WO2018100561A1 - Composés de coordination, synthèses, nanoformulation et leur utilisation en oncologie - Google Patents

Composés de coordination, synthèses, nanoformulation et leur utilisation en oncologie Download PDF

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WO2018100561A1
WO2018100561A1 PCT/IB2017/057593 IB2017057593W WO2018100561A1 WO 2018100561 A1 WO2018100561 A1 WO 2018100561A1 IB 2017057593 W IB2017057593 W IB 2017057593W WO 2018100561 A1 WO2018100561 A1 WO 2018100561A1
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group
optionally
coordination
ligand
groups
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Chiara NARDON
Dolores Fregona
Leonardo BRUSTOLIN
Nicolò PETTENUZZO
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Nardon Chiara
Dolores Fregona
Brustolin Leonardo
Pettenuzzo Nicolò
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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
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/12—Gold compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12

Definitions

  • the present invention regards mononuclear Au-based and Cu-based coordination compounds, pharmaceutical formulations thereof, the related synthesis and encapsulation method in macromolecules, supramolecular aggregates or nanostructures, as well as their use in the diagnosis and/or the treatment of neoplasms.
  • coordination compounds and/or their formulations can be glycoconjugated with carbohydrates which act as cancer- targeting moieties thus increasing the therapeutic selectivity.
  • Cisplatin is a milestone among the anticancer compounds and, since its introduction in pharmacopoeia in 1978, has shown to be one of the most effective drugs, particularly in the treatment of testicular, ovarian, lungs, bladder and uterine cervix cancer, mesothelioma and head and neck carcinoma. Despite its therapeutic efficacy, the clinical use of cisplatin is characterized by severe side effects. The most serious one is the high toxicity, especially to kidneys, to auditory apparatus and to bone marrow. In addition, cisplatin demonstrates intrinsic or acquired resistance to certain tumors.
  • a first strategy aims to synthesize new coordination compounds with metal centers other than platinum that can maintain the antitumor activity but, at the same time, are characterized by a better toxicological profile.
  • Fregona et al. were able to synthesize a class of Au(lll) dithiocarbamato complexes, described in ITMI20030600 which proved intrinsically less toxic than the Pt(ll) counterparts.
  • WO2010105691 A1 Fregona et al. have claimed a new class of Au(lll) dithiocarbamato compounds functionalized with a peptide moiety designed to be internalized by tumor cells by PEPT transporters.
  • Au(lll) complexes with different metal-DTC ligand stoichiometry (1 :1 , 1 :2) is represented by the compounds reported by M. Altaf et al. (Altaf, RSC Advances, 2015). In this work, dimethylamine, diethylamine and dibenzylamine Au(lll) dithiocarbamato molecules are studied and their in vitro antitumor activity is evaluated.
  • glucose and other carbohydrates are potentially useful biomolecules to selectively target antitumor agents.
  • FDG fluoro-2-deoxy-D- glucose
  • glucose and other carbohydrates are potentially useful biomolecules to selectively target antitumor agents.
  • glyco-conjugates made up of known cytotoxins or chemotherapeutics linked to glucose (or other carbohydrates) have been synthesized to increase their selectivity to and absorption by the tumor cells.
  • the glyco-conjugate glufosfamide is currently in clinical trials for the treatment of ovarian and pancreatic cancer, glioblastoma multiforme and non-small cell lung carcinoma.
  • oxalilplatin encapsulated in liposomes (known under the trade term of Lipoxal ® ) is currently in an advanced stage of development, while the same oxalilplatin, encapsulated in transferrin-conjugated liposomes (MBP-426), has completed the Phase I.
  • a modified oxalilplatin (NC-4016) wherein a PEG is linked to the platinum(ll) metal center via a polyglutamic acid linker is about to start the phase I.
  • drugs based on coordination compounds still represent one of the most promising anti-cancer option, but there is a need to make available a large number of new compounds with metal center other than platinum, which may replace cisplatin in the future, considering that most candidate compounds do not pass the advanced preclinical or clinical tests and therefore do not become drugs.
  • the present inventors intend to overcome the existing limits in the state-of-the-art related to coordination compounds useful as antitumor agents.
  • a first and main object of the present invention to design and synthesize Au- based and Cu-based mononuclear coordination compounds to be used as antitumor agents.
  • a second object of the present invention is to identify mononuclear Au-based and Cu-based coordination compounds with carbohydrate-functionalized ligands which act as selective cancer-targeting moieties.
  • the present invention intends to disclose the advantageous use of carbohydrates as selective cancer-targeting moieties.
  • carbohydrates could provide the additional advantage of increasing the solubility of the final compound in aqueous media.
  • a third important object of the present invention is to identify coordination compounds endowed with low or negligible toxicity with respect to other metal-based compounds, such as cisplatin and subsequent compounds
  • a fourth object of the present invention is to identify coordination compounds characterized by high solubility in aqueous media, high stability and bioavailability, inherent or achieved by encapsulation in macromolecules, nanostructures or supramolecular aggregates, such as micelles, liposomes, proteins or cyclodextrins.
  • such structures may or not be functionalized with carbohydrates on the outer surface.
  • a fifth object of the present invention is to provide a stable pharmaceutical formulation including one or more of said coordination compounds, usable as an antitumor agent and preferably administrable intravenously or orally.
  • Such formulations may optionally include additional anticancer drugs.
  • a further object of the present invention is to provide a method for synthesizing said mononuclear Au-based and Cu-based coordination compounds, bioconjugated or not with carbohydrates, as well as a method for encapsulating said compounds in macromolecules, supramolecular aggregates made up of biocompatible polymers, functionalized or not with carbohydrates.
  • a further object of the present invention is to disclose the use of said coordination compounds as antitumor agents, particularly in the treatment of "orphan tumors", such as the "triple negative” breast cancer (TNBC), the castration-resistant prostate cancer (CRPC), head and neck cancer, the NSCLC, the melanoma, the mesothelioma, the lung, pancreas and liver carcinoma.
  • TNBC triple negative breast cancer
  • CRPC castration-resistant prostate cancer
  • head and neck cancer the NSCLC
  • the melanoma the mesothelioma
  • the lung pancreas and liver carcinoma.
  • a final object of the present invention is to produce coordination compounds which, besides possessing the necessary chemical-biological properties, are stable and obtainable through a synthesis process both able to intrinsically yield high-purity compounds and being industrially applicable with known and cost-effective technologies compared to state- of-the-art solutions.
  • M identifies the metal center of the coordination compound which can be Au(lll), Cu(ll) or Cu(lll).
  • the mononuclear coordination compounds herein disclosed are neutral or ionic complexes whose charge is neutralized by at least one counter-ion G and have different coordination geometries, for example square-planar, tetrahedric or pyramidal.
  • the coordination compounds of formula l(a) or l(b) are not bioconjugated with a cancer-targeting moiety and act as antitumor agents due to the inherent reactivity of the Au and Cu metal centers. Surprisingly, some of these compounds exhibit an unexpected solubility in physiological media in spite of the presence of hydrophobic groups in the structure.
  • the coordination compounds of formula l(a) or l(b) are bioconjugated with a carbohydrate which acts as a selective cancer-targeting moiety, advantageously exploiting the so-called "Warburg effect".
  • a carbohydrate which acts as a selective cancer-targeting moiety, advantageously exploiting the so-called "Warburg effect”.
  • the presence of the cancer-targeting moiety, in combination with the physico-chemical properties of the final compound ⁇ e.g. ionic nature) can result in a very high solubility in physiological media.
  • the coordination compounds of formula l(a) or l(b) are encapsulated in macromolecules, nanostructures or in supramolecular aggregates, such as liposomes or cyclodextrins, acting as carriers to carry out a passive- targeting mechanism mediated by the Enhanced Permeability and Retention (EPR) effect that characterizes tumor districts.
  • Said compounds may be or not conjugated with carbohydrates.
  • the coordination compounds described in the formula l(a) or l(b) may be addressed to the tumor site by encapsulating such compounds in macromolecules, nanostructures or supramolecular aggregates, for example micelles, in turn functionalized with carbohydrates to achieve an active-targeting approach ("Warburg effect"), which accompanies and strengthens the passive-targeting mechanism of the previous embodiment.
  • the encapsulated compounds can be or not conjugated with carbohydrates.
  • the present invention discloses Au-based and Cu-based coordination compounds, glycoconjugated or not, which, according to experimental tests, possess remarkable anti-tumor properties. Furthermore, various synthesis processes of said coordination compounds have been disclosed, characterized by high yields: they allow the expert to choose the most advantageous scheme depending on the metal center and type of desired ligands, including those containing a cancer-targeting moiety represented by a specific carbohydrate. Said cancer targeting moiety and metal centers can in turn be chosen based on the molecular profile of the patient's neoplasm according to the paradigm of personalized medicine.
