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WO2013057186A1 - Coupleur photolabile pour la synthèse d'acides hydroxamiques - Google Patents

Coupleur photolabile pour la synthèse d'acides hydroxamiques Download PDF

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Publication number
WO2013057186A1
WO2013057186A1 PCT/EP2012/070648 EP2012070648W WO2013057186A1 WO 2013057186 A1 WO2013057186 A1 WO 2013057186A1 EP 2012070648 W EP2012070648 W EP 2012070648W WO 2013057186 A1 WO2013057186 A1 WO 2013057186A1
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Prior art keywords
solid support
linker
compound
functionalized
library
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PCT/EP2012/070648
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English (en)
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Thomas E. NIELSEN
Katrine Qvortrup
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Danmarks Tekniske Universitet
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Publication of WO2013057186A1 publication Critical patent/WO2013057186A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/60—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups having oxygen atoms of carbamate groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B80/00—Linkers or spacers specially adapted for combinatorial chemistry or libraries, e.g. traceless linkers or safety-catch linkers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/24—Anthracenes; Hydrogenated anthracenes

Definitions

  • the present invention relates to a photolabile hydroxamate linker based on the o- nitroveratryl group and its application for multistep solid-phase synthesis and controlled photolytic release of hydroxamic acids.
  • Solid phase synthesis Solid-phase organic synthesis originally developed by Merrifield for peptide synthesis, J . Am. Chem . Soc. 1963, 85, 2149-2154, has become an attractive synthetic technique that offers unique advantages over conventional solution phase chemistry, both in terms of purification and simplicity. Solid-phase synthesis may also be used for the preparation of non-peptide molecules. Both in academia and industry, there has been considerable interest in the solid-phase synthesis of combinatorial libraries for the identification of biologically active compounds in early drug discovery efforts (Moos et. al ., Annu . Rep. Med . Chem . 1993, 28, 315-324).
  • Hydroxamic acid derivatives represent an increasingly important class of biologically active compounds with a wide spectrum of antibacterial, antifungal, and anticancer properties.
  • the hydroxamic acid moiety is present in numerous biologically active molecules of both natural and unnatural origin (Minucci et. al., Nature Reviews 2006, 6, 38-51). In addition, they are versatile intermediates that can be
  • Hydroxamic acids are strong metal ion chelators and are known to inhibit enzymes having metal ions in their active sites. In particular, they have been identified as potent inhibitors of matrix metalloproteinases (MMPs), a family of zinc-dependent endoproteinases involved in both normal and diseased tissue remodeling, and as effective histone deacetylases (HDACs) inhibitors.
  • MMPs matrix metalloproteinases
  • HDACs histone deacetylases
  • HDACs have been linked to gene silencing causing repression of anti-cancer genes.
  • SAHA is one example of a small molecule hydroxamic acid having anti-cancer activity. It was recently approved for treatment of cutaneous T cell lymphoma.
  • hydroxamic acids may be obtained by direct cleavage of resin-bound esters with hydroxylamine (Dankwardt, Synlett 1998, 761; Thouin and Lubell, Tetrahedron Lett. 2000, 41, 457-460; Ho et al., J . Org. Chem . 2005, 70, 4873-4875; Dankwardt et al ., Bioorg. Med . Chem . Lett.
  • Photolysis offers a method for cleavage which is fully orthogonal to chemical methods (James, Tetrahedron 1999, 55, 4855-4946). Furthermore, photolytic cleavage offers exceedingly mild conditions, which are attractive for direct applications in biological screening where contamination with cleavage reagents is undesired .
  • R is hydrogen for use in solid-phase synthesis of carboxylic acids.
  • R is hydrogen or ethyl for use in solid-phase synthesis of 4- substituted NH-l,2,3-triazoles.
  • WO 96/00378 discloses photolabile linkers for use in solid-phase synthesis, for example in the synthesis of small molecule and peptide libraries.
  • the photolabile linking group is represented by the formula :
  • WO 96/262323 discloses linkers carrying a hydroxylamine or protected hydroxylamine group for use in solid-phase synthesis, where the linkers are chemically or photolytically cleavable.
  • Example 5 discloses a photolabile linker on a solid support:
  • WO 96/262323 does not disclose a photolabile linker according to the present invention for the synthesis and release of a class of hydroxamic acids, which linker provides a simple and very efficient tool for attachment to any suitable solid support without the need for solid-phase hydroxylamination reaction steps to functionalize the linker.
  • the present invention relates to a photolabile linker based on the o-nitroveratryl group which linker is capable of releasing hydroxamic acids upon UV irradiation from a solid support.
  • the linker unit can be applied in a multi- detachable fashion. By simply varying the solvent, photolysis can be controlled to mediate either C-0 or C-N bond cleavage, and thereby allow the controlled release of either hydroxamic acid or carboxamide derivatives, respectively. This strategy may introduce further diversity into target molecules and compound libraries.
  • the linker further provides a possibility of screening released hydroxamic acid derivatives in situ, i.e. testing the released derivatives when still present in a solid support, such as beads.
  • Figure 1 Experimental setup used in photolysis reactions.
  • Figure 2 UV spectra for photolabile construct 15 in different solvents (0.05 mM)
  • Figure 3 Product formation resulting from photolysis of 15 at 360 nm under variation of solvent.
  • Figure 4 Illustration of the "split-and-mix” synthesis.
  • Figure 5 Illustration of the "in-bead” screening technology HDAC used in a screen of putatively active HDAC inhibitors.
  • Figure 6 Illustration of a post-screening structure determination strategy.
  • FIG. 7 SAHA-containing beads (25c) showing HDAC-inhibitory activity when subjected to the "in-bead" HDAC-inhibition assay.
  • the photolysis step was omitted no SAHA was released and no quenching of HDAC-activity was observed.
  • Beads functionalized with a ligand devoid of HDAC-inhibitory activity (25d) resulted in no quenching of fluorescence following photolysis.
  • Figure 8 Representative microscopy images of small, bead-based library (25a-h) subjected to in-bead HDAC-inhibition assay with a photolysis time of 2 min.
  • Figure 9 Representative microscopy images of small, bead-based library (25a-h) subjected to in-bead HDAC-inhibition assay with a photolysis time of 0.5 min.
  • Figure 10 Microscopy pictures of SAHA-containing beads (25c) resulting from in- bead HDAC-inhibition assay with