic in the kidneys. Indeed, 30-40% of cisplatin-treated patients develop acute kidney injury (Volarevic et al., 2019). To overcome these clinical limitations, different cisplatin analogues were synthesized and are currently used for the treatment of various types of tumors. These include carboplatin and oxaliplatin, which showed efficiency and less toxicity (Desoize et al., 2002; Ali et al., 2013).
  • this object is solved by a compound comprising a cisdiamminedichloroplatinum II component (cisplatin component) and a 2-methoxy-4-(prop-2- en-l-yl)phenol component (eugenol component) which are covalently connected via a linker.
  • this object is solved by providing the compound of the present invention or the compound obtained by the present invention or the pharmaceutical composition of the present invention for use in medicine.
  • this object is solved by providing the compound of the present invention or the compound obtained by the present invention or the pharmaceutical composition of the present invention for use in a method of treatment of cancer.
  • this object is solved by a method of treatment of cancer, comprising administering to a subject in need thereof a therapeutically amount of a compound of the present invention or a compound obtained by the method of the present invention or the pharmaceutical composition of the present invention.
  • this object is solved by the use of the compound in accordance with the present invention for the manufacture of a medicament for the treatment of cancer.
  • the present invention provides compounds a cis-diamminedichloroplatinum II component (cisplatin component) and a 2-methoxy-4-(prop-2-en-l-yl)phenol component (eugenol component).
  • the compound of the present invention comprises a cisplatin component and an eugenol component, which are covalently connected via a linker.
  • Cisplatin is a chemotherapy medication used to treat a number of cancers.
  • Other names are cisplatinum, platamin, neoplatin, cismaplat, cA-diamminedichloroplatinum II (CDDP).
  • the IUPAC name is: CS7 J -4-2)-diamminedichloridoplatinum(II).
  • the sum formula is [Pt(NH3)2C12] or PtCl 2 (NH3) 2 .
  • Cisplatin has the formula:
  • cisplatin component refers to cisplatin and to cisplatin analogues with the sum formula PtCl(NH3)2.
  • Eugenol is an allyl chain-substituted guaiacol, a member of the allylbenzene class of chemical compounds. It is a colorless to pale yellow, aromatic oily liquid extracted from certain essential oils especially from clove, nutmeg, cinnamon, basil and bay leaf. It is present in concentrations of 80-90% in clove bud oil and at 82-88% in clove leaf oil.
  • the preferred IUPAC name is 2-methoxy-4-(prop-2-en-l-yl)phenol. The sum formula is C10H12O2.
  • Eugenol has the formula:
  • a “eugenol component” as used herein refers to eugenol and to eugenol analogues with the sum formula C10H11O2.
  • the compound of the present invention preferably has the general formula I
  • Cis is the cisplatin component
  • L is a linker
  • Eug is the eugenol component.
  • a “linker” as used herein is preferably a covalent bond between the cisplatin component and the eugenol component.
  • the compound of the present invention can be obtained by reacting eugenol with cisplatin, preferably in presence of a base.
  • the compound of the present invention can be called eugenoplatin (EP).
  • EP eugenoplatin
  • the compound of the present invention is an anti-cancer compound.
  • the compound of the present invention has preferably the sum formula PtCl(NH3)2CioHn02.
  • the compound of the present invention also comprises the pharmaceutically active salts.
  • the compound of the present invention has preferably the formula wherein
  • R2 is -OCH3 or -OCH2-CH3, or a pharmaceutically active salt thereof.
  • the compound of the present invention has the formula or a pharmaceutically active salt thereof.
  • the present invention provides a method of synthesizing the compound of the present invention.
  • Said method comprises the following steps
  • step (1) eugenol and a base are added to water.
  • the base is preferably NaOH or KOH.
  • eugenol and the base have a similar molarity / are added in a ratio of about 1 : 1 by molarity.
  • the mixture of eugenol and the base is preferably stirred, such as for about 1 to 4 hours, such as about 2 hours, at a temperature from about 15 to about 25°C, such as at room temperature.
  • step (2) cisplatin is added to the mixture of (1).
  • cisplatin and eugenol and the base have a similar molarity / are added in a ratio of about 1 : 1 : 1 by molarity.
  • the mixture of eugenol and the base and cisplatin is preferably stirred, such as for about 18 to 30 hours, such as about 24 hours, at a temperature from about 15 to about 25°C, such as at room temperature.