  • the Ru-based and Ga-based coordination compounds according to the present invention can be loaded into supramolecular aggregates or macromolecules, consisting of a wide range of biocompatible polymers so to obtain stable nanoformulations. In other words, said compounds do not react nor establish interactions with other loaded complexes, and with the polymeric carrier neither.
  • the coordination compounds and nanoformulations allow to realize a both active and passive cancer-targeting mechanism.
  • These compounds are characterized by optimal LiPE values for a promising pharmaceutical development ⁇ "druglikeness").
  • nanoformulations not only make the hydrophobic active principles soluble in the aqueous media but also mask the active principles herein described, both hydrophobic and hydrophilic, from reactions/interactions with the cellular and molecular components of the blood. Additional objects and advantages of the invention will be set forth in part in the detailed description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
  • FIG. 1 shows the levels of expression of the glucose transporter (Glutl ) in different cell lines.
  • Glutl glucose transporter
  • letter A Northern analysis of the Glutl mRNA levels evaluated in healthy human prostate samples and in three different human prostate cancer cell lines with decreasing differentiation.
  • LNCaP is a hormone-sensitive cancer cell line, whereas the
  • DU-145 and PC3 lines represent poorly-differentiated tumors (source: P. Effert et al., Anticancer Research 24: 3057-3064, 2004).
  • letter B Western analysis of Glutl protein levels evaluated in samples derived from 4 different cell lines: cervix adenocarcinoma (HeLa), lymphoblast T (Jurkat), epidermoid skin cancer (A431 ), human embryonic kidney (HEK293) (from Abeam pic).
  • FIG. 2 illustrates the structure of some compounds solved by X-ray crystallography.
  • FIG. 4 shows the UV-Vis spectra of the coordination compound [Cu(ProOMeDTC) 2 ] with general structure (IV).
  • said compound is dissolved in aqueous medium consisting of pH 7.4 phosphate buffer/human serum (94.5-5% v/v), with a final
  • DMSO concentration 0.5% i//i/ (the kinetics recorded at 37 °C for 72 hours).
  • DMSO is an organic solvent used to pre-dissolve the compound.
  • the same coordination derivative is encapsulated in PF127 (5 mg/mL) micelles, dissolved in aqueous medium consisting of phosphate buffer pH 7.4 - human serum 95-5% v/v.
  • FIG. 5 shows the UV-Vis kinetic study recorded over 72 hours for the [Cu(PipeDTC) 2 ] complex encapsulated in ⁇ - ⁇ -CD in phosphate buffer/cell culture medium 9:1 v/v (at 37 °C).
  • Figure 6 represents TEM images of the formulations according to the third and fourth embodiments of the present invention in which micelles of PF127 (90%)/ glucose- conjugated PF127 ( ⁇ anomer, O-glycoside) (10%) encapsulate the complex
  • the chemical elements are defined by means of the respective symbols as reported in a common Periodic Table of Elements, such as that present in the "Handbook of Chemistry and Physics, 93rd ed ".
  • the chemical symbol includes all isotopes and ions. Therefore, the chemical symbols C, F, Cu, Ga , Au and I include, as an example, their respective isotopes 11 C, 18 F, 64 Cu, 63 Cu, 65 Cu, 68 Ga, 198 Au, 131 1, 127 l, 129 l.
  • the claimed and described structures are intended to include all possible isomers such as coordination isomers, structural isomers, and conformational isomers.
  • the claimed and described structures are intended to include all possible optical isomers, such as enantiomers and/or diastereoisomers, their mixtures, either as racemic mixture or in various ratios.
  • These chiral centers may be present in the coordination compound or already present in the involved chelating ligands, for instance in the molecular fragments comprising a carbohydrate T.
  • the coordination compounds having formula l(a) and/or l(b) are bioconjugated to cancer-targeting moieties.
  • cancer-targeting moieties This is a well-known term for an expert in the field, and it defines a molecular fragment of the compound (moiety), which has been ad hoc engineered for its recognition by cell-membrane proteins present in tumor cells.
  • said "cancer-targeting moiety” is a carbohydrate, and according to this, the terms “glycoconjugation” and “glycoconjugates” will be also used to indicate the “bio- conjugation” and the "bio-conjugates", respectively.
  • the synthetic processes of the first and second embodiments involve amino functional groups for the preparation of the dithiocarbamato ligand. These groups may be ad hoc introduced in a specific stage of the process, or alternatively they can be generated by subsequent reactions during the previous steps. On the other hand, a suitable amine reagent can be purchased and used as such. Again, in the context of the present patent, these amino groups and amine reagents will be defined "precursor amine(s)" for brevity.
  • Some embodiments of the present invention involve the term "pharmaceutical formulations" to define preparations made up of a therapeutically-effective amount of the coordination compounds of Formula I (a) and/or l(b ) together with "pharmaceutically acceptable” additives and/or diluents and/or excipients.
  • pharmaceutically acceptable additives and/or diluents and/or excipients are intended to be compounds that, in contact with animal or human tissues, in light of their composition, dosage and administration route or anything else, do not cause any toxicity, irritation, allergy, and other complications considered excessive or unacceptable by a specialized physician based on a reasonable risk/benefit ratio.
  • Said compounds may optionally be encapsulated in "pharmaceutically acceptable" macromolecules or supramolecular structures or nanostructures.
  • encapsulation means a process by which a therapeutically-effective amount of the coordination compounds of Formula 1(a) and/or 1(b), establishes intermolecular bonds ⁇ e.g. van der Waals forces, hydrogen bonds) with the single units of a "nanocarrier” or with specific structural domains.
  • the surface or the hydrophobic core of the nanocarrier e.g., micelles
  • the hydrophilic core ⁇ e.g., liposomes
  • the term "theranostic compound” or more generally “theranostic agent” will refer to the coordination compound according to this invention, the composition containing at least one of said coordination compounds, or also a pharmaceutical formulation made up of the said compound and/or composition, which combines therapeutic properties with regard to a pathology, preferably neoplastic pathologies, along with the property to be detectable by suitable devices/detectors, hence to be usable in association with diagnostic and imaging systems for patient follow-up in therapeutic treatments and, if possible, to take the necessary corrective action.
  • a pathology preferably neoplastic pathologies
  • Said mononuclear coordination compounds herein disclosed are neutral or ionic complexes whose charge is neutralized by at least one counter-ion G.
  • X and Y are independently selected and have the following meaning:
  • M identifies the metal center of the compound and is selected from Au(lll), Cu(ll) or Cu(lll), also briefly Cu(ll, III).
  • X represents a monoatomic neutral or ionic ligand, for example bromide, iodide, or is a donor atom that is part of a neutral or ionic ligand, for example oxygen in oxalate or sulfur in dithiocarbamate.
  • X is selected from the group consisting of: CI, Br, I, F, N, S, O, P, C and Se.
  • Y may be the same or different from X, and similarly to X it represents a monoatomic neutral or ionic ligand or a donor atom that is part of a neutral or ionic ligand.
  • the G symbol identifies at least one counter-ion having the total charge d, being an integer ranging from -4 to +4.
  • G is pharmaceutically acceptable ion, which, by way of example and not limitation, is selected among: selected among: CI-, I-, F-, Br-, CH 3 C0 2 ⁇ , PF 6 " , BF 4 ⁇ , SbF 6 " , [B ⁇ C 6 H 3 (CF 3 ) 2 ⁇ 4 ] ⁇ , [B(C 6 F 5 ) 4 ] ⁇ , OH " , S0 3 NH 2 ⁇ , nitrites and nitrates (e.g., N0 2 ⁇ , N0 3 " ), acetates, phosphates (e.g., hexafluorophosphate, H 2 P0 4 ⁇ , P0 4 3 ⁇ ), sulfates (e.g., triflate, HS0 4 ⁇ ), carbonates, perchlorates, acetylacetonates (e.g., hexafluoroacetylacetonate), propionat
  • the compounds according to the present invention have different coordination geometries, for example square-planar, tetrahedric, pyramidal, or one of the previously distorted-structure geometries.
  • the stylized arch connecting the S- donor atoms indicates a bidentate chelating dithiocarbamato ligand (DTC), in compliance with the usual chemical notation.
