WO2018015493A1 - Complexes métalliques ayant des applications thérapeutiques - Google Patents
Complexes métalliques ayant des applications thérapeutiques Download PDFInfo
- Publication number
- WO2018015493A1 WO2018015493A1 PCT/EP2017/068369 EP2017068369W WO2018015493A1 WO 2018015493 A1 WO2018015493 A1 WO 2018015493A1 EP 2017068369 W EP2017068369 W EP 2017068369W WO 2018015493 A1 WO2018015493 A1 WO 2018015493A1
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- WIPO (PCT)
- Prior art keywords
- metal complex
- aryl
- metal
- ligand
- complex
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- 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
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic Table without C-Metal linkages
Definitions
- the present invention relates to metal complexes having histone deacetylase inhibitory activity. Also contemplated are methods of treatment of cancers comprising administering a metal complex of the invention to a patient.
- Pt platinum
- carboplatin carboplatin
- oxaliplatin a Pt drug that has been approved for worldwide clinical use, namely cisplatin, carboplatin and oxaliplatin.
- the cytotoxicity of Pt drugs is attributed to their ability to bind DNA and induce apoptosis.
- the widespread application and efficacy of classical Pt drugs is hindered by toxic side effects, their limited activity against many common human cancers and their susceptibility to intrinsic/acquired drug resistance.
- Pt-drugs such as cisplatin, c s-[Pt"(NH3)2Cl2]
- cisplatin c s-[Pt"(NH3)2Cl2]
- hydrated species such as [Pt"(NH3)2(H20)2] 2+ which bind to DNA nucleobases (of which 60-65% consists of 1 ,2-intrastrand GpG crosslinks between two adjacent guanines), distorting the DNA helix and interfering with DNA processes such as transcription and replication.
- Chromatin a complex structure that plays a key role as an epigenetic regulator of gene expression, is one such target. Its fundamental repeating unit, the nucleosome, consists of core histones around which DNA coils. Some histone residues protrude the nucleosome and are subject to many enzyme-catalysed post-translational modifications including methylation and acetylation. Acetylation is controlled by two enzymes, histone
- HATs acetyltransferases
- HDACs histone deacetylases
- SAHA Suberoylanilide hydroxamic acid
- Metal complexes having dual histone deacetylase inhibitory and DNA binding activity are described in PCT/EP2010/060089. These complexes comprise a compound having a terminal HDAC inhibitory active site, coordinated to DNA-binding heavy metal ions by means of a linker comprising a monodentate, bidentate, or chelating oxygen donor group.
- the linker may be labile whereby when it is coordinated to a DNA binding metal ion the corresponding metal complex is susceptible to activation e.g. by hydrolysis in-vivo, releasing the HDAC inhibitor and leaving the metal ion free to bind DNA.
- the ligands show the tendency to form bi- and trinuclear species with copper(ll) ions due to the ⁇ ( ⁇ , ⁇ '); ( ⁇ , ⁇ ') ⁇ bis-(bidentate) chelating-and-bridging mode involving (0,0')-hydroxamate chelate formation combined with ( ⁇ , ⁇ ') chelating with participation of the pyridine and hydroxamic nitrogen atoms, so that the hydroxamate groups play a ⁇ 2-( ⁇ ,0) ⁇ 3 ⁇ 4 ⁇ role.
- Kasparkova et al (Angewante Chemie Int. Ed. Eng., 2015, 54, 48, 14478-14482) describes a photoactivatable Pt(IV)-HDAC inhibitor conjugate targeting genomic DNA and HDACs.
- the HDACi in question is suberoyl-bis-hydroxamic acid and it is coordinated to the Pt(IV) in a monodentate fashion.
- the present invention exploits the unique chemical environment of tumour cells by generating bioreductively-activated redox active metal-phenanthroline-HDAC inhibitor prodrugs that, upon entry into the reducing environment of a tumour cell, are activated by metal ion reduction, facilitating both oxidative DNA damage with concomitant release of the HDAC inhibitor which is free to inhibit HDACs within the tumour cell.
- a number of exemplary chemotypes including [Cu(DPQ)(SAHA)] + , [Cu(DPPZ)(SAHA)] + ,
- the metal complex has a general formula I
- R-Z is a HDAC inhibitor in which Z a terminal hydroxamate group
- M is a redox active metal
- n+ is the positive charge on the complex cation
- B n is a balancing counterion
- a nitrogen donor ligand selected from a bipyridine ligand or a phenanthroline ligand or phenanthroline-type ligand,
- R-Z is not a dual HDAC/PARP inhibitor.
- the complexes of the invention exhibit improved stability due to the metal binding the HDAC inhibitor with 0,0' bidentate coordination.
- the charged complex of the invention is bio-reductively activated, allowing targeting of the compounds to tumour cells.
- M is a first-row transition element. In one embodiment, M is selected from copper, iron, manganese or cobalt.