  • step (3) the compound is obtained.
  • the compound obtained in step (3) is preferably a solid.
  • the solid is preferably washed and dried.
  • a solid is formed and in addition to that a (yellow) solution.
  • the (yellow) solution is removed by centrifugation and the sticky solid is washed three times with methanol, and is isolated by centrifugation, and then dried under vacuum.
  • the obtained compound is characterized by HPLC analysis and/or mass spectroscopy.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising
  • the present invention provides the compound of the present invention or the compound obtained by the method of the present invention or the pharmaceutical composition of the present invention for use in medicine.
  • the compounds of the present invention show potent anti-cancer activities against various types of cancer cells. Therefore, the compounds have great therapeutic value for the treatment of different types of tumors.
  • the present invention provides the compound of the present invention or the compound obtained by the method of the present invention or the pharmaceutical composition of the present invention for use in a method of treatment of cancer.
  • the cancer is breast cancer, ovarian cancer, osteosarcoma, colorectal cancer, glioblastoma, leukemia, lymphoma, lung cancer or thyroid cancer.
  • the compound of the present invention or the compound obtained by the method of the present invention or the pharmaceutical composition of the present invention is used in combination with at least one further anti cancer treatment, such as chemotherapy and/or immunotherapy.
  • the chemotherapeutic agent can be docetaxel, paclitaxel or doxorubicin.
  • different immunotherapeutic molecules can be used.
  • said method of treatment of cancer comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or a compound obtained by the method of the present invention or the pharmaceutical composition of the present invention.
  • the step of administering in said method of treatment is via infusion.
  • the present invention also relates to the use of the compound in accordance with the present invention for the manufacture of a medicament for the treatment of cancer.
  • Treatment method As outlined above, the present invention provides a method of treatment of cancer.
  • Said method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or a compound obtained by the method of the present invention or the pharmaceutical composition of the present invention.
  • a “therapeutic amount” or a “therapeutically effective amount” of a compound of the present invention refers to the amount which has to be administered to a subject in need thereof in order to achieve a desired therapeutic result or outcome. The skilled artisan will be able to determine said therapeutically effective amount and the suitable administration regimen.
  • the cancer is breast cancer, ovarian cancer, osteosarcoma, colorectal cancer, glioblastoma, leukemia, lymphoma, lung cancer or thyroid cancer.
  • the administration is via infusion.
  • the method of the present invention is carried out in combination with at least one further anticancer treatment, such as chemotherapy and/or immunotherapy.
  • the invention relates to the synthesis of a cisplatin analogue called eugenoplatin consisting of an association between cisplatin (PtCh(NH3)2) and eugenol (C10H12O2).
  • PtCh(NH3)2CioHn02 shows potent anti-cancer activities against various types of cancer cells.
  • eugenoplatin is highly toxic against cancer cells from different types: breast cancer, ovarian cancer, osteosarcoma, colorectal cancer, glioblastoma, and leukemia with different IC50 (Table 1).
  • Table 1 shows also that the cytotoxic effect of eugenoplatin is higher than that of cisplatin against breast cancer, osteosarcoma and glioblastoma cells.
  • Eugenoplatin showed also higher toxicity against colorectal cancer, ovarian cancer and leukemia cells than oxaloplatin, carboplatin and cytarabine (Ara-C), respectively ( Figure 3 and Table 1).
  • eugenoplatin promotes mainly apoptosis in both breast cancer (MDA-MB-231) as well as ovarian cancer (OV-2774) cells (Fig. 5A and 5B). Indeed, at 3 pM and 5 pM of eugenoplatin the proportion of apoptotic cells reached 68% in breast cancer and ovarian cancer cells, respectively (Fig. 5A and 5B). This was confirmed in different cancer cell lines using immunoblotting and antibodies specific for the pro-apoptotic protein PAR.P, caspase-3, caspase-9.
  • Figure 5C shows that eugenoplatin increased the level of cleaved PARP, caspase-3 and caspase- 9 in breast cancer (MDA-MB-231), ovarian cancer (OV-2774), osteosarcoma (MG-64), colon cancer (HCT-116), lung cancer (H-1937), glioblastoma (A1235) and leukemia cells (THP-1).