  • DTC dithiocarbamato ligand
  • the arch connecting the two S-atoms represents a first dithiocarbamato (DTC) ligand
  • DTC dithiocarbamic chelating ligand
  • said first or second DTC ligand has a closed structure such as that depicted below, which is presented by way of example but not limitation of the present invention:
  • Such structure comprises groups Ri , R 2 , R 3 and R 4 and optionally one R 5 group.
  • the Ri group and - if present - the R 5 group are bound to the dithiocarbamic nitrogen atom and to the R 2 and R 4 groups, respectively; the remaining R, groups are bound to the next and the previous group in the cyclic structure. If R 5 is absent, R 4 is directly bound to the dithiocarbamic nitrogen atom. All the bonds involving the R, groups, where i is an integer ranging from 1 to 5, may be single or double.
  • the DTC ligand with the closed structure herein described comprises a glucide or carbohydrate T, which is bound to at least one of said R, groups directly or through a unit A by respectively T-R, bonds or T-A-R, bonds, which can be single, double or triple.
  • bonds may be: C-C, C-O, O-C, C-N, N-C, C-S, S-C, C-P, P-C, C-Se, Se-C.
  • other chemically-equivalent molecular fragments may be selected by the expert of the branch.
  • said first or second DTC ligand has an open structure of the type depicted below by way of example, but not limitation:
  • the structure comprises a terminal group R linked to the dithiocarbamic nitrogen atom, and optionally one or more R 2 , R 3 , R 4 and R 5 groups.
  • the R 4 group if present, is a terminal group and is bound to R 5 or to said nitrogen atom; alternatively, R 4 is bound to R 5 or to said nitrogen atom and is bonded to R 3 or R 2 , depending on whether the R 3 or R 2 groups are absent or not.
  • the DTC ligand with the open structure herein described comprises at least one glucide or a carbohydrate T.
  • Said unit T is linked to said dithiocarbamic nitrogen atom or to at least one of the said R, groups (where i is an integer from 1 to 5) directly with respectively T-N or T-R, bonds, or alternatively via a unit A, by T-A-N or T-A-R, bonds.
  • said bonds may be single, double or triple, and of the type: C-C, C-O, O-C, C-N, N-C, C-S, S-C, C-P, P-C, C-Se, Se-C.
  • the unit A may be an atom or a functional group or a spacer, as well as the unit A is made up of other chemically-equivalent molecular fragments.
  • said unit A or said R, group (where i is an integer ranging from 1 to 5) are preferably selected from: an atom such as H, C, O, N, S, P, Se or a group selected among -CH, -CH 2 , -CH 3 , -C(CH 3 ) 3 , - NH, -NH 2 , -NHR S , -NR s2 , -S-S-, -SH, -PH, -OH, -COOH, -CH-Br, -CHCH 2 NH 2 , -CHCH 2 OH, - CHCH 2 NH-, -CHCH 2 0-, (-CN), -CF 3 ,
  • unit A or groups R it is possible to use molecular fragments being chemically-equivalent to those those herein reported by way of example, but not limitation of the present invention.
  • said first or second chelating DTC ligand may contain in the unit A or in the R, groups chemical groups in salified form comprising pharmaceutically acceptable counterions ⁇ e.g., -NH 3 + CI " ).
  • the unit A or the various R, groups may be variously substituted, in any combination and position, with one or more of said atoms or said groups.
  • the first or the second chelating DTC ligand may also a priori have different isomeric forms.
  • the herein disclosed formulae are intended to include any form of isomerism, preferably coordination isomers, structural isomers, conformational isomers, optical isomers such as enantiomers and/or diastereoisomers, mixtures thereof, as racemic mixtures or in various ratios.
  • said glucide or carbohydrate T is preferably a monosaccharide or a deoxy-monosaccharide, in particular a triose, a tetrose, a pentose, an esose, an eptose.
  • said glucide or carbohydrate T is selected from the group consisting of: glucose, galactose, mannose, xylose, rhamnose, arabinose, glucosamine, galactosamine, mannosamine, fructose, fructosamine, ribose, ribulose, sedoheptulose, erythrose, threose, erythrulose, allose, altrose, lixose, gulose, idose, talose.
  • said glucide or carbohydrate T is a natural or synthetic polysaccharide, also in deoxy-carbohydrate form, for example maltose, cellobiose, lactose, trealose, sucrose, amylose, amylopectin.
  • the T-R, or T-A-(R,) bond (where i is an integer ranging from 1 to 5) takes preferably place in at least one of the carbon positions of the T moiety, preferably in the positions C1 or C2 or C3 or C4 or C6, for the hexoses, and preferably in the C1 or C2 or C3 or C5 positions for pentoses.
  • the T-N or T-R, bond, or T-A-N or T-A-R, bond occurs preferably in the C1 or C2 or C3 or C4 or C6 positions for the hexoses, and preferably in the C1 or C2 or C3 or C5 positions for pentoses.
  • the ligand may have an overall neutral ⁇ e.g., zwitterionic), positive or negative charge.
  • one or more functional groups can be suitably protected during the synthetic process.
  • Well-known groups are available for the protection of hydroxyl, amine, amide and carboxylic acid groups, as well as the conditions in which protection and deprotection can occur, even in so-called orthogonal conditions.
  • protecting groups are introduced during the synthesis to avoid undesirable side- reactions and may be removed or not at the end of the synthetic procedure.
  • the new herein disclosed compounds may contain protective groups, even mutually different, in order to modulate the in vivo therapeutic profile, for example in terms of reactivity, solubility, stability and bioavailability.
  • one or more of the hydroxyl groups (also known as alcoholic) of one or more cancer-targeting moieties T of the second embodiment can be functionalized with equal or different protecting groups chosen, for example, from silyl ethers ⁇ e.g., trimethylsilyl ether or dimethyltertbutylsilylether) or esters ⁇ e.g., acetate, pivalate, propionate, carbonate, phosphate, butyrate).
  • the abovementioned protecting groups are indicated here by the notation R 6 ;
  • the substituent in position C1 may have an a or ⁇ conformation, and this monosaccharide binds, directly or through the unit A, to said R, groups or to the dithiocarbamic nitrogen atom in position C2 (as indicated by the black rectangle).
  • the protecting groups are again indicated by the notation R 6 ; the substituent in position C1 may have an a or ⁇ conformation, and this monosaccharide binds, directly or through the unit A, to said R, groups or to the dithiocarbamic nitrogen atom in position C5 (as indicated by the black rectangle).
  • the first and the second chelating dithiocarbamato (DTC) ligand may be either equal to or different from each other.
  • the coordination compound is referred to as homoleptic, while in the latter it is heteroleptic. Examples of homoleptic compounds (Examples 6-13) and heteroleptic compounds (Example 21 ) will be described below, by way of example but not limitation.
  • the coordination compounds having the general formula I (a) and l(b ) may be conveniently synthesized by a process including at least the following steps:
  • This process may optionally include a further step d) related to the purification and drying of the coordination compound obtained at the end of the step c).
  • the synthesis of the dithiocarbamato ligands is carried out at a temperature ranging from -30 and 60 °C in water, or methanol, or dry THF via reaction between an amine precursor and carbon disulfide (CS 2 ), optionally in the presence of a base, such as KOH or sodium tert- butoxide, or an excess of said amine precursor.
  • a base such as KOH or sodium tert- butoxide, or an excess of said amine precursor.
  • the volume of the solvent is reduced and the DTC ligand can be isolated via precipitation or co- precipitation by adding diethyl ether, washed with diethyl ether and dried under vacuum in presence of P 2 0 5 .
  • the synthesis of the coordination compound of general formula I (a) and/or l(b) is carried out in water or in an organic solvent, and it involves the coordination of the dithiocarbamato ligand (DTC), which has been optionally isolated in the previous step, to a selected metal center among Cu(ll,lll), and Au(lll).
  • DTC dithiocarbamato ligand
  • the metal center is selected starting from the corresponding precursors, preferably chlorides or metal-halide salts, or complex salts, for instance copper chloride in the case the selected metal center is Cu(ll,lll).
  • the precursors are metal derivatives with the metal center presenting a lower or higher oxidation state, such as organometallic-, amino-, thioether- precursors, or phosphine derivatives, or alternatively some of said coordination compounds can be themselves precursors, useful for the synthesis of other complexes.
  • contrast agents can be advantageously integrated in the coordination compound according to the invention in the form, for example, of radioisotopes such as 11 C, 18 F, 64 Cu, 198 Au, 127 l, 129 l, 131 1.
  • these isotopes can be included in the DTC ligand, or they may coincide with the metal center or also introduced into the counter-ion.
  • these contrast agents allow to combine the treatment of the neoplastic diseases with the diagnosis.