- M is copper
- Ri to Rs are each, independently, selected from oxygen, hydrogen, hydroxyl, a carboxyl, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, aryloxy, alkyloxy, arylalkyloxy, amino, alkylamino, hydroxylamino, dialkylamino, or alkoxy group, or pyridine, or are fused to form a monocyclic or polycyclic aromatic hydrocarbon or heterocycle.
- the metal complexes of the invention may include many classes of hydroxamate-type HDAC inhibitors, such as the hydroxamate inhibitors described in Cancer Lett., 2009, 280, 233-241 , and the HDAC inhibitors described in the Journal of Hematology & Oncology, 2009, 2, 22 and Bioorg. Chem., 2016, 67, 18-42.
- hydroxamate-type inhibitors are described in patents US6,087,367, US6,552,065, and US6,888,027, which have a terminal hydroxamate group which is the active site inhibiting group.
- hydroxamate-type HDAC inhibitors are SAHA (Vorinostat), Panobinostat, or Belinostat.
- the HDAC inhibitor R-Z has a general formula III either in its protonated or deprotonated form:
- Rg and R10 are each, independently, a hydrogen, hydroxyl, a substituted or unsubstituted, branched or unbranched alkyl, for example a C1-C6 alkyl, alkenyl, cycloalkyl, for example a C 4 -Cg cycloalkyl, aryl, acyl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxy, alkyloxy, arylalkyloxy, aromatic polycycles, non-aromatic polycycles, mixed aryl and non-aryl polycycles, polyheteroaryl, non-aromatic polyheterocycles, and mixed aryl and non-aryl polyheterocycles, or a pyridine group,
- n is an integer from 5 to 8.
- R10 is a hydrogen atom.
- Rg is a substituted or unsubstituted phenyl group.
- the phenyl group is substituted with a halogen, for example, a chloro, bromo, fluoro, or iodo group, a methyl, cyano, nitro, trifluoromethyl, amino, methylcyano, sulphonate, or aminocarbonyl group.
- Rg is selected from the group consisting of methoxy, cyclohexyl, hydroxyl, benzyloxy, and pyridine.
- HDAC inhibitors of general formula II are described in US 6,087,367, especially the specific structures described in Table 1 spanning Columns 29 to 36 of US 6,087,367. The complete contents of US 6,087,367 are incorporated herein by reference.
- the hydroxamate-type HDAC inhibitor R-Z of general formula lii preferably has the following structure (either in its protonated or deprotonated form):
- the HDAC inhibitor R-Z is a hydroxamate-type HDAC inhibitor having a general formula IV either in its protonated or deprotonated form:
- A is an aryl group
- Qi is a covalent bond or an aryl leader group
- J is a sulfonamide linkage selected from where Rn is a sulfonamide substituent
- Q2 is an acid leader group
- Z is a terminal hydroxamate group, with the proviso that then Qi is an aryl leader group.
- hydroxamate-type HDAC inhibitor R-Z of general formula IV preferably has the following structure either in its protonated or deprotonated form:
- the HDAC inhibitor R-Z is a hydroxamate-type HDAC inhibitor having a general formula V either in its protonated or deprotonated form:
- Ri2 is H, halo, or a straight chain C1-C6 alkyl
- Ri3 and R14 are the same or different and independently selected from H, halo, Ci to C 4 alkyl, such as CH 3 and CF 3 , N0 2 , C(0)Ri 2 , OR12, SR19, CN, NR20R21 ;
- Ri5 is selected from H, Ci to C10 alkyl, C 4 to C9 cycloalkyl, C 4 to Cg heterocycloalkyl,
- heteroarylalkyl -(CH 2 ) n C(0)Ri 3 , -(CH 2 ) n O(0)Ri 3 , amino acyl, and HON-C(O)-
- CH C(Ri)-aryl-alkyl
- R18 is selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aromatic polycycles, non-aromatic polycycles, mixed aryl and non-aryl polycycles, polyheteroaryl, non-aromatic polyheterocycles, and mixed aryl and non-aryl polyheterocycles;
- Rig is selected from C1-C4 alkyl, for example CH 3 and CF 3 , C(0)-alkyl, for example C(0)CH 3 and C(0)CF 3 ;
- R20 and R21 are the same or different and independently selected from H, C1-C4 alkyl, and -C(0)-alkyl;
- ⁇ - ⁇ , n2 and n 3 are the same or different and independently selected from 0-6, when ni is 1 -6, each carbon atom can be optionally and independently substituted with Rg
- HDAC inhibitor R-Z comprises the compounds falling within the scope of Claim 1 of US6,552,056.
- the complete contents of US 6,552,056 are incorporated herein by reference.
- hydroxamate-type HDAC inhibitor R-Z of general formula V preferably has the following structures either in their protonated or deprotonated forms selected from the group:
- the redox active metal is typically a transition metal, and in one embodiment a first row transition element. Examples include copper, iron, manganese and cobalt. In one embodiment, the redox metal is selected from copper and iron. In one embodiment, where the metal is copper, the copper ion is in the +2 oxidation state with the overall complex being neutral. In one embodiment, the redox active metal excludes platinum. When the HDAC inhibitor-copper-phen complex enters a tumour cell, the reducing environment of the tumour cell activates the complex causing a Cu 2+ to Cu + reduction, resulting in the release of the HDAC inhibitor.
