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US20100202975A1 - Novel fluorescent derivatives of polyamines, method for preparing same and applications thereof as diagnosis tools in the treatment of cancerous tumors - Google Patents

Novel fluorescent derivatives of polyamines, method for preparing same and applications thereof as diagnosis tools in the treatment of cancerous tumors Download PDF

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Publication number
US20100202975A1
US20100202975A1 US12/670,611 US67061108A US2010202975A1 US 20100202975 A1 US20100202975 A1 US 20100202975A1 US 67061108 A US67061108 A US 67061108A US 2010202975 A1 US2010202975 A1 US 2010202975A1
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compound
methyl
compound according
nitrobenzo
alkyl
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Inventor
Jean-Philippe Annereau
Jean-Marc Barret
Yves Guminski
Thierry Imbert
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Pierre Fabre Medicament SA
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Pierre Fabre Medicament SA
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Publication of US20100202975A1 publication Critical patent/US20100202975A1/en
Assigned to PIERRE FABRE MEDICAMENT reassignment PIERRE FABRE MEDICAMENT ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ANNEREAU, JEAN-PHILIPPE, BARRET, JEAN-MARC, GUMINSKI, YVES, IMBERT, THIERRY
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • a fluorescent probe is a conjugated molecule, consisting of a fluorophore or fluorochrome group linked covalently to a group having specific interaction properties with an adequate biological environment.
  • This fluorescent probe has the property of absorbing the light energy received at a well-defined wavelength, thereby forming the excitation phase, then of restoring this energy in the form of fluorescent light called the emission phase. Therefore, after excitation, once the energy of the photon has been absorbed, the molecule lies in an electronically excited state and then returns to the state of fundamental energy by emitting a photon. This photon emission, a fluorescence phenomenon, occurs at a wavelength that is slightly greater than the excitation wavelength. A fluorescence spectrum can then be recorded which is specific to the molecule.
  • fluorochromes such as the derivatives of fluorescein or rhodamine. Not all of them are suitable for biological follow-up.
  • the essential characteristics are: the values of the excitation and emission wavelengths for feasibility of the study, an extinction coefficient adapted to the concentration of the probe used for the study, the quantum yield which allows a significant signal to be obtained with no energy loss and which is stable over time i.e. having a fairly long half-life in the excited state.
  • the chosen fluorophore it is desirable for the chosen fluorophore to take part in the least manner possible in chemical reactions within its environment during measurement, otherwise this would lead to loss of its fluorescence properties i.e. signal loss.
  • Derivatives which have a benzoxadiazole backbone also called benzofurazanes, have the required fluorescence properties.
  • the values of the wavelengths used for excitation and emission, and the quality of the phenomenon in intensity and stability, are related to the structure of the compound and of its substituents.
  • Cancer remains one of the major causes of mortality in the Western world.
  • the means to fight cancer i.e. prevention, surgery, radiotherapy, immunotherapy and chemotherapy still do not allow the disease to be eradicated in numerous cases.
  • a cancerous cell requires a large number of essential biological elements, which include polyamines (spermine, spermidine, putrescine).
  • Polyamines are indispensable for any cell in proliferation. Under normal conditions, endogenous synthesis of polyamine is sufficient for the cell, but with cancer cells an exogenous polyamine contribution is most often necessary by means of an active transport. The detection of this active transport allows detection of cancer cells and the follow-up of their progression in terms of growth and dissemination.
  • the transporter of polyamine in human cells has not been identified at molecular level. The only method to demonstrate its presence is therefore to use a probe recognized by this transporter which, by accumulating within the cell, gives information on the activity of the transporter.
  • the polyamine transporter is a protein complex whose structure is not known in detail.
  • This transporter plays an important role in the intracellular importing of natural polyamines i.e. putrescine, spermidine, and spermine.
  • Arginine converts to ornithine, ornithine undergoes decarboxylation to provide putrescine.
  • This putrescine (C4) can be extended by a C3 chain by means of an adenosine methionine, followed by decarboxylation, to provide spermidine. The latter can again be extended by a C3 chain also by means of another methionine residue, to provide spermine.
  • polyamines can also be broken down by oxidation with polyamineoxidases, and thereby convert back to spermidine and putrescine.
  • the intracellular mechanism is disturbed (e.g. cancerous cell)
  • the intracellular metabolism can no longer meet the cell's needs, and it will therefore procure polyamines from outside the cell.
  • the epipodophyllotoxin structural moiety grafted on the spermine does not appear to modify recognition of the polyamine transporter, enabling the compound to be internalised in the tumor cell, which will subsequently play its part as cytotoxic agent.
  • fluorescent probes having a polyamine moiety will be recognized by the polyamine transporter.