  • the purification is optionally carried out using techniques well-known to the skilled in the art, for instance by chromatography, precipitation from organic solvent, washing with water or organic solvents and drying of said coordination compound.
  • step b describes further details of the process described in the step b), related to the coordination of the DTC ligand to a specific metal center.
  • the first approach consists in the oxidative addition of the halide Br 2 or Cl 2 to the corresponding Au(l)-DTC precursor of the type ([Au 2 (DTC) 2 ]), that is synthesized through an in situ reduction of an Au(lll) salt, such as NaAuCI 4 -2H 2 0, with Na 2 S0 3 in a saturated aqueous saline solution forming the Au(l) derivative ([CI-Au-CI] " ).
  • This reaction is followed by the addition of 1 eq. of DTC ligand, leading to the formation of a precipitate that is dried under reduced pressure in presence of phosphoric anhydride.
  • the oxidative addition is carried out in dichloromethane/chloroform solvent mixture (50:50% v/v) under reflux. After about one hour, the volume is reduced, and the product is precipitated by the addition of diethyl ether.
  • the product is then centrifuged and can be washed optionally with water or ether and dried under reduced pressure.
  • the Au(lll) complexes of the type [AuX 2 (DTC)] were prepared from the corresponding [AuCI 2 (DTC)] complex.
  • the di-chloro compound was dissolved in
  • the resulting solution is then filtered and an intermediate of the type [Cu'(DTC)] is isolated, for example by precipitation with organic solvent, preferably diethyl ether.
  • Said intermediate is subsequently dissolved in an organic solvent, preferably halogenated, and put to react with at least one equivalent of halogenated oxidizing agent, preferably bromine Br 2 or chlorine Cl 2 .
  • the synthesis involves the coordination of the DTC ligand (prepared in the above step, 2 eq.) to the metal precursor, preferably but not exclusively, copper(ll) chloride in a stoichiometric metal- ligand ratio of 1 : 2.
  • the reaction is carried out in water or methanol at room temperature, resulting in the precipitation of the neutral compound [Cu(DTC) 2 ].
  • the compound is then centrifuged, washed with water and methanol and dried under vacuum with P 2 0 5 .
  • the counterion G can be advantageously chosen or replaced using techniques well-known to the skilled in the art, in order to optimize the pharmaceutical profile in terms of antitumor activity, "off-target” toxicity, solubility and stability.
  • coordination compounds having formula l(a) or l(b) are reported below.
  • such complexes do not contain a cancer-targeting moiety in the form of carbohydrate.
  • Such compounds contain, for example, dithiocarbamato ligands derived from: piperidine, morpholine, L-proline methyl ester, L-proline ferf-butyl-ester, pyrrole, and which for brevity are named, respectively, as PipeDTC, MorphDTC, ProOMeDTC, ProOtBuDTC, PyrrDTC.
  • the compounds were characterized by means of various techniques, including elemental analysis, NMR spectroscopy, FT-IR spectrophotometry and ESI-MS mass analysis.
  • the enclosed Figure 2 shows the structures of some of these compounds solved by X-ray diffraction.
  • v (cm 1 ) 539.66 (v s , CSS); 366.20 (v a , Au-S); 349.71 (v a , Au-CI); 334.59 (v s , Au-S); 315.67 (v s , Au-CI).
  • v (cm 1 ) 538.90 (v s , CSS); 369.79 (v a , Au-S); 350.61 (v s , Au-S); 239.1 1 (v a Au-Br); 223.85 (v s , Au-Br).
  • v (cm 1 ) 540.70 (v s , CSS); 379.35 (v a , Au-S); 344.53 (v s , Au-S); 238.34 (v a , Au-Br); 219.02 (v s , Au-Br).
  • the coordination compounds of Formula l(a) and Formula l(b) contain dithiocarbamato ligands functionalized with carbohydrates which act as a selective cancer-targeting moiety towards cancerous cells in vivo, advantageously exploiting the Warburg effect.
  • the glycoconjugation process involves a number of synthetic steps for the functionalization of a specific amino precursor with a likewise specific carbohydrate. Such amino precursor is subsequently converted to the corresponding dithiocarbamato (DTC) ligand, through the phase a) of the procedure of the first embodiment.
  • DTC dithiocarbamato
  • the synthesis involves the protection of the hydroxyl groups of carbohydrate with protecting groups which are orthogonal to the reaction conditions of the subsequent synthetic steps.
  • the carbohydrate e.g., glucose, mannose
  • a molecular fragment containing an amine preferably secondary, which is able to react with CS 2 to form a DTC ligand, ready for the subsequent complexation to the metal center (Au, Cu).
  • amine group or other functional group for example -OH, is not directly used to prepare the dithiocarbamato ligand, but its reactivity could be exploited to bind a molecular fragment which, depending on the molecular design, may have different length and chemical composition.
  • said molecular fragment must contain, after one or more synthetic steps, an amine group (that is, the precursor amine, as an example a proline) on which the CS 2 -based reaction will be carried out to form the DTC ligand.
  • an amine group that is, the precursor amine, as an example a proline
  • the deprotection of protecting groups can be performed by means of chemical or biochemical methods including the use of enzymes or pseudoenzymes.
  • Pseudoenzymes are generally referred to proteins, such as the HSA (Human Serum Albumin), which may hydrolyze, for example, ester substrates due to the presence of several nucleophilic residues (such as lysine) on their surface, but which do not return to the native state after the hydrolysis reaction.
  • HSA Human Serum Albumin
  • the Scheme 1 reported below shows the synthesis of a dithiocarbamato ligand (a-g), bearing a glucose moiety functionalized in position 1 of the pyranosic ring ( ⁇ -amido-glycoside).
  • a-g dithiocarbamato ligand
  • ⁇ -amido-glycoside a dithiocarbamato ligand
  • the Scheme 2 reported below as a non-limitative example of the present invention shows the synthesis of a dithiocarbamato ligand (A-D) functionalized with a glucopyranosyl moiety, through the position 1 of the carbohydrate ring.
  • A-D dithiocarbamato ligand
  • a DTC ligand bearing a ⁇ -D-O-glucopyranosyl fragment is isolated in this case.
  • the complexation with a Cu(ll) center occurs, followed by the purification through a C-18 column chromatography.
  • the Scheme 3 reported below shows the synthesis of a dithiocarbamato ligand ⁇ c-g), being a glucose derivative, functionalized in position C-2 (glucosamide, namely an amide derivative of glucosamine).
  • glucosamide namely an amide derivative of glucosamine
  • Such amine function can in turn be functionalized with a molecular fragment on which the dithiocarbamato group is synthesized, or alternatively, such amine group can be directly converted to dithiocarbamate by reaction with CS 2 or may be advantageously modified in a different functional group, for example a secondary amine or an isothiocyanate, in order to conduct subsequent reactions for the bioconjugation of the metal.
  • step A-D the synthesis of dithiocarbamato ligand bearing a C-1 functionalized glucoside with an ct-anomeric conformation is depicted.
  • step E the complexation with a Cu(ll) center occurs, followed by the purification through a C-18 column chromatography.
  • coordination compounds according to the second embodiment i.e. containing glucides or carbohydrates in one or more dithiocarbamato ligands.
  • Homoleptic complexes i.e. containing glucides or carbohydrates in one or more dithiocarbamato ligands.
  • v (cm 1 ) 1648 (v a , N-CSS); 385, 358 (v a,s , Au-S); 345, 318 (v a,s , Au-CI).
  • Example 17 [Cu(tetra-0-Acetyl-glucopyranosyl prolyl amido DJC) 2 ]
  • Example 19 [Cu bis(N-methyl, O-ethylamino, glucopyranoside DTC].
  • Example 20 [Cu bis(N-methyl, O-ethylamino, 2-deoxyglucopyranoside DTC].
  • This strategy also allows to combine the first and second embodiments, obtaining compounds in which only one ligand contains a carbohydrate, such as that of the Example 19 reported below as a non-limitative example, which was obtained starting from the compound of the previous Example 14 and substituting the two bromides with the piperidine DTC (pipeDTC) ligand.
  • piperidine DTC piperidine DTC
  • this technique allows to obtain water-soluble cationic Cu(lll) and Au(lll) complexes, to modulate the solubility/hydrophilicity (increasing or decreasing it depending based on the nature of the second dithiocarbamato ligand undergoing metal coordination) of the final complex in physiological environment, to increase/decrease the redox reactivity of the metallic center (in terms of reduction potentials), to modulate the immunogenic response as well as the overall steric hindrance.