- the nitrogen donor ligand is selected from bipyridine or phenanthroline (Phen) or a derivative thereof that is capable of forming a coordination complex with a redox active metal ion, whereby the coordination complex is typically capable of exhibiting chemical nuclease activity.
- the nitrogen donor ligand has a structure of general formula II:
- Ri to Rs are each, independently, selected from oxygen, hydrogen, hydroxyl, a carboxyl, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, aryloxy, alkyloxy, arylalkyloxy, amino, alkylamino, hydroxylamino, dialkylamino, or alkoxy group, or pyridine, or are fused to form a monocyclic or polycyclic aromatic hydrocarbon or heterocycle.
- the nitrogen donor-ligand is selected from bipyridine or 1 ,10- phenanthroline or phenanthroline derivatives selected from:
- counter ions examples include: acid addition salts such as the hydrochlorides, hydrobromides, perchlorates, phosphates, sulphates, hydrogen sulphates, alkylsulphates, arylsulphonates, acetates, benzoates, citrates, gluconates, maleates, fumarates, succinates, lactates, and tartrates; alkali metal cations such as Na, K, and Li; alkali earth metal salts such as Mg or Ca; or organic amine salts.
- the counterion may be one anion, or a plurality of anions, where the composite charge of the plurality of anions balances the charge on the complex cation.
- the Metal Complex formulae provided hereafter do not illustrate a counter ion.
- the invention also relates to a metal complex comprising a redox active metal ion such as Cu 2+ coordinated to a hydroxamic acid group of a HDAC inhibitor and a nitrogen donor ligand, especially a phenanthroline ligand, and typically capable of being reduced in a tumour cell to provide a free HDAC inhibitor and a redox active metal-nitrogen donor ligand complex ion that in one embodiment exhibits DNA binding and/or chemical nuclease activity (hereafter "Metal Complex").
- the HDAC inhibitor may be in a protonated or deprotonated form.
- the complex binds DNA, and exhibits potent chemical nuclease and HDAC inhibition activity.
- the complex is cytotoxic at low microM or nanoM concentrations in the in-vitro cytotoxicity assay described below.
- Exemplary Metal Complexes of the invention have one of the following general formula VI, VII and VIII:
- VIM in which N N , 9 to Ris, n, n ⁇ i , n2, n3, Q2, J, Q1 and A are as defined above.
- the Metal Complex of the invention has a structure selected from:
- the Metal Complex of the invention has a structure selected from: ⁇
- the invention provides a method of treating a proliferative disorder, for example a cancer, in an individual, comprising a step of administering to the individual a therapeutically effective amount of the Metal Complex of the invention.
- the invention in another aspect, relates to a method of treating a cell to inhibit proliferation of the cell comprising a step of treating the cell with a therapeutically effective amount of the Metal Complex of the invention.
- the invention relates to a method of treating a cancer comprising a step of treating an individual with a therapeutically effective amount of the Metal Complex of the invention, wherein the Metal Complex is typically capable of exhibiting DNA binding and HDAC inhibitory activity in-vivo.
- the invention relates to a method of treating a cancer comprising a step of treating an individual with a therapeutically effective amount of the Metal Complex of the invention, wherein the Metal Complex is typically capable of being activated in-vivo to provide an active HDAC inhibitor and an active DNA-binding heavy metal ion.
- the invention provides a pharmaceutical composition comprising a therapeutically effective amount of the Metal Complex of the invention and a
- the invention relates to the use of the Metal Complex of the invention as a medicament.
- the invention relates to the use of the Metal Complex of the invention in the manufacture of a medicament for the treatment of cancer.
- the method is a one-pot method, where the redox active metal perchlorate salt is first added, a non-aqueous suspension of HDAC inhibitor is then added, before a non-aqueous suspension of the nitrogen donor ligand is then added. The mixture is then agitated and a resultant precipitated is separated.
- the invention relates to a one-pot method of synthesising a complex of the invention comprising the steps of:
- nitrogen donor ligand is selected from a bipyridine ligand and a phenanthroline ligand or phenanthroline-type ligand;
- the second mixture comprises substantially equimolar amounts of redox active metal perchlorate salt, HDAC inhibitor, and nitrogen donor ligand.
- the non-aqueous solution of HDAC inhibitor and non-aqueous solution of nitrogen donor ligand are each, independently, warmed prior to addition to the aqueous solution of the redox active perchlorate salt.
- the method comprises a step of adding a strong base to the second reaction mixture prior to or during the agitation step.
- the HDAC inhibitor is selected from SAHA, Panabinostat and
- the nitrogen donor ligand is selected from BIPY, PHEN, DPQ, DPPZ, DPPN and Phendio.