  • a targeted anticancer agent e.g. the compound in example 27 of patent application WO 2005/100363.
  • the present invention therefore relates to compounds consisting of a polyamine moiety bonded to a substituted benzoxadiazole moiety carrying fluorescence, which can be used as said probes.
  • the polyamine part of these molecules will effectively be recognized by the polyamine transport system and the molecule will be internalised inside the cancer cell, whilst the moiety carrying fluorescence will be detected by conventional analysis systems in a biological medium, thereby allowing to select tumors which express the polyamine transport system.
  • this polyamine transport system therefore allows to select tumor-carrying patients who are able to be treated by an anti-cancer compound vectored by the polyamine transport system, irrespective of its mechanism of action.
  • the present invention concerns novel fluorescent derivatives consisting of a polyamine moiety on which a fluorescence-carrying moiety is bonded, i.e. substituted benzoxadiazole, their method of preparation and their use in detection of the polyamine transport system inside cells. It also concerns their use in selecting tumors expressing the polyamine transport system and their use in selecting patients carrying said tumors.
  • R 1 represents one or two NO 2 groups at position 4 and/or 6, or a SO 2 Ph, SO 2 NMe 2 , SO 2 NH 2 , SO 3 H group;
  • the polyamine chain can be at position 5, 6 or 7;
  • R 2 is a hydrogen, a C 1-6 alkyl, a benzyl, a perfluoroalkyl group
  • the values of a, b, c can be 2 to 5, independently of each other, and represent alkylene chains separating the amino groups;
  • the values d and e can be 0 or 1 independently, but cannot represent value 0 at the same time;
  • R2 cannot be a hydrogen
  • the compounds of the present invention can be in the form of mineral or organic addition salts.
  • pharmaceutically acceptable which can be used to prepare a pharmaceutical composition which is generally safe, non-toxic and not biologically or otherwise undesirable, and which is acceptable for veterinary use and for human pharmaceutical use.
  • salts which are pharmaceutically acceptable such as defined herein and which have the desired pharmacological activity of the parent compound.
  • addition salt in the meaning of the present invention, is particularly meant an addition salt of a mineral or organic acid.
  • acid addition salts formed with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and similar; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethane-sulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphtoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphtalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid and similar.
  • mineral acids such as hydrochloric acid
  • 4-NO 2 under the present invention is meant a NO 2 (nitro) group at position 4.
  • alkyl under the present invention is meant a saturated, straight or branched hydrocarbon chain, comprising 1 to 6 carbon atoms.
  • it may be a methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl or hexyl group.
  • perfluoroalkyl under the present invention is meant an alkyl group such as defined above in which all the hydrogen atoms have been replaced by fluorine atoms.
  • R 1 represents one or two NO 2 groups at position 4 and/or 6, and more particularly a NO 2 group at position 4.
  • the present invention concerns the compounds in which:
  • R 1 4-NO 2
  • R 2 Methyl
  • R 1 4-NO 2
  • R 2 Methyl
  • the invention also concerns a method to synthesize the compounds of formula 1, characterized in that it comprises the following steps a), b) and c):
  • R 1 represents one or two NO 2 groups at position 4 and/or 6, or a SO 2 Ph, SO 2 NMe 2 , SO 2 NH 2 or SO 3 H group; and advantageously a NO 2 group at position 4;
  • R 3 is a halogen substituent, mobile at ortho or para position of group R 1 ,
  • the polyamine reacts with the benzoxadiazole by substitution of the halogen via treatment with a base in an inert solvent.
  • the compound of formula 2 is 4-nitro-7-chlorobenzoxadiazole.
  • the inert solvent is acetonitrile and the base is Caesium carbonate.
  • the compound derived from the coupling reaction a) is alkylated by an alkyl halide in the presence of a base in an inert solvent.
  • a base in an inert solvent.
  • THF tetrahydrofurane
  • sodium hydride or an alkaline carbonate is used as base.
  • THF is used as solvent.
  • step b) The compound derived from step b) is then deprotected in acid medium at ambient temperature to obtain the compounds of formula 1.
  • this deprotection step is performed in hydrochloric acid or in trifluoroacetic acid.
  • R 1 represents one or two NO 2 groups at position 4 and/or 6, or a SO 2 Ph, SO 2 NMe 2 , SO 2 NH 2 or SO 3 H group;
  • the polyamine chain can be at position 5, 6 or 7;
  • R 2 is a hydrogen, a C 1-6 alkyl, a benzyl, a perfluoroalkyl group
  • the values of a, b, c can be 2 to 5, independently of each other, and represent alkylene chains separating the amino groups;
  • the values of d and e can be 0 or 1 independently, but cannot represent value 0 at the same time;
  • the compounds of the present invention can be in the form of mineral or organic addition salts.
  • R 1 represents one or two NO 2 groups at position 4 and/or 6, and more particularly a NO 2 group at position 4.
  • the compounds of formula 1 which can be used as fluorescent diagnostic probe concern the compounds in which:
  • R 1 4-NO 2
  • R 2 Methyl
  • R 1 4-NO 2
  • R 2 Methyl
  • Stage 3 R 2 alkylation.
  • tertiobutylic ester of (3- ⁇ t-butoxycarbonyl-[4-(t-butoxycarbonyl- ⁇ 3-methyl-(7-nitrobenzo[1,2,5]oxadiazol-4-yl)-amino]-propyl ⁇ -amino)-butyl]-amino ⁇ -propyl)-carbamic acid of formula 5.