  • Example 21 [Au(PipeDTC)(tetra-0-Acetyl-glucopyranosylamido-ProDTC)]CI.
  • the human tumor cell lines MeWo (malignant melanoma) and LoVo (colon adenocarcinoma) were cultured in RPMI-1640 and Hams-F12 medium, respectively.
  • the cells (8 x 10 3 / mL) were seeded in 96-well plates in the growth medium previously mentioned (100 ⁇ _) and then incubated at 37 °C in a controlled atmosphere of carbon dioxide. After 24 hours, the cell culture medium was removed and replaced with fresh one containing the tested compound, previously dissolved in DMSO (0.1 % v/v, freshly prepared solution mantained in the dark), or saline solution, at various concentrations.
  • K-Glucosamine-ProDTC > 15 ⁇ > 15 MeWo LoVo HeLa HCT116 HepG2/CTR HepG2/SB3 ⁇ 549 Jurkat CH2335
  • Table 1 In vitro cytotoxic activity (IC 50, expressed in ⁇ ) of some compounds and DTC ligands against the h uman tumor cell lines MeWo (malignant melanoma) and LoVo (colon adenocarcinoma) after 24 hours of treatment; against the human tumor cell lines: cervix adenocarcinoma (HeLa), colon neoplasia (HCT116), HepG2 : epithelial cells of human liver hepatoma and its more aggressive cou nterpart HepG2/SB3, overexpressing the anti-apoptotic protein SerpinB3; NSC lung carcinoma (A-549); acute T cell leukemia (Jurkat); triple negative breast cancer (crl2335) after 72 hours of treatment.
  • IC 50 In vitro cytotoxic activity (IC 50, expressed in ⁇ ) of some compounds and DTC ligands against the h uman tumor cell lines MeWo (malignant melanoma) and LoVo (colon aden
  • IC 50 concentration expressed in ⁇ able to inhibit the 50% of the cancer cell growth compared to the control (cells treated with the vehicle).
  • the data represent the mean ⁇ SD of at least four independent experiments.
  • the inventors have shown that such antitumor activity is due to the combination, in a single compound, of a properly-designed DTC ligand with a metal center endowed with specific chemical (oxidation state, reduction potential, geometry coordination, kinetic and thermodynamic properties) and biochemical properties.
  • mice Some compounds were tested in vivo to evaluate the acute toxicity by intravenous administration of a single dose to male mice (provided by Charles River Laboratory Italy, Calco, Lecco; 6-week-old mice).
  • This administration route has been chosen because it presents a reduced barrier to substance absorption, provides a more stringent toxicity measure compared to other in vivo assays and it is a typical route of administration in humans.
  • the species/strain mouse/CD-1® was chosen because many regulatory authorities accept and indicate that preclinical acute toxicity tests are performed with this species/strain, in light of the large amount of related bibliography.
  • the administered dose (10 mg/kg) was selected based on the dosages clinically used on humans ⁇ e.g., 2 mg/kg) in order to highlight potential signs of toxicity.
  • the tested compounds are: [Cu(tetra-0-Acetyl-glucopyranosylamidoProDTC) 2 ], [AuBr 2 (tetra-0- Acetyl-glucopyranosylamidoProDTC)] and [Au(PipeDTC)(tetra-0-Acetyl-glucopyranosylamido ProDTC)]CI.
  • the chosen vehicle is DMSO-EtOH-RL 50:10:40 % v/v in which RL stands for Ringer lactate (Eurospital ® ).
  • RL stands for Ringer lactate (Eurospital ® ).
  • a physiological solution was chosen as a vehicle.
  • Each experimental group consisted of 6 mice + 4 control animals (vehicle- treated only).
  • mice Body weights of the treated and non-treated (control) mice. Each dose was prepared by dissolving a calculated amount of compound in DMSO; this volume was subsequently diluted with ethanol and Ringer lactate (RL) to obtain the final desired concentration.
  • the administration of the antitumor compound under study was performed by intravenous injection into the caudal artery of each mouse. Each treated animal received an accurate injected volume of 100 ⁇ _, containing the amount of test substance as described above, that is the equivalent of 10 mg/kg. All animals were treated with a single dose at T 0 after detecting the body weight of each mouse. Clinical observations were recorded at the time of injection, during the first hour and then in the following days for total 7 experimental days, the same for the body weight.
  • advantageous supramolecular systems encapsulating the active compound can be micelles, vesicles (liposomes), cyclodextrins, dendrimers, organic polymeric nanoparticles, for instance derived from proteins or peptides, and inorganic nanoparticles ⁇ e.g., silica, zirconia, titanium dioxide).
  • Said supramolecular architectures can be in turn produced with different polymers, natural and synthetic, as well as with proteins or other organic molecules, such as chitosan, polyethylene glycol (PEG), mPEG acid, poly(lactic-co-glycolic acid) (PLGA), Pluronic ® , cholesterol, derivatives of phosphatidylcholine and phosphatidylethanolamine, Cremophor ® , pullulan, hyaluronic acid, ferritin, human serum albumin (HSA), heparin, dextran, polyaminoacids (e.g., a- poly-L-glutamic acid) and their derivatives ⁇ e.g., PHEA, PHEG), polyglycerol, polyacrylamide, polyvinylpyrrolidone, poly(2-oxazoline) and their derivatives.
  • these polymers or molecules such as PEG-PLGA or PEG Pluronic ® , may be used for the construction of appropriate
  • block copolymers such as those with the A-B-A or A-B architecture, can be advantageously used to prepare supramolecular systems suitable for the delivery of the coordination compounds herein disclosed.
  • said building blocks which can be equal or different each other, can be intended both as the monomer ⁇ e.g., ethylene oxide) of a polymer such as PEG or PF127, or of an inorganic nanostructure ⁇ e.g., Ti0 2 ), and the same polymer inside aggregates, for instance micelles.
  • nanostructures encompasses also for example micelles, liposomes, protein- and peptide-based aggregates and carriers consisting of cyclodextrins or dendrimers.
  • biocompatible polymers and oligomers natural or synthetic, identical or different ⁇ e.g., phospholipids, pullulan, PEG, PF127, cholesterol) can form micelles or liposomes, in order to modulate the final properties of the composition and therefore of the final formulation.
  • These polymers, identical or different are the constituent units that aggregate during the formation of the supramolecular system.
  • One of them or all of these polymers can be conveniently functionalized with carbohydrates (by using the functional groups exploitable for this purpose), and in an independent manner, with yields up to 100%.
  • This/these polymer(s) can then be diluted with the same or other polymers to achieve, for example, a micelle or a liposome with a water-exposed surface having a variable percentage of functionalization, ranging from 1 to 50% mol/mol .
  • the range 10 "5 ⁇ 10 "10 mol of compound/mg of formulation can be achieved when preparing compositions of said coordination compound.
  • said compound can be encapsulated in the hydrophobic core of a micelle, or in the hydrophilic counterpart of a liposome, or in their lipidic/polymeric layer.
  • Such supramolecular architectures can in turn be made with different polymers, natural and synthetic, as well as with proteins or other organic molecules, such as chitosan and polyethylene glycol.
  • the nanocarrier e.g., liposome, micelle
  • the surface of the supramolecular aggregate is hidden from blood components, including the opsonin proteins, which are responsible for the recognition and attack of the nanocarriers by phagocytes (monocytes, macrophages).
  • This masking strategy allows the supramolecular systems to sidestep the natural processes of biotransformation/elimination of exogenous constituent entities or substances. Moreover, it determines an increased bioavailability and, hence, a prolonged circulation time of the compound loaded into the carrier, if compared to supramolecular aggregates incorporating the coordination compounds according to the present invention and non-covered with said hydrophilic and biocompatible coating.
  • the application of the "effect stealth" to the coordination compounds according to the first and the second embodiment of the present invention may also limit or eliminate any problem at the physiological level, such as hemolysis or immunogenicity of the active compound.
  • the hydrophilic coating of nanocarrier obtained with polymers such as PEG reduces the self- aggregation of the particles by means of steric stabilization, thus resulting in an immediate impact on the freshly-prepared formulation for the administration at the hospital level and storage.
  • the surface of the nanocarrier can be coated, by adsorption or conjugation, with human serum albumin (HSA) in order to conveniently increase the stability, the circulation times, and the biocompatibility of the formulation.
  • HSA human serum albumin
  • the whole supramolecular aggregate reduces the off-target release of the drug by the so-called EPR effect (Enhanced Permeability and Retention).
  • EPR effect is based on the anomalous and high permeability of blood vessels in the tumor region, characterized by not-adherent endothelial cell-to-cell junctions, if compared to normal tissue capillaries.
