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DE102005047308A1 - Platinum compounds based on propane-1,3-diamine derivatives for treating carcinomas that are resistant to cis-platin, induce apoptosis but not by activation of caspase - Google Patents

Platinum compounds based on propane-1,3-diamine derivatives for treating carcinomas that are resistant to cis-platin, induce apoptosis but not by activation of caspase Download PDF

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DE102005047308A1
DE102005047308A1 DE200510047308 DE102005047308A DE102005047308A1 DE 102005047308 A1 DE102005047308 A1 DE 102005047308A1 DE 200510047308 DE200510047308 DE 200510047308 DE 102005047308 A DE102005047308 A DE 102005047308A DE 102005047308 A1 DE102005047308 A1 DE 102005047308A1
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resistant
platin
cis
activation
caspase
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DE102005047308A8 (en
Inventor
Reinhard Dr. Paschke
Wieland Dr. Voigt
Thomas Müller
Jutta Dr. Kalbitz
Karsten Prof. Dr. Mäder
Andrea Dietrich
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Martin Luther Universitaet Halle Wittenberg
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Martin Luther Universitaet Halle Wittenberg
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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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • Biochemistry (AREA)
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Abstract

Platinum(II) compounds (A1)-(A3) for treatment of resistant carcinoma. Platinum(II) compounds of formulae (A1)-(A3) for treatment of resistant carcinoma R : tetrahydropyran-2-oxy, cyclohexyloxy or Me; n : 2-16 . An independent claim is included for a method for increasing the solubility of (A1)-(A3) by addition of mixed micelles and/or cylodextrins in polar solvents. [Image] ACTIVITY : Cytostatic. The compound THP ((A2) with n = 11; R not stated) was tested against the cell line 1411HP, resistant to cis-platin (cP) in a 2 hour contact test. At a concentration of 3 mu M viability was reduced to zero while a concentration of 1 mu M reduced viability to about 85%. The concentration of cP required for zero viability was 100 mu M. MECHANISM OF ACTION : Induction of apoptosis by a mechanism that is not based on activation of caspases (contrast cis-platin).

Description

Es ist bekannt, verschiedene Platinverbindungen als Chemotherapeutikum in der Therapie von Tumoren einzusetzen. So wird beim Keimzelltumor durch eine auf Cisplatin basierende Chemotherapie eine hohe Heilungsrate erzielt. Ein Nachteil dieser Therapieoption besteht in der Entwicklung oder dem Vorliegen einer Chemotherapie-Resistenz. Daher ist es erforderlich, neue bzw. entsprechend modifizierte Substanzen zu entwickeln, die die Fähigkeit besitzen, Chemotherapie-Resistenzen zu überwinden.It is known, various platinum compounds as a chemotherapeutic agent to be used in the therapy of tumors. This becomes the germ cell tumor Cisplatin-based chemotherapy provides a high cure rate achieved. A disadvantage of this treatment option is the development or the presence of chemo-resistance. Therefore, it is necessary develop new or appropriately modified substances that the ability possess to overcome chemo-resistance.

Es wurde gefunden, Platin(II)verbindungen, des Typs A1 bis A3

Figure 00010001
hergestellt aus 2-substitutierten Propan-1,3-diaminen B1
Figure 00020001
und n = 2-16
zur Behandlung von Karzinomen einzusetzen.Platinum (II) compounds of the type A1 to A3 were found
Figure 00010001
prepared from 2-substituted propane-1,3-diamines B 1
Figure 00020001
and n = 2-16
used for the treatment of carcinomas.

1 zeigt an einem Zelllinienmodell, bestehend aus einer Cisplatin-sensitiven und einer Cisplatin-resistenten Zelllinie, konnte im SRB-Zytotoxizitäts-Assay, dass die Verbindung A2 mit n = 11 die Cisplatin-Resistenz überwinden kann. 1 shows on a cell line model consisting of a cisplatin-sensitive and a cisplatin-resistant cell line, in the SRB cytotoxicity assay, the compound A2 with n = 11 could overcome the cisplatin resistance.

Chemotherapeutische Substanzen entwickeln ihre zytotoxische Wirkung in dem sie in den Tumorzellen den apoptotischen Zelltod auslösen. Die Cisplatin-Resistenz der resistenten Zelllinie ist durch eine verminderte Induktion der Apoptose begründet, so dass eine hohe Cisplatindosis verwendet werden muss, die jedoch keine in vivo-Relevanz besitzt. Es konnte durch Trypan-Ausschlusstest und der DNA-Fragmentierung gezeigt werden, dass THP ähnlich wie Cisplatin in den Tumorzellen die Apoptose auslöst. Dabei wurde deutlich, dass für eine Induktion der Apoptose in der resistenten Zelllinie eine ähnlich niedrige Dosis an THP ausreichte, wie im Falle der sensitiven Zelllinie (2).Chemotherapeutic substances develop their cytotoxic effect by inducing apoptotic cell death in the tumor cells. The cisplatin resistance of the resistant cell line is due to a reduced induction of apoptosis, so that a high cisplatin dose must be used, which, however, has no in vivo relevance. It could be shown by Trypan exclusion test and DNA fragmentation that THP triggers apoptosis similar to cisplatin in the tumor cells. It became clear that a similar low dose of THP would be sufficient for induction of apoptosis in the resistant cell line, as in the case of the sensitive cell line (FIG. 2 ).

Die insgesamt stärkere zytotoxische Wirkung der Verbindung THP im Vergleich zu Cisplatin ist mit einer deutlich erhöhten Akkumulation der Substanz in der Tumorzelle begründet.The overall stronger cytotoxic effect of the compound THP compared to cisplatin is with a significantly increased Accumulation of the substance in the tumor cell justified.