  • the compound obtained at the preceding stage (4.4 g) is dissolved in 150 mL acetonitrile, in the presence of 4 g Caesium carbonate and 2.05 mL methyl iodide.
  • the reaction medium is stirred at ordinary temperature for four hours.
  • TLC: Heptane-AcOEt (30-70) Rf 0.4.
  • Stage 1 In 5 mL acetonitrile, reflux for 30 minutes, a mixture consisting of 200 mg of 4-chloro-7-nitrobenzo[1,2,5]oxadiazole and of 190 mg of tertiobutyl ester of (4-aminobutyl)-carbamic acid, and of 320 mg of Caesium carbonate. After cooling, the medium is poured onto water and extracted with ethyl acetate. It is decanted and the organic phase is dried over sodium sulphate. Filter and evaporate in vacuo.
  • Stage 1 250 mg of triBOC spermine obtained at stage 1 in example 1 are left to react with 100 mg of dimethylamide of 4-fluorobenzo[1,2,5]oxadiazole-4-sulfonic acid in the presence of 0.17 mL of triethylamine in 10 mL of acetonitrile under stirring at ordinary temperature for 30 minutes.
  • Stage 2 250 mg of the protected compound previously obtained are stirred at room temperature for 30 minutes in 2 mL of trifluoroacetic acid and 10 mL of CH 2 Cl 2 . After evaporation, crystallization is performed with a quantitative yield of 260 mg of trifluoroacetate of N-(3-aminopropyl)-N′-[3-(7-methylbenzo[1,2,5]oxadiazol-4-ylamino)-propyl]-butane-1-4-diamine in isopropyl ether, with traces of acetone.
  • Cells taken from biopsies are mechanically separated with or without the presence of trypsin depending on the constitution of the tissue under consideration.
  • the haematopoietic cells are separated and isolated following conventional preparation methods for blood cells. Once isolated after a fairly short time to ensure the viability of the cells being examined, the cells are placed in the presence of the probe such as synthesized in examples 1 to 3 for example, and left to incubate in the recommended culture medium for the tissue under consideration in the presence of aminoguanidine.
  • Aminoguanidine is used to prevent in vitro denaturating of the polyamines. No serum is used (too rich in polyamine and hence a source of measurement error).
  • An incubation time of one to four hours is sufficient and allows detection of fluorescence by immunochemistry or flow cytometry, by choosing excitation and emission wavelengths compatible with the substituent of the fluorescent probe.
  • This analysis is conducted by flow cytometry or histochemistry following standard methodology in the study described below, by exciting the probe obtained in example 1, N-(3-aminopropyl)-N′- ⁇ 3-[methyl-(7-nitrobenzo[1,2,5]oxadiazol-4-yl)-amino]-propyl ⁇ -butane-1,4-diamine with a 488 nm source and measuring fluorescence emission at 525 nm.
  • A549 cells derived from a human lung cancer tumor were assayed by comparison with MRC-5 cells derived from a healthy lung and commercially available from cell line banks.
  • FIG. 1 gives the images obtained with a standard fluorescence microscope of slide cultured cells. It shows much greater incorporation of the probe of example 1 in the tumoral cells ( FIG. 1A ) than in the cells from healthy tissue ( FIG. 1B ). This differential was also confirmed by flow cytometry.
  • cytotoxicity was measured using a standard method (here measurement of residual ATP using the ATPlite kit from Perkin-Elmer).
  • An anticancer compound is used, a derivative of epipodophyllotoxin, whose intracellular penetration is dependent on the polyamine transporter, such as the compound described in example 27 of patent application WO 2005/100363 and, as reference compound, etoposide which is a non-vectored epipodophyllotoxin.
  • a panel of leukemic lines was assayed to ascertain probe incorporation, here the one described in example 1, regarding the sensitivity to a vectored agent such as the compound in example 27 of patent application WO 2005/100363 and by comparison with non-vectored etoposide.
  • cytotoxicity was evaluated using the ATPlite kit.
  • Cells from the same line were also incubated in the presence of the probe described in example 1, and were analyzed by flow cytometry. Fluorescence intensity measured at 525 nm was followed from 0 to 1 hour 30 minutes and the slope of intensity variation was calculated.
  • the capacity to incorporate the fluorescent probe characterized by the fluorescence measured by flow cytometry, was also measured.
  • the differential obtained by flow cytometry is comparable with that seen at histochemistry. It is possible to conduct a simpler assay by only measuring fluorescence at a given time. This was verified by performing this fluorescence measurement after an incubation time of only 1 hour and 30 minutes. This may be of advantage in a hospital environment to provide a rapid result for the selection of responding cells.
  • said measurements may be applied to patient blood blasts taken by blood sampling or lumbar puncture during routine analysis.
  • Measurement of fluorescence intensity can be made using routine flow cytometry or histocytochemistry in all hospitals equipped with a cytology and/or anatomopathology unit.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
US12/670,611 2007-07-26 2008-07-28 Novel fluorescent derivatives of polyamines, method for preparing same and applications thereof as diagnosis tools in the treatment of cancerous tumors Abandoned US20100202975A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0756743 2007-07-26
FR0756743A FR2919287B1 (fr) 2007-07-26 2007-07-26 Nouveaux derives fluorescents de polyamines, leur procede de preparation et leurs applications en tant qu'outils de diagnostic dans le traitement des tumeurs cancereuses.
PCT/EP2008/059890 WO2009013360A1 (fr) 2007-07-26 2008-07-28 Nouveaux dérivés fluorescents de polyamines, leur procédé de préparation et leurs applications en tant qu'outils de diagnostic dans le traitement des tumeurs cancéreuses.