  • Appropriate nanocarrier sizes ranging from 20 to 100 nm (as reported in the examples of this invention), result in a prolonged circulation of the supramolecular systems in the blood stream, and the consequent selective extravasation into tumor tissues, resulting in a passive targeted therapy, which positively influences the toxicological profile.
  • the lack of lymphatic drainage of cancerous compartments promotes the selective accumulation of the nanocarriers in the tumor microenvironment.
  • the functionalization of the nanocarriers with cancer-targeting moieties can also restrict the onset of side effects, thereby improving the chemotherapeutic index in terms of toxicity/activity ratio (active targeting).
  • nanocarriers are functionalized with carbohydrates as cancer-targeting moieties
  • these supramolecular or macromolecular systems give the possibility to increase the water-solubility and the stability of the encapsulated compound(s) as well as to improve the bioavailability, and to extend and facilitate the selective release towards cancer cells.
  • the first cancer-targeting strategy, associated with the third embodiment, is related to the passive targeting mediated by EPR effect described above.
  • the second strategy, presented in the fourth embodiment takes into account the active targeting via glycoconjugation of the supramolecular nanosystem, thus providing an additional way to achieve a high therapeutic selectivity.
  • the encapsulation allows the loaded compounds to increase their blood circulation times, as well as to improve the chemotherapeutic index of the active compound (ratio between the lethal dose LD 50 and the effective dose ED 50 ), in other words their pharmacokinetic and pharmacodynamic profiles.
  • n-octanol/water P
  • P partition coefficient
  • logP logarithmic form
  • the coordination compounds having a general Formula l(a) and/or Formula l(b) are encapsulated in supramolecular aggregates, in particular micelles, to achieve a passive targeting mechanism mediated by the EPR effect.
  • Said encapsulated compounds may be those of the second embodiment, and hence conjugated to carbohydrates, or without a cancer-targeting moiety (first embodiment).
  • the ideal size of supramolecular systems ranges from 10 nm to 100 nm.
  • a fast drainage from the injection site and an effective distribution in vivo are obtained with particles characterized by a hydrodynamic diameter (DH) ranging from 10 to 70 nm.
  • DH hydrodynamic diameter
  • the nanocarriers with DH ⁇ 100 nm at the cellular level can be absorbed by an endocytic process.
  • the size of the aggregates can significantly affect the circulation times and the bioavailability of the encapsulated compound.
  • n- octanol/water (P) expressed in its logarithmic form, logP
  • logP logarithmic form
  • this procedure is fundamental for the choice of the most suitable supramolecular system for a specific type of compound and/or application.
  • concentration of the compounds in the two immiscible phases has been determined in n-octanol before and after mixing with a defined volume of water.
  • n-octanol was pre-saturated with deionized water for 24 hours under stirring, then let to equilibrate for 6 h at 25 °C.
  • a procedure for the loading of some compounds according to the invention having logP ⁇ 0 (Examples 13 and 1 1 ) in nanolipidic systems, namely in vesicles also known as liposomes, is described below.
  • the liposomes were prepared by dissolving DPPC (4 mg) and the compounds of Examples 1 1 and 1 3 (0.4 mg) in chloroform. The solvent was slowly evaporated by nitrogen stream, thus obtaining thin homogeneous DPPC / [Au(ProOtBuDTC) 2 ]Br and DPPC / [Au(PipeDTC) 2 ]CI films, which were further dried under reduced pressure. The subsequent hydration took place at temperatures above the critical temperature of the phospholipids (about 50 °C) by adding 1 mL of saline solution (NaCl aq 0.9% w/v).
  • the obtained suspension was then stirred for 30 min and then subjected to 5 fast freezing/thawing cycles in liquid nitrogen and water bath at 37 °C to obtain large polydispersed unilamellar vesicles.
  • the latter were then subjected to an extrusion process through a porous polycarbonate membrane having an average pore diameter of 1 00 nm, in order to isolate, advantageously, small unilamellar vesicles.
  • the liposomes thus obtained were subjected to a dialysis process for two hours against saline to eliminate traces of non-encapsulated coordination compound and free phospholipid. Finally, after extrusion the systems were analyzed using Dynamic Light Scattering (DLS) to evaluate their hydrodynamic diameter.
  • DLS Dynamic Light Scattering
  • a first procedure involves: the dissolution of the biocompatible polymer or more than one in an organic solvent such as chloroform; removal of solvent; hydration of the lipid film with an aqueous solution and treatment of the suspension obtained by sonication; extrusion through membranes having a certain cut-off; dialysis against aqueous solution such as saline or phosphate buffer; incubation of the compound with the solution in a T> T c water bath under continuous stirring for at least 20 minutes; lyophilization (in the presence of cryoprotector); hydration and extrusion.
  • the cryoprotector may be, for example, mannitol or lactose or sucrose or trealose or glucose or maltose, ethanol or a combination thereof.
  • a second process involves: dissolution of the biocompatible polymer in water or glycerol/ethanol mixture or alternatively the dissolution of several polymers in an organic solvent such as chloroform, followed by removal of the solvent; addition of the aqueous solution of the compound; agitation of the obtained mixture and multiple freeze/thaw cycles in liquid nitrogen and water bath at 37 °C; extrusion.
  • a third process involves the dissolution of the biocompatible polymer (or biocompatible polymers) in organic solvent, for example chloroform; the addition of the aqueous solution of the compound, forming an emulsion; agitation of the obtained mixture and evaporation of the solvent medium; the addition of a buffer and purification via extrusion.
  • organic solvent for example chloroform
  • the encapsulation of the complexes having Formula l(a) and/or Formula l(b) in PF127 micelles was obtained via a process comprising the following steps, described herein as non- limitative examples of the present invention: 1 ) Co-dissolution of the compound to be loaded and the polymer in the desired stoichiometric ratio (e.g., 0.5 mg and 500 mg, respectively) in an organic solvent, preferably chloroform; 2) Evaporation of the organic solvent, preferably under reduced pressure, followed by drying of the obtained powder, preferably under vacuum; 3) Hydration of the powder by addition of deionized water; 4) in order to remove the non- encapsulated compound, bacteria and other impurities, purification for instance by filtration with a membrane with a 0.20 ⁇ cut-off; 5) Freezing of the sample in a dry ice/acetone cooling bath at -78 °C and cryoesiccation to remove the residues of the aqueous solvent, thus obtaining a stor
  • the amount of the encapsulated coordination compound was assessed by UV-Vis analysis, after dilution in DCM of a defined amount of lyophilized micellar formulation.
  • concentration of the compound was defined using the Lambert- Beer law, after experimental determination of the molar extinction coefficient ⁇ in DCM (based on the "matrix effect", in the presence of the same polymer used for the preparation of micelles) for some absorption bands. The obtained results are reported in the following Table.
  • the encapsulation in micelles of the metal-based compounds according to the present invention increases their stability in physiological media and make them water-soluble for at least 72 hours.
  • the collected electronic spectra surprisingly show no significant change over time for the considered formulations (if compared to the not encapsulated compound) once dissolved in a physiological environment consisting of phosphate buffer/cell culture medium 9: 1 v/v, and phosphate buffer/human serum 95: 5 v/v.
  • compositions comprising the coordination compounds according to the present invention, characterized by a complete solubility and stability in physiological media compared to the corresponding non-encapsulated compounds, thus reaching a further goal of the present invention.
  • micellar systems with hydrodynamic diameters of about 25 nm are particularly advantageous pharmaceutical applications, in particular in the oncological field for the intravenous administration, thus exploiting to the best the EPR effect.
  • PF127 does not limit the scope of the present invention, since other polymeric substrates can be conveniently used.
  • a procedure for loading cyclodextrins with a Cu(ll) coordination compound having logP > 0 is described below.
  • the present inventors hereby provide, for example, a 2-hydroxypropyl ⁇ -cyclodextrin ( ⁇ - ⁇ -CD) formulation, a cyclic oligomer consisting of seven a-(1 ,4)-D-(+)-glucopyranoside units with a degree of molar substitution for hydroxypropyl groups of 0.8.
  • the ⁇ - ⁇ -CD cyclodextrins are a nanocarrier with high biocompatibility and biodegradability and are already used in clinics in formulations administered parenterally.
  • the samples are prepared by dissolving the cyclodextrin and the coordination compound [Cu(PipeDTC) 2 ] (1 :1 molar ratio) in DMSO and keeping the system under stirring for 15 hours. The organic solvent is then removed under reduced pressure conditions and the residue dissolved in water, centrifuged and the filtered liquid phase (0.22 ⁇ filter) is lyophilized to obtain a ready-to-use formulation.