- the redox active metal is selected from a first row transition element.
- the redox active metal is copper.
- the method comprises the steps of:
- a non-aqueous suspension of nitrogen donor ligand to the non-aqueous solution of a redox active metal salt, in which the nitrogen donor ligand is selected from a bipyridine ligand and a phenanthroline ligand or phenanthroline-type ligand; agitating the first mixture to precipitate an intermediate complex;
- the salt is selected from a nitrate, sulphate, or chloride.
- the redox active metal is a first row transition metal. In one embodiment, the redox active metal is copper.
- the redox active metal salt is suspended in ethanol.
- the nitrogen donor ligand is suspended in ethanol.
- the HDAC inhibitor is suspended in methanol.
- the second mixture comprises base, for example potassium hydroxide.
- the method employs substantially equimolar amounts of redox active metal salt, HDAC inhibitor, and nitrogen donor ligand.
- the agitation steps are carried out under reflux.
- Multifunctional Cu 2+ complexes reduce HDAC activity: SKOV-3 Cells were seeded in a 75 cm 2 tissue culture flask then grown to 70-80% confluency. Cells were incubated with Cu(ll) complexes and SAHA corresponding to the IC50 value for 24, 48 or 72 Hrs. Nuclear isolates were isolated according to the protocol recommended by the manufacturer. SKOV-3 nuclear extracts were tested for their HDAC activity according to the protocol reccomended by the manufacturer (Epigentek, USA).
- Lanes 1 - 4 DNA + Complex
- Lanes 5 - 8 + 10mM Kl
- Lanes 9 - 12 + 10mM NaN 3
- Lanes 13 - 16 + 10 mM Tiron
- Lanes 17 - 20 + 10% DMSO.
- “comprising,” are to be read to indicate the inclusion of any recited integer (e.g. a feature, element, characteristic, property, method/process step or limitation) or group of integers (e.g. features, element, characteristics, properties, method/process steps or limitations) but not the exclusion of any other integer or group of integers.
- a recited integer e.g. a feature, element, characteristic, property, method/process step or limitation
- group of integers e.g. features, element, characteristics, properties, method/process steps or limitations
- the term "disease” is used to define any abnormal condition that impairs physiological function and is associated with specific symptoms.
- the term is used broadly to encompass any disorder, illness, abnormality, pathology, sickness, condition or syndrome in which physiological function is impaired irrespective of the nature of the aetiology (or indeed whether the aetiological basis for the disease is established). It therefore encompasses conditions arising from infection, trauma, injury, surgery, radiological ablation, poisoning or nutritional deficiencies.
- treatment refers to an intervention (e.g. the administration of an agent to a subject) which cures, ameliorates or lessens the symptoms of a disease or removes (or lessens the impact of) its cause(s) (for example, the reduction in accumulation of pathological levels of lysosomal enzymes).
- the term is used synonymously with the term “therapy”.
- treatment refers to an intervention (e.g. the administration of an agent to a subject) which prevents or delays the onset or progression of a disease or reduces (or eradicates) its incidence within a treated population.
- treatment is used synonymously with the term “prophylaxis”.
- an effective amount or a therapeutically effective amount of an agent defines an amount that can be administered to a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, but one that is sufficient to provide the desired effect, e.g. the treatment or prophylaxis manifested by a permanent or temporary improvement in the subject's condition.
- the amount will vary from subject to subject, depending on the age and general condition of the individual, mode of administration and other factors. Thus, while it is not possible to specify an exact effective amount, those skilled in the art will be able to determine an appropriate "effective" amount in any individual case using routine experimentation and background general knowledge.
- a therapeutic result in this context includes eradication or lessening of symptoms, reduced pain or discomfort, prolonged survival, improved mobility and other markers of clinical improvement. A therapeutic result need not be a complete cure.
- the term subject defines any subject, particularly a mammalian subject, for whom treatment is indicated.
- Mammalian subjects include, but are not limited to, humans, domestic animals, farm animals, zoo animals, sport animals, pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows; primates such as apes, monkeys, orangutans, and chimpanzees; canids such as dogs and wolves; felids such as cats, lions, and tigers;
- the subject is a human.
- the term "cancer” should be taken to mean a cancer selected from the group consisting of: fibrosarcoma; myxosarcoma; liposarcoma; chondrosarcom; osteogenic sarcoma; chordoma; angiosarcoma; endotheliosarcoma; lymphangiosarcoma;
- lymphangioendotheliosarcoma synovioma; mesothelioma; Ewing's tumor;
- adenocarcinoma sweat gland carcinoma; sebaceous gland carcinoma; papillary carcinoma; papillary adenocarcinomas; cystadenocarcinoma; medullary carcinoma;
- bronchogenic carcinoma renal cell carcinoma; hepatoma; bile duct carcinoma;
- choriocarcinoma seminoma; embryonal carcinoma; Wilms' tumor; cervical cancer; uterine cancer; testicular tumor; lung carcinoma; small cell lung carcinoma; bladder carcinoma; epithelial carcinoma; glioma; astrocytoma; medulloblastoma; craniopharyngioma;
- the cancer is selected from the group comprising: breast; cervical; prostate; ovarian, colorectal, lung, lymphoma, and leukemias, and/or their metastases.