  • MDA-MB-231 breast cancer
  • ovarian cancer ovarian cancer
  • osteosarcoma MG-64
  • colon cancer HCT-116
  • lung cancer H-1937
  • glioblastoma A1235
  • THP-1 leukemia cells
  • cancer stem cells are the most resistant type of cells, which are responsible for recurrence and metastasis (Garcia- Mayea et al., 2020). Therefore, we decided to investigate the effect of eugenoplatin on the self-renewal ability and sternness capacity of cancer cells. To this end, cancer cells were first either sham-treated (DMSO) or challenged with eugenoplatin (3 pM) for 24 h, and then were incubated in 96 well ultra-low attachment plates in the presence of stem cells culture medium. After 10 days, the formed spheroids with a diameter > 100 pm were counted (Fig. 7A).
  • DMSO sham-treated
  • eugenoplatin 3 pM
  • Figure 7B shows that eugenoplatin treatment reduced by 3-fold and 40-fold the capacity of MDA-MB-231 and MG-64 cells to form tumorespheres, respectively. Furthermore, tumorespheres were first formed, and then they were either sham-treated (DMSO) or challenged with eugenoplatin (3 pM) or cisplatin (50 pM) for 24 h and the cytotoxicity was assessed using WST1.
  • Figure 7C shows that while the proportion of survival CSC was reduced to 70% (MDA-MB-231) and 50% (MG-64) upon treatment with eugenoplatin, it was not affected by cisplatin treatment. This indicates that while cancer stem cells are not sensitive to cisplatin, they showed sensitivity to eugenoplatin.
  • Figure 8 shows that eugenoplatin has higher effects than ciplatin on the expression of several cancer stem cells biomarkers. Indeed, eugenoplatin had a strong effect on CD44 and CD24, the two major breast cancer stem cells markers, while the effect of cisplatin was only marginal (Figure 8). Similar effect was observed on the pro-cancer stem cells pathway STAT3 and on the epithelial maker E-cadherin ( Figure 8). This shows that eugenoplatin can also target cancer stem cells in vivo, while cisplatin is ineffective against these highly resistant type of cells. 6.
  • Eugenoplatin promotes DNA damage in human fibroblast cells
  • cisplatin is a DNA damaging chemotherapeutic drug
  • eugenoplatin can also promote DNA damage in cells.
  • human fibroblast cells HFSN1
  • DMSO sham-treated
  • cisplatin 50 pM
  • eugenoplatin 3 pM
  • the level of the DNA damage sensing protein y-H2AX was assessed by immunofluorescence. While no y-H2AX immunostaining was detected in the control cells, a strong nuclear staining was observed in response to cisplatin, confirming cisplatin-dependent induction of DNA damage (Fig. 9A).
  • the IC50 are indicated by lines in dots.
  • MCF-10A Breast luminal cells
  • PBMCs of healthy donors' blood cells
  • Humanized orthotopic tumor xenografts were created by injecting breast cancer cells (MDA- MB-231) under the nipple of 15 nude mice. After the growth of the tumors, animals were randomized into 3 sub-groups and treated as follows: DMSO, cisplatin (2 pg/Kg), eugenoplatin (0.2 pg/Kg). The graph is showing tumor volume, error bars represent mean ⁇ S.D.
  • Cells (2000) were first either sham-treated (DMSO) or challenged with eugenoplatin (3 pM) for 24 h, and then were incubated in 96 well ultra-low attachment plates in the presence of stem cells culture medium. After 10 days, the formed spheroids with a dimeter > 100 pM were counted.
  • DMSO sham-treated
  • eugenoplatin 3 pM
  • HFSN1 Human fibroblast cells
  • DMSO sham-treated
  • cisplatin 50 pM
  • eugenoplatin 3 pM
  • y-H2AX DNA damage sensing protein
  • PI propidium iodide
  • PI and Alexa Flour 488 annexin V Molecular Probes, Eugene
  • HFSN1 cells were fixed in formaldehyde (4%) for 19 minutes and blocked with Goat serum (5%), triton X (0.3%) and 1% sodium azide (5%) for 1 hour.