  • the UV-Vis curves collected over time do not show significant spectral variations, demonstrating the high stability of the formulations herein presented.
  • the supramolecular system here presented represents an effective carrier for pharmaceutical applications since the corresponding K B compound/cyclodextrin was approximately 558 M ⁇ 1 .
  • the present inventors have surprisingly demonstrated the ability to encapsulate the coordination compounds of general formula l(a) and l(b) in macromolecules or in a supramolecular system, overcoming evident limitations in the state of the art in a non-trivial way. In fact, the encapsulation techniques of metal-based compounds are still at the forefront, due to the intrinsic reactivity of inorganic molecules.
  • the encapsulation allows said compounds to be protected from biotransformation and to avoid interactions/reactions with biomolecules or cells present in the blood stream.
  • the encapsulation allows to increase the stability as well as the solubility of the hydrophobic compounds in the physiological media as demonstrated by the data herein presented.
  • the coordination compounds described above, having general Formula l(a) and l(b), are advantageously encapsulated in supramolecular aggregates and functionalized with carbohydrates. Therefore, they are directed to the tumor site according to an active-targeting approach which is paralleled with (hence boosting it) the mechanism of passive targeting of the previous embodiment
  • the whole supramolecular aggregate acts as a cancer-targeting carrier, conveniently exploiting the Warburg effect, to further improve the therapeutic selectivity.
  • the inventors aim to implement a mechanism wherein a coordination compound according to the invention is absorbed by the cell by endocytosis along with the whole supramolecular aggregate; alternatively, said compound can be released from the nanocarrier in the extracellular matrix, and consequently diffusing inside the cell if hydrophobic enough, or entering the cell through alternative mechanisms of uptake, or also triggering its antitumor activity at the cell membrane level.
  • compounds of the first embodiment which by their chemical nature inherently exhibit affinity for the cell membrane, or compounds of the second embodiment that can exploit the presence of a cancer-targeting moiety T in the selective recognition by carbohydrate transporters (e.g., GLUT1 ), are advantageously used, alternately or in combination between them.
  • supramolecular aggregates with a variable degree of functionalization, for example ranging from 1 to 50%.
  • convenient supramolecular aggregates can be micelles, vesicles (liposomes), cyclodextrins, dendrimers, organic polymeric nanoparticles, for instance of protein or peptide nature, and inorganic nanoparticles ⁇ e.g., silica, zirconia, titania).
  • Carbohydrates can be monosaccharides, polysaccharides, pentoses, hexoses, aldoses, ketoses.
  • Such supramolecular aggregates may have a mixed structure, for example being made up of pullulan and PF127, or PLA and PEG.
  • the biopolymer so functionalized with a carbohydrate after dilution with a non-functionalized biopolymer (equal or different), is used to form a supramolecular aggregate with a degree of functionalization, ranging from 1 % to 50% mol/mol.
  • a degree of functionalization ranging from 1 % to 50% mol/mol.
  • the functionalization degree was equal to 100%, considering the integration values of NMR signals corresponding to the aromatic protons of the tosylate and the methyl protons of the terminal methoxy group of mPEG5000 polymer.
  • IR: v (cm 1 ) 2885, 1467, 1344, 1 1 13, 1060, 842, 664.
  • the polymer mPEG5000-Ts was refluxed in dry DMF for 5 hours in presence of 20 eq. of phthalimide potassium salt (Phta K). Successively, after filtration of byproducts and precipitation with diethyl ether, a light yellow solid was isolated.
  • the functionalization degree was equal to 100%, in light of the integration values of the NMR signals corresponding to the aromatic protons of the phthalimide and methyl protons of the terminal methoxy group of mPEG5000 polymer.
  • IR: v (cm 1 ) 2885, 1716, 1467, 1344, 1 1 14, 1060, 842, 724, 690.
  • This reaction allows the conversion of the terminal hydroxyl group to a carbonate which is very reactive towards nucleophiles due to the presence of a succinimido leaving group.
  • the reaction was performed in a Schlenk line. Briefly, mPEG5000 was dissolved in dry 1 ,4-dioxane and was added to a mixture of DMAP (6 eq) and ⁇ /, ⁇ /'-disuccinimmidil carbonate (DSC) in dry acetone. After 6 hours, the by-products were filtered and the solution volume was reduced to precipitate a white solid after the addition of diethyl ether.
  • the functionalization degree is 100%, considering the integration values of NMR signals corresponding to the methylene protons of the succinimido group and the methyl protons of the terminal methoxy group of mPEG5000 polymer.
  • the bio-conjugated mPEG5000-GluOAc was obtained via nucleophilic attack of the terminal hydroxyl group of the polymer to the anomeric C1 carbon of 1 ,2,3,4,6-penta-0-acetyl ⁇ - glucopyranose in the presence of BF 3 Et 2 0.
  • 3 eq. of BF 3 Et 2 0 were added to a mixture of mPEG5000 and 1 ,2,3,4,6-penta-0-acetyl ⁇ -D-glucopyranose (3 eq.) in dry CH 2 CI 2 dry at 0 °C, and the mixture was stirred for 48 hours.
  • the functionalization degree was equal to 20%, based on the integration values of NMR signals corresponding to the methyl protons of the acetate and the methyl protons of terminal methoxy group of mPEG5000 polymer.
  • IR: v (cm 1 ) 2887, 1759, 1467, 1344, 1 1 1 1 , 1060, 842.
  • the polymer mPEG5000 functionalized with ⁇ -D-glucopyranose was obtained from the product of the previous step (mPEG5000-GluOAc) via deprotection of the acetyl groups under basic conditions (NaOMe in dry methanol) under stirring for 15 hours. Then, the reaction mixture was neutralized with an acid resin (e.g., Amberlite ® H+ form) for one hour under stirring. After the filtration of the resin, the product was precipitated with diethyl ether and dried under vacuum.
  • IR: v (cm 1 ) 3453, 2886, 1759, 1467, 1344, 1 1 12, 1060, 842.
  • the obtained polymer results 20% functionalized as O-glycoside (in C1 position), and can be used as such to encapsulate the coordination compounds, thus forming micelles or aggregates.
  • it may be used in diluted form in combination with other biocompatible polymers to obtain cancer-targeting nanoformulations such as, without loss of generality: mixed micelles, liposomes, HSA nanoparticles.
  • the latter covered with a carbohydrate-functionalized mPEG, exhibit a "stealth effect", which is known to be associated with a decreased opsonization.
  • the degree of oxidation to aldehyde (evaluated via 1 H-NMR in CD 2 CI 2 ) was equal to 80%, considering the integration values of NMR signals corresponding to the aldehyde proton and the methyl protons of the central PPO unit of the PF127 polymer.
  • IR: v (cm 1 ) 2884, 1630, 1467, 1344, 1 1 15, 1061 , 842.
  • PF127-GlnOAc has been obtained by reductive amination between the PF127-CHO derivative described above and 1 ,3,4,6-tetra-0-acetyl-2-amino-2-deoxy ⁇ -D-glucopyranose HCI.
  • the first step involves the nucleophilic attack of the glucosamine, reaction carried out in acetonitrile for 2 hours at room temperature. Subsequently, the reduction of the imine to amine was obtained by the addition of sodium cyanoborohydride.
  • the reaction occurs in acetonitrile for 30 minutes at room temperature with a total stoichiometric ratio 1 :1 :3 between PF127-CHO, glucosamine- HCI and NaCNBH 3 , respectively. Subsequently the solvent was removed under reduced pressure and the residue is taken up in DCM, washed in a separatory funnel with "brine". The organic phase is anhydrified and the product precipitated with diethyl ether.
  • the degree of functionalization (assessed via 1 H-NMR in CD 2 CI 2 ) was equal to 44%, considering the integration values of NMR signals corresponding to the acetate protons of glucosamine and the methyl protons of the central PPO unit of the PF127 polymer.
  • the polymer PF127 functionalized with 2-amino-2-deoxy-D-glucose (glucosamine) was obtained from the PF127-GlnOAc of the previous step by deprotection of the acetyl groups under basic conditions (NaMeO in dry methanol) under stirring for 15 h. Subsequently, the mixture was treated with an acid resin (e.g., Amberlite ® H+ form) for one hour under stirring. After filtration, the product was precipitated with diethyl ether and dried under vacuum.
  • an acid resin e.g., Amberlite ® H+ form
  • IR: v (cm 1 ) 3432, 2885, 1467, 1344, 1 1 12, 1060, 842.