- “Lower alkyl” means an alkyl group, as defined below, but having from one to ten carbons, more preferable from one to six carbon atoms (eg. "C - C - alkyl”) in its backbone structure.
- “Alkyi” refers to a group containing from 1 to 8 carbon atoms and may be straight chained or branched. An alkyi group is an optionally substituted straight, branched or cyclic saturated hydrocarbon group. When substituted, alkyi groups may be substituted with up to four substituent groups, at any available point of attachment. When the alkyi group is said to be substituted with an alkyi group, this is used interchangeably with “branched alkyi group”.
- Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, a- butyl, isobutyl, pentyl, hexyl, isohexyl, 4, 4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like.
- substituents may include but are not limited to one or more of the following groups: halo (such as F, CI, Br, I), Haloalkyl (such as CCI 3 or CF3), alkoxy, alkylthio, hydroxyl, carboxy (-COOH), alkyloxycarbonyl (- C(O)R), alkylcarbonyloxy (-OCOR), amino (-IMH2), carbamoyl (-NHCOOR-or-OCONHR), urea (-NHCONHR-) or thiol (-SH).
- Alkyi groups as defined may also comprise one or more carbon double bonds or one or more carbon to carbon triple bonds.
- “Lower alkoxy” refers to O-alkyl groups, wherein alkyi is as defined hereinabove.
- the alkoxy group is bonded to the core compound through the oxygen bridge.
- the alkoxy group may be straight-chained or branched; although the straight-chain is preferred.
- Examples include methoxy, ethyloxy, propoxy, butyloxy, t-butyloxy, i-propoxy, and the like.
- Preferred alkoxy groups contain 1 -4 carbon atoms, especially preferred alkoxy groups contain 1 -3 carbon atoms. The most preferred alkoxy group is methoxy.
- Halogen means the non-metal elements of Group 17 of the periodic table, namely bromine, chlorine, fluorine, iodine and astatine.
- alkyi alkyi
- cycloalkyl heterocycloalkyl
- cycloalkylalkyl aryl
- acyl aromatic polycycle
- heteroaryl arylalkyl
- heteroarylalkyl heteroarylalkyl
- amino acyl amino acid
- non-aromatic polycycle mixeded aryl and non-aryl polycycle
- polyheteroaryl non-aromatic polyheterocyclic
- mixed aryl and non-aryl polyheterocycles amino acids
- Halogen means the non-metal elements of Group 17 of the periodic table, namely bromine, chlorine, fluorine, iodine and astatine.
- aryl leader group and “acid leader group” are defined in pages 25-54 of WO02/30879.
- “Substituted” unless otherwise defined means substituted with a substituent selected from halogen, oxygen, hydrogen, hydroxyl, a carboxyl, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, aryloxy, alkyloxy, arylalkyloxy, amino, alkylamino, hydroxylamino, dialkylamino, or alkoxy group, or pyridine, or are fused to form a monocyclic or polycyclic aromatic hydrocarbon or heterocycle.
- salt and counter ion designate a pharmaceutically acceptable salts/counter ions and can include acid addition salts such as the hydrochlorides, hydrobromides, phosphates, nitrates, sulphates, hydrogen sulphates, alkylsulphates, arylsulphonates, acetates, benzoates, citrates, gluconates, maleates, fumarates, succinates, lactates, and tartrates; alkali metal cations such as Na, K, Li; alkali earth metal salts such as Mg or Ca; or organic amine salts.
- Exemplary organic amine salts are tromethamine (TRIS) salts and amino acid salts (e.g. histidine salts) of the compounds of the invention.
- Histone deacetylase inhibitor or "HDAC inhibitor” (R-Z) refers to a hydroxamate-type HDAC inhibitor, i.e. a HDAC inhibitor having a terminal hydroxamate group, that typically exhibits HDAC inhibitory activity in a tumour cell.
- the HDAC inhibitor preferably has at least micromolar and preferably nanomolar inhibitory activity (IC50) against any HDAC isoform as determined using the HDAC inhibition assay described in Yuan et al (Bioorganic and Medicinal Chemistry, 2017 - http://dx.doiorg/10.1016/j.bmcx.2017.05.058).
- the HDAC inhibitor is selected from the group consisting of: SAHA or SAHA-like HDAC inhibitors (general formula III above); Panabinostat or Panabinostat-like inhibitors (general formula V); and Belinostat or Belinostat-like inhibitors (general formula IV).
- the HDAC inhibitor is selected from the group consisting of: SAHA or SAHA-like HDAC inhibitors (general formula III above); Panabinostat or Panabinostat-like inhibitors (general formula V); and Belinostat or Belinostat-like inhibitors (general formula IV).