Dabei zeigt sich eine selektiv vermehrte Aufnahme der Substanz in den Cisplatin-resistenten Tumorzellen, wodurch die Überwindung der Resistenz erklärt werden kann (3).This shows a selectively increased uptake of the substance in the cisplatin-resistant tumor cells, whereby the overcoming of the resistance can be explained ( 3 ).

Für den Prozess der Apoptose ist die Aktivierung der Caspasen notwendig, wobei die Caspase-3 für die Durchführung des apoptotischen Programms eine Schlüsselrolle spielt. Eine Inhibierung der Caspasen-Aktivierung ist mit einer Resistenz gegenüber chemotherapeutischen Substanzen assoziiert. Es konnte durch Western-Blotting gezeigt werden, dass THP im Gegensatz zu Cisplatin eine Caspasen-unabhängige Apoptose induzieren kann (4).For the process of apoptosis, the activation of caspases is necessary, with caspase-3 playing a key role in the implementation of the apoptotic program. Inhibition of caspase activation is associated with resistance to chemotherapeutic agents. It could be shown by Western blotting that THP, in contrast to cisplatin, can induce caspase-independent apoptosis ( 4 ).

Ein Problem bestand in der schlechten Wasserlöslichkeit der Verbindungen A. Es wurde gefunden, dass dieses durch Einschließen dieser Verbindungen in Mischmizellen und Cyclodextrinen gelöst werden kann. Die Herstellung dieser Einschlussverbindungen bzw. Mischmizellen wurde durch gängige Verfahren erreicht. Das Cyclodextrin kann hierbei reines oder derivatisiertes a-, b-, g- oder d-Cyclodextrin sein und die Micellen können aus reinen Gallensäuresalzen (einfaches System), binären (Gallensäuresalz plus Phosphorlipid oder Fettsäure) oder ternären (Gallensäuresalz plus Phosphorlipid plus Fettsäure) Systemen bestehen..One Problem was the poor water solubility of the compounds A. This has been found to be by inclusion of these Compounds in mixed micelles and cyclodextrins can be solved. The preparation of these inclusion compounds or Mischmizellen became commonplace Procedure achieved. The cyclodextrin may be pure or derivatized a-, b-, g- or d-cyclodextrin and the micelles can be made pure bile acid salts (simple system), binary (Bile salt plus phospholipid or fatty acid) or ternary (Bile salt plus phospholipid plus fatty acid) Systems exist ..

Die so behandelten und solubilisierten Verbindungen A zeigten weiterhin eine vergleichbare zytotoxische Wirkung und die Fähigkeit, die Cisplatin-Resistenz zu überwinden (5).The compounds A thus treated and solubilized continued to show a comparable cytotoxic effect and the ability to overcome cisplatin resistance ( 5 ).

Claims (2)

Verbindungen der Struktur A1–A3 mit n = 2-16
Figure 00040001
zur Behandlung von resistenten Karzinomen.Compounds of structure A1-A3 with n = 2-16
Figure 00040001
for the treatment of resistant carcinomas. Verfahren zur Erhöhung der Löslichkeit der Verbindungen nach Anspruch 1, gekennzeichnet dadurch, dass Mischmizellen und/oder Cyclodextrine in polaren Lösungsmitteln zugesetzt werden.Procedure for increasing the solubility the compounds according to claim 1, characterized in that mixed micelles and / or cyclodextrins in polar solvents.
DE200510047308 2005-09-30 2005-09-30 Platinum compounds based on propane-1,3-diamine derivatives for treating carcinomas that are resistant to cis-platin, induce apoptosis but not by activation of caspase Ceased DE102005047308A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0181166A2 (en) * 1984-11-02 1986-05-14 Johnson Matthey Public Limited Company Solubilised platinum compounds
EP0518645A1 (en) * 1991-06-10 1992-12-16 Toray Industries, Inc. Platinum (II) complex and antitumor agent
EP0636631A1 (en) * 1992-04-17 1995-02-01 Seikagaku Corporation Platinum complex and antineoplastic agent

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0181166A2 (en) * 1984-11-02 1986-05-14 Johnson Matthey Public Limited Company Solubilised platinum compounds
EP0518645A1 (en) * 1991-06-10 1992-12-16 Toray Industries, Inc. Platinum (II) complex and antitumor agent
EP0636631A1 (en) * 1992-04-17 1995-02-01 Seikagaku Corporation Platinum complex and antineoplastic agent

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
H. Brunner et al. "Synthesis and Antitumor Activi- ty of Pt(II) Complexes fo Benzyl-1,2-dianinoethane Ligands" Chemische Berichte 1990, 123, 1029-1038
H. Brunner et al. "Synthesis and Antitumor Activi-ty of Pt(II) Complexes fo Benzyl-1,2-dianinoethaneLigands" Chemische Berichte 1990, 123, 1029-1038 *
JP 03093788 A, zitiert als Abstract, Patent Ab- stracts of Japan und als Chemical Abstract, Acc. No. 1991:621939. *
R. Paschke et al. "Cholic acid-carboplatin com- pounds (CarboChAPt) as models for specific drug delivery: sythesis of novel carboplatin analogous derivatives and comparsion of cytotoxic proper- ties with corresponding cisplatin compounds", Journal of Inorganic Biochemistry 2003, 94(4), 335-342. *
R. Paschke et al. "Novel spacer linked bile acid- cisplatin compounds as a model for specific drug delivery, synthesis and characterization", Inor- ganica Chimica Acta 2000, 304(2), 241-249 *

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