  • the obtained polymer results 44% functionalized with glucosamine in C2 position and can be used as such to encapsulate the coordination compounds, forming micelles. Alternatively, it may be used in combination with other biocompatible polymers to obtain cancer-targeting nanoformulations.
  • mixed micelles or supramolecular aggregates can be prepared starting from this derivative, after "dilution" with non-functionalized PF127, or another biocompatible polymer, in order to obtain different degrees of functionalization of the supramolecular aggregate, preferably in the range 2 ⁇ 18%.
  • the purification is often troublesome due to the high chemical similarity between the polymeric reagents and their products, characterized by minimal changes (in terms of molecular weight and introduced functional groups) in the molecular structure.
  • the functionalization/bio-conjugation yields are often low ( ⁇ 50%), and the assessment of the degree of functionalization of the products results difficult because of the abovementioned purification problems and the instrument sensitivity.
  • the coordination compounds according to the first and second embodiment of the present invention possess a remarkable anticancer activity.
  • said compounds loaded into aggregates, according to the third and fourth embodiment maintain such antitumor capacity, thus achieving a further advantageous object of the present invention.
  • the encapsulation does not alter the anticancer properties of said compounds, independently on the functionalization of the aggregate itself.
  • these supramolecular aggregates play only the role of nanocarriers, in particular increasing the stability and solubility of said compounds in aqueous medium, and anyway allowing the release of the active compound within the cancer cell or in the extra-cellular matrix, or in general, in the bloodstream.
  • the previously presented in vitro results concerning the antitumor activity of the coordination compounds can be extended also to the described formulations, with reference to the third and fourth embodiments.
  • the antitumor activity of IC50 micelles loaded with Cu complexes is presented in the following table.
  • the coordination compounds, the compositions, and the pharmaceutical formulations according to the present invention can be used as "theranostic agents". Therefore not only for the treatment of human or animal diseases, in particular neoplastic diseases, but also for the diagnosis and the patient follow-up.
  • such mechanism that combines therapy and diagnosis can be achieved in many ways, properly including one or more contrast agents in a coordination compound, or in a composition comprising at least one of said coordination compound, or also in a pharmaceutical formulation that includes said compound and/or composition.
  • the contrast agent can be "intrinsic" to the compound, for example when the metal center M is a radionuclide, such as 64 Cu o 198 Au, previously introduced.
  • the donor atoms X o Y present in Formulae l(a) o l(b) may possess radioactive properties ⁇ e.g., 131 1, 127 l, 129 l), as well as T can be 2-deoxy-2-[ 18 F]-fluoroglucose.
  • the coordination compound, the unit A, the carbohydrate or glucide T and/or T is paramagnetic or diamagnetic.
  • the contrast agent can be "exogenous" to the compound, and may be included in the composition that comprises at least one coordination compound according to the present invention, or also in a pharmaceutical formulation, that includes said compound and/or composition.
  • this category comprises a carrier that encapsulates said compound, such as a up-converting bismuth oxide nanoparticle (e.g. Italian patent 0001419393, in the name of BEP Sri et al.).
  • the contrast agent is a dual-mode contrast agent that take advantage of the X-ray absorption and the optical emission (through a NIR->NIR or NIR->VIS mechanism) exhibited by the doped bismuth oxide nanoparticles.
  • the "exogenous" contrast agent may also be a component of the pharmaceutical formulation, for example, a known contrast agent.
  • a “combined” contrast agent can be used and obtained mixing one or more "intrinsic" contrast agents with “exogenous” contrast agents.
  • radionuclides such as 131 1, 127 l, 129 l may be previously introduced as donor atoms X or Y in the Formula l(a) and/or l(b); the coordination compound can be linked to a carrier consisting of a photoactivatable nanoparticle, such as a properly doped bismuth oxide nanoparticle.
  • Contrast agents capable of spontaneously emit a detectable signal are, for example, radionuclides such as 11 C, 18 F, 64 Cu and 198 Au (in this case the signal is a radiation and/or a particle), or radiopaque materials (the signal here is related to the X-ray absorption spectrum).
  • Other contrast agents emit a signal which is detectable after an external stimulus, which is typically the irradiation with particles and suitable electromagnetic radiations (based on the needs).
  • this category comprises: luminescent photoactivable contrast agents, such as nanoparticles, dye-molecules or luminophores, capable of emitting IR-VIS radiation as a result of laser irradiation with a suitable wavelength; contrast agents capable of emitting a detectable signal due to the presence of dipoles or magnetic domains within their structure, which interact with an appropriate electromagnetic field; it is also possible to generate radionuclides inside of the compound and/or the composition according to the invention, treating them with particles and electromagnetic radiations with the suitable energy, using known techniques.
  • luminescent photoactivable contrast agents such as nanoparticles, dye-molecules or luminophores, capable of emitting IR-VIS radiation as a result of laser irradiation with a suitable wavelength
  • contrast agents capable of emitting a detectable signal due to the presence of dipoles or magnetic domains within their structure, which interact with an appropriate electromagnetic field
  • theranostic applications of the coordination compounds having general Formula I (a) and/or l(b) are very promising in view of the high selectivity and bioavailability, being as above presented, related to the presence of the carbohydrate or glucide T and/or T', that acts as cancer-targeting moieties able to implement a passive and active targeting-mechanism towards the tumor cells.
  • Pluronic® is a trademark of BASF AG
  • Cremophor ® is a trademark of BASF AG
  • CD-1 ® is a trademark of di Charles River Laboratories, Inc. Corp.
  • Eurospital ® is a trademark of Eurospital Spa
  • Lipoxal ® is a trademark of Regulon A.E;
  • Amberlite ® is a trademark of Santa Cruz Biotechnology Inc.

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Abstract

La présente invention concerne des composés de coordination mononucléaires d'Au et de Cu, des formulations pharmaceutiques à base de ceux-ci, le procédé relatif de synthèse et d'encapsulation des composés dans des macromolécules, des agrégats supramoléculaires ou des nanostructures, ainsi que leur utilisation pour le diagnostic et/ou le traitement de la néoplasie. De manière avantageuse, de tels composés et/ou formulations de coordination peuvent contenir des glucides qui agissent en tant que "fractions ciblant le cancer", ce qui permet d'augmenter la sélectivité thérapeutique. Lesdits composés et formulations sont caractérisés par un profil toxicologique prometteur, une activité anticancéreuse remarquable et hautement sélective, ainsi qu'une stabilité et une solubilité dans des milieux physiologiques.
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CN111384273A (zh) * 2018-12-29 2020-07-07 Tcl集团股份有限公司 一种量子点发光二极管及其制备方法
CN114702515A (zh) * 2022-04-18 2022-07-05 中山大学 一种金(iii)配合物及其在癌症光治疗中的应用
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US11542299B2 (en) 2017-06-09 2023-01-03 Chugai Seiyaku Kabushiki Kaisha Method for synthesizing peptide containing N-substituted amino acid
US11891457B2 (en) 2011-12-28 2024-02-06 Chugai Seiyaku Kabushiki Kaisha Peptide-compound cyclization method

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US11787836B2 (en) 2017-06-09 2023-10-17 Chugai Seiyaku Kabushiki Kaisha Method for synthesizing peptide containing N-substituted amino acid
US11542299B2 (en) 2017-06-09 2023-01-03 Chugai Seiyaku Kabushiki Kaisha Method for synthesizing peptide containing N-substituted amino acid
US11492369B2 (en) 2017-12-15 2022-11-08 Chugai Seiyaku Kabushiki Kaisha Method for producing peptide, and method for processing bases
US11957757B2 (en) 2017-12-18 2024-04-16 Auburn University Method for preparing stabilized metal ion ligand nanocomplex and compositions thereof
WO2019126054A1 (fr) * 2017-12-18 2019-06-27 Auburn University Procédé de préparation de nanocomplexe d'ion métal-ligand stabilisé et compositions associées
US11045553B2 (en) 2017-12-18 2021-06-29 Auburn University Method for preparing stabilized metal ion ligand nanocomplex and compositions thereof
WO2020111238A1 (fr) * 2018-11-30 2020-06-04 中外製薬株式会社 Procédé de déprotection et procédé d'élimination de résine dans une réaction en phase solide d'un composé peptidique ou d'un composé amide, et procédé de production d'un composé peptidique
US11732002B2 (en) 2018-11-30 2023-08-22 Chugai Seiyaku Kabushiki Kaisha Deprotection method and resin removal method in solid-phase reaction for peptide compound or amide compound, and method for producing peptide compound
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