- the HDAC inhibitor is selected from the group consisting of: SAHA, Panabinostat and
- the term "dual HDAC/PARP inhibitor” refers to a hybrid compound that targets PARP and HDAC concurrently. Dual HDAC/PARP inhibitors are described in Yuan et al (Bioorganic and Medicinal Chemistry, 2017).
- the dual PARP/HDAC inhibitor has inhibitory activity against any PARP isoform, for example PARP1 or 2 and any HDAC isoform, for example HDAC 1 or 6, with I C50- values in at least the micromolar, and preferably nanomolar range, as determined by the HDAC inhibitory assay described in Yuan et al.
- the dual PARP/HDAC inhibitor is a hybrid of the PARP inhibitor Olaparib and a hydroxamate-type HDAC inhibitor.
- the invention provides methods of, and compositions for, treatment and prevention by administration to a subject in need of such treatment of a therapeutically or prophylactically effective amount of a metal complex of the invention.
- Various delivery systems are known and can be used to administer a compound or composition of the invention, e.g., encapsulation in liposomes, microparticles,
- Methods of introduction include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes.
- the compounds or compositions may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local.
- Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent. It may be desirable to administer the compounds or compositions of the invention locally to the area in need of treatment; this may be achieved, for example and not by way of limitation, by topical application, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
- the compounds can be delivered in a vesicle, in particular a liposome (see Langer, Science, 1990, 249, 1527-1533; Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327).
- the compounds or compositions of the invention can be delivered in a controlled release system.
- a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed.
- polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Press., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol.
- a controlled release system can be placed in proximity of the therapeutic target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 1 15-138 (1984)). Other controlled release systems are discussed in the review by Langer (Science, 1990, 249, 1527-1533).
- compositions comprise a therapeutically effective amount of an Active Compound of the invention, and a pharmaceutically acceptable carrier.
- pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals and more particularly in humans.
- carrier refers to a diluent, adjuvant, excipient, or vehicle with which the compound or pro-drug of the invention is administered.
- Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
- Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol and water.
- compositions can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
- These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
- composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
- Oral formulation can include standard carriers such as
- compositions will contain a therapeutically effective amount of the compound or pro-drug of the invention, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient.
- the formulation should suit the mode of administration.
- the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings.
- compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
- the composition may also include a solubilizing agent and a local anaesthetic such as lignocaine to, ease pain at the, site of the injection.
- the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
- composition is to be administered by infusion
- it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
- amount of the therapeutic of the invention which will be effective in the treatment or prevention of cancer will depend on the type, stage and locus of the cancer, and, in cases where the subject does not have an established cancer, will depend on various other factors including the age, sex, weight, and clinical history of the subject.
- the amount of therapeutic may be determined by standard clinical techniques.
- in vivo and/or in vitro assays may optionally be employed to help predict optimal dosage ranges.
- the precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the cancer, and should be decided according to the judgment of the practitioner and each patient's circumstances.
- Routes of administration of a therapeutic include, but are not limited to, intramuscularly, subcutaneously or intravenously. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
- the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the compositions of the invention.
- Infra-Red spectra were recorded on a Perkin Elmer Spectrum GX Bruker spectrometer. Electrospray lonisation mass spectrometry (ESI-MS) experiments were carried out on an Advion Expression Compact Mass Spectrometer. Elemental analysis (C, H, N) were carried out on an Starbucks Analytical CE440 elemental analyser. Cu analysis was carried out on a Varian 55B atomic absorption spectrometer. CI analysis was determined via combustion in an oxygen flask followed by titration with mercuric nitrate.
- ESI-MS Electrospray lonisation mass spectrometry
- Cu(CIC>4)2-6H20 (106.4 mg, 0.287 mmol) was dissolved in 1 ml of deionised water .
- To the Cu solution warm solutions of SAHA (75.9 mg, 0.287 mmol) and DPPZ (81.04 mg, 0.287 mmol) in methanol (3ml) were added sequentially. The resulting suspension was stirred at room temperature for 30 min. The solid green product (Cu-SAHA-DPPZ) was filtered, washed with cold deionised water, methanol and dried under vacuum, Scheme 1 . Yield 127 mg, 60.5%.
- C32H31CICUN6O7 requires C - 54.09 %; H - 4.40 %; N - 1 1 .83 %; Cu - 8.94 %; CI - 4.99 % ; found C - 53.70 %; H - 3.83 %; N - 1 1.65 %; Cu - 9.05 %; CI 4.80 %.
- ESI- MS [M-H] + ) (MeOH) m/z: 609 ([Cu(SAHA.i H )(DPPZ)] + ) 265.2 (SAHA).
- C26H26CICU N4O10 requires C - 47.79 %; H - 4.01 %; N - 8.57 %; Cu - 9.72 %; CI - 5.43 %; found C - 47.55 %; H - 3.99 %; N - 8.37 %; Cu - 9.51 %; CI - 5.21 %.