  • the slides were then stained overnight at 4 °C with y-H2AX antibody (pSerl39) (Novusibio) that diluted in BSA (1%), triton X (0.3%) and 1 % sodium azide (5%), and subsequently incubated with alexa flour 594- conjugated goat anti -rabbit IgG and DAPI for 1 hour. Images were acquired using fluorescence microscope (Zeiss). 1.4 3D spheroid assay
  • Cells were seeded in 96 well ultra-low attachment plate at a density of 1000 viable cells/well. Cells were cultured in 171 medium supplemented with 1% ABM, 2% B-27, 20 ng/mL EGF, 500 ng/ml HC, 4% FBS and 5 pg/ml insulin. Cells were incubated for 10 days at 37°C under 5% CO2. Mammospheres with a diameter of >100 pm were counted using OPTIKA light microscope.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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Abstract

La présente invention concerne un composé comprenant un composant cisplatine et un composant eugénol. La présente invention concerne en outre un procédé de synthèse dudit composé, des compositions pharmaceutiques comprenant le composé et ses utilisations médicales. La présente invention concerne en outre une méthode de traitement du cancer.
PCT/EP2023/070805 2022-07-29 2023-07-27 Analogue de cisplatine ayant un puissant effet anti-cancereux et de ciblage de cellules souches cancéreuses et synthèse de celui-ci WO2024023197A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP22187899.4 2022-07-29
US17/877,339 US20240033360A1 (en) 2022-07-29 2022-07-29 Cisplatin analogue with potent anti-cancer effects and synthesis thereof
EP22187899.4A EP4311830A1 (fr) 2022-07-29 2022-07-29 Analogue de cisplatine avec effets anti-cancer puissants et sa synthèse
US17/877,339 2022-07-29

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070286905A1 (en) * 2003-10-13 2007-12-13 Salama Zoser B Method for the Preparation of Trans-or Cis-Diammoniumdichlorodihydroxoplatinum(IV) and the Use Thereof in the Production of Pharmaceutical Active Substances

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070286905A1 (en) * 2003-10-13 2007-12-13 Salama Zoser B Method for the Preparation of Trans-or Cis-Diammoniumdichlorodihydroxoplatinum(IV) and the Use Thereof in the Production of Pharmaceutical Active Substances

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
ALI IWANI WASALEEM KHAQUE A.: "Platinum compounds: a hope for future cancer chemotherapy", ANTICANCER AGENTS MED CHEM., vol. 13, no. 2, 2013, pages 296 - 306
DESOIZE BMADOULET C: "Particular aspects of platinum compounds used at present in cancer treatment", CRIT REV ONCOL HEMATOL., vol. 42, no. 3, 2002, pages 317 - 25
GARCIA-MAYEA YMIR CMASSON FPACIUCCI RME LL.: "Insights into new mechanisms and models of cancer stem cell multidrug resistance", SEMIN CANCER BIOL., vol. 60, 2020, pages 166 - 80, XP086076438, DOI: 10.1016/j.semcancer.2019.07.022
ISLAM SSABOUSSEKHRA A.: "Sequential combination of cisplatin with eugenol targets ovarian cancer stem cells through the Notch-Hes1 signalling pathway", J EXP CLIN CANCER RES., vol. 38, no. 1, 2019, pages 382
ISLAM SSAL-SHARIF ISULTAN AAL-MAZROU AREMMAL AABOUSSEKHRA A: "Eugenol potentiates cisplatin anti-cancer activity through inhibition of ALDH-positive breast cancer stem cells and the NF-kappaB signaling pathway", MOL CARCINOG., vol. 57, no. 3, 2018, pages 333 - 46
TCHOUNWOU PBDASARI SNOUBISSI FKRAY PKUMAR S.: "Advances in Our Understanding of the Molecular Mechanisms of Action of Cisplatin in Cancer Therapy", J EXP PHARMACOL., vol. 13, 2021, pages 303 - 28
THANH CHI NGUYEN THI ET AL: "Synthesis and spectral characterization of platinum(II) complexes containing eugenol, a natural allylphenol", JOURNAL OF COORDINATION CHEMISTRY, vol. 70, no. 6, 2 February 2017 (2017-02-02), London, pages 1008 - 1019, XP093015618, ISSN: 0095-8972, DOI: 10.1080/00958972.2017.1281917 *
VOLAREVIC VDJOKOVIC BJANKOVIC MGHARRELL CRFELLABAUM CDJONOV VARSENIJEVIC N.: "Molecular mechanisms of cisplatin-induced nephrotoxicity: a balance on the knife edge between renoprotection and tumor toxicity", J BIOMED SCI., vol. 26, no. 1, 2019, pages 25

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