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US (2) US20100202975A1 (fr)
EP (1) EP2183230B9 (fr)
JP (2) JP5698533B2 (fr)
CN (1) CN101809007B (fr)
AR (1) AR067687A1 (fr)
AU (1) AU2008278978B2 (fr)
BR (1) BRPI0813550B8 (fr)
CA (1) CA2694474C (fr)
FR (1) FR2919287B1 (fr)
MX (1) MX2010001030A (fr)
MY (1) MY149523A (fr)
TW (1) TWI444199B (fr)
WO (1) WO2009013360A1 (fr)
ZA (1) ZA201001347B (fr)

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FR2967675B1 (fr) * 2010-11-24 2015-02-27 Pf Medicament Derives fluorescents de cyanines polyamines en tant que sonde de diagnostic
FR2967671A1 (fr) 2010-11-24 2012-05-25 Pf Medicament Complexe de technetium 99m en tant qu'outil de diagnostic in vivo des tumeurs cancereuses
KR101503626B1 (ko) * 2010-12-15 2015-03-24 엔이씨 유럽 리미티드 전력선 접속부를 통해 전력 공급 디바이스에 의해 적어도 하나의 전동식 디바이스를 식별하는 방법 및 시스템
CN108299485B (zh) * 2018-02-09 2020-05-12 湖北大学 一种用于检测活细胞内过氧化氢的荧光探针及其制备方法和应用
CN113929639B (zh) * 2020-06-29 2023-03-21 东南大学 一类以gstp1为靶点的抗肿瘤化合物及其制备方法与应用