- IR (ATR) cm "1
- Copper(ll) perchlorate hexahydrate (Cu(CI04)2-6H20) (100 mg, 0.270 mmol) was dissolved in a minimum volume of deionised water (1 ml).
- Warm solutions of SAHA (71 .4 mg, 0.270 mmol) and nitrogen donor ligand of either Bipy (42.5 mg, 0.270 mmol), Phen (48.7 mg, 0.270 mmol) or DPQ (46.7 mg, 0.270 mmol) in 1 ml of methanol were added sequentially.
- a solution of potassium hydroxide (15.1 mg, 0.270 mmol) in 1 ml of deionised water was immediately added and the resulting suspension stirred at room temperature for 30 min.
- C26H28CICUN4O9 requires C - 48.83 %; H - 4.41 %; N - 8.76 %; Cu - 9.94 %; CI - 5.54 %; found C - 49.25 %; H - 4.56 %; N - 8.62 %; Cu - 10.36 %; CI - 5.44 %.
- Copper(ll) nitrate trihydrate (0.1042g; 0.431 mmol; 1 eq; limiting reagent) or copper(ll) sulphate (0.1 1 12g; 0.697mmol; 1 eq; limiting reagent) were suspended in 5ml of EtOH at reflux.
- Suspensions of DPQ or DPPZ (1 eq) in 5ml of hot EtOH were added and the resulting suspension was left to stir at reflux for 30 minutes. The solution was allowed to cool and a solid precipitate was filtered and dried under vacuum.
- Copper(ll) nitrate trihydrate (0.1068g; 0.442mmol; 1 eq; limiting reagent) copper (II) chloride (0.1038g; 0.772mmol; 1 eq limiting reagent) or copper(ll) sulphate (0.1029g; 0.645mmol; 1 eq; limiting reagent) were suspended in 5ml of EtOH at reflux.
- Suspensions of DPQ or DPPZ (1 eq) in 5ml of hot EtOH were added and the resulting suspension was left to stir at reflux for 30 minutes. The solution was allowed to cool and a solid precipitate was filtered and dried under vacuum.
- SK-OV-3 and DU 145 cells were seeded overnight in 96 well tissue culture plates (Costar) at an initial density as outlined in Table 2.
- DMSO stocks of Doxorubicin (Sigma-Aldrich, Ireland) and complexes were prepared at ⁇ 10 mM. Stock solutions were diluted in supplemented RPMI 1640 medium to give the following final concentrations in 200 ⁇ wells: 10, 7.5, 5, 2.5 and 1 .25 ⁇ , while Doxorubicin stocks were diluted giving the following final concentrations: 1 , 0.75, 0.5, 0.25 and 0.125 ⁇ . A DMSO control of the highest drug incubation was also included. Cells were incubated for 24, 48 and 72 hr at 37 °C in a humidified atmosphere with 5% CO2.
- SK-OV-3 cells were seeded in a 75 cm 3 flask and grown until 80-90% confluency. The cells were treated at isotoxic concentrations corresponding to the I C50 value (Error! Reference source not found.) for 24 hr (Cu-SAHA-Phen, Cu-SAHA-Phendio, Cu-SAHA-DPQ, Cu- SAHA-DPPZ, 48 hr (Cu-SAHA-Bipy) or 72 hr (SAHA). Cells were washed twice with ice cold PBS, scraped and collected into a 1 .5 ml microcentrifuge tube (Eppendorf, Germany).
- Nuclear extracts were prepared following the protocol recommended by the manufacturer of the EpiQuik® Nuclear Extraction Kit (Epigentek, USA). Protein concentration of the nuclear isolates was determined by following the protocol of the manufacturer of the Quick StartTM Bradford protein assay (Bio-Rad, CA, USA).
- the SK-OV-3 nuclear extracts were tested for HDAC activity following the protocol recommended by the manufacturer of the EpiQuik® Colorimetric HDAC Activity/Inhibition assay kit (Epigentek, USA).
- the standard curve was constructed using the standard included in the kit; the absolute amount of deacetylated product was calculated from the standard curve.
- HDAC activity was calculated by:
- pUC19 vector New England Bio-Labs, N3041
- UltraPure calf thymus DNA (ctDNA, Invitrogen, 15633-019, £ 260
- Viscosity measurements were conducted using a method previously reported by Mc Cann, M; Kellett, A. et al., Chem. Comm., 2013, 49, 2341 -2343. Briefly, a 15 ml solution of stDNA was prepared at 1 10 "3 M in 80 mM HEPES buffer for each working sample. Stock solutions prepared in DMF were added according to the gradual increasing [drug]/[DNA] (r) ratios of 0.02, 0.04, 0.06, 0.08, 0.10, 0.12, 0.14, 0.16, 0.18 and 0.2.
- Viscosity values, n, (unit: cP) were directly obtained by running 0# spindle in working samples at 60 rpm via DV-ll-Programmable Digital Viscometer equipped with Enhanced Brookfield UL Adapter at room temperature. Data were presented as ⁇ / ⁇ 0 versus [compound]/[DNA] ratio, in which Ho and ⁇ refers to viscosity of each DNA working sample in the absence and presence of complex' 11 .
- DNA-EtBr or DNA-Hoechst working solutions were placed each well of a 96 well microplate with the exception of the blanks which contained 100 ⁇ _ HEPES buffer and 5 ⁇ of either Hoechst or EtBr.
- Serial aliquots of the tested compound were added to the working solutions and the volume was adjusted to 100 ⁇ _ in each well such that the final concentration of ctDNA and EtBr/Hoechst were 25 ⁇ and 5 ⁇ , respectively.
- the plate was allowed to incubate at room temperature for 5 minutes before being analysed using a Bio-Tek synergy HT multi-mode microplate reader with excitation and emission
- Thermal melting analysis were conducted using a method previously reported by Molphy, Z; Kellett, A. et al., Inorg. Chem., 2014, 53, 5392-5404. Analysis was carried out on an Agilent Cary 100 dual beam spectrophotometer equipped with a 6 x 6 Peltier multicell system with temperature controller.
- test reagent [compound]/[nucleotide]).
- test reagent and respective alternating copolymer were then incubated for 10 min at 20 °C prior to commencing the temperature ramp.
- Thermal melting measurements were recorded at 260 nm at 0.25 s intervals.
- Temperature was ramped at 3 °C/min over the range of 20.0-97.0 °C.
- the spectral bandwidth (SBW) was set to 1.
- Reactions were incubated for 30 minutes at 37 °C and quenched with 6X loading dye (Fermentas) containing 10mM Tris-HCI, 0.03% bromophenol blue, 0.03% xylene cyanole FF, 60% glycerol and 60 mM EDTA. Samples were then loaded onto an agarose gel (1 .2%) containing 4 ⁇ of EtBr. Electrophoresis was completed at 70 V for 2 hrs in 1X TAE buffer.
- 6X loading dye Fermentas
- SK-OV-3 cells were seeded at an intial density of 6 x 10 4 cells ml "1 overnight.
- Cu(ll) complexes were added to SK-OV-3 cells at isotoxic concentrations corresponding to the IC50 value and incubated for 24 hours.
- EdU incorporation was measured according to the protocol recommended by the manufacturer of the EdU cell proliferation kit (Baseclick GmBH). Analysis was performed on a Guava EasyCyte HT flow cytometer. DNA metallodrug interactions
- the complex series did not exhibit a degree of discrimination for quenching either EtBr or Hoechst with the Cu-SAHA-DPPZ and Cu-SAHA-DPQ complexes having the highest Q values of the series and also being higher than Cu-Phen.
- both of these complexes displace Hoescht with slight preference over EtBr wheras with Cu-Phen, this effect is essentially reversed.
- no significant was observed for both the Cu- SAHA-Bipy and Cu-SAHA-Phendio complexes at concentrations >150 ⁇ .
- Table 4 Summarised DNA binding data (A) competitive ethidium bromide displacement, (B) fluorescence quenching and (C) viscosity analysis.
- Cu-Phen enhanced the thermal temperature of poly[d(G-C) 2 ] ( ⁇ 7 ⁇ 6.64 ⁇ 1 .58) thereafter followed by Cu-SAHA-Phen ( ⁇ 7 ⁇ 4.30 ⁇ 0.51 ). Compared to ploy[d(G-C)2] all of the complexes had neglible or negative effects on thermal stabilization.
- the Cu 2+ complexes bind both G C and A co-polymers where K app values being similar for both nucleotides tested.
- Table 5 Effect of Actinomycin D, Netropsin, SAHA and Cu 2+ complexes on the thermal denaturation of poly[d(G- C) 2 ] and poly[d(A-T) 2 ]
- the capability of the Cu 2+ complexes to induce oxidative DNA damage in vitro was assessed using a 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay.
- Exogenous nucleoside analogues of thymidine such as EdU can be incorporated into cellular DNA following oxidative DNA damage.
- the complexes Cu-SAHA-DPQ and Cu-SAHA-DPPZ were found to have -30% reduction in EdU incorporation compared to control (non drug treated cells).
- the complex Cu-SAHA-Phendio was found to have on par to the clinical agent, doxorubicin ( Figure 4).
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Abstract
La présente invention concerne un complexe métallique de formule générale (I), dans laquelle : R-Z est un inhibiteur de HDAC dans lequel Z un groupe hydroxamate terminal ; M est un métal actif redox ; n+ est la charge positive sur le cation complexe ; Bn- est un contre-ion d'équilibrage ; Z se lie à M par l'intermédiaire d'une coordination O,O' bidendate ; et la formule (A) est un ligand donneur d'azote choisi parmi un ligand bipyridine ou un ligand phénanthroline ou un ligand de type phénanthroline à condition que R-Z ne soit pas un double inhibiteur de HDAC/PARP.
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