Citations (2)

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Publication number Priority date Publication date Assignee Title
US5468854A (en) * 1991-08-01 1995-11-21 Pharmaceutical Discovery Corporation Characterization of specific drug receptors with fluorescent ligands
US6172261B1 (en) * 1997-07-15 2001-01-09 Oridigm Corporation Polyamine analogues as therapeutic and diagnostic agents

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JPH10218871A (ja) * 1997-02-10 1998-08-18 Tokyo Kasei Kogyo Kk 新規蛍光ラベル化剤４−〔（ω−アミノアルキル）ア ミノ〕−７−Ｎ，Ｎ−ジメチルアミノスルホニル−２， １，３−ベンゾオキサジアゾール
JP2001081082A (ja) * 1999-09-13 2001-03-27 Tokyo Kasei Kogyo Kk 新規蛍光標識試薬４−アシルアミノ−７−メルカプト−２，１，３−ベンゾオキサジアゾール
JP2004061476A (ja) * 2002-07-29 2004-02-26 Tokyo Kasei Kogyo Kk 新規蛍光キレート試薬と金属イオンの測定法
GB0307855D0 (en) * 2003-04-04 2003-05-14 Novartis Ag Organic compounds
ITRM20030194A1 (it) * 2003-04-24 2004-10-25 Univ Roma Uso di derivati del 7-nitro-2, 1, 3-benzossadiazolo per
FR2869035B1 (fr) * 2004-04-16 2006-07-14 Pierre Fabre Medicament Sa Derives (poly)aminoalkylaminoacetamide d'epipodophyllotoxine leur procede de preparation et leurs applications en therapeutique comme agent anticancereux

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5468854A (en) * 1991-08-01 1995-11-21 Pharmaceutical Discovery Corporation Characterization of specific drug receptors with fluorescent ligands
US6172261B1 (en) * 1997-07-15 2001-01-09 Oridigm Corporation Polyamine analogues as therapeutic and diagnostic agents

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AU2008278978A1 (en) 2009-01-29
FR2919287B1 (fr) 2012-10-12
FR2919287A1 (fr) 2009-01-30
US20120252059A1 (en) 2012-10-04
EP2183230A1 (fr) 2010-05-12
US8569011B2 (en) 2013-10-29
CN101809007A (zh) 2010-08-18
EP2183230B1 (fr) 2013-11-13
HK1147479A1 (en) 2011-08-12
TWI444199B (zh) 2014-07-11
BRPI0813550B1 (pt) 2019-10-15
AR067687A1 (es) 2009-10-21
WO2009013360A9 (fr) 2010-02-18
MX2010001030A (es) 2010-03-01
MY149523A (en) 2013-09-13
BRPI0813550A2 (pt) 2014-12-23
JP5698533B2 (ja) 2015-04-08
CN101809007B (zh) 2012-07-04
AU2008278978B2 (en) 2012-12-20
JP2010534638A (ja) 2010-11-11
TW200914053A (en) 2009-04-01
BRPI0813550B8 (pt) 2021-05-25
EP2183230B9 (fr) 2015-09-02
JP2015038114A (ja) 2015-02-26
ZA201001347B (en) 2010-11-24
CA2694474A1 (fr) 2009-01-29
JP5889987B2 (ja) 2016-03-22
CA2694474C (fr) 2016-06-14
WO2009013360A1 (fr) 2009-01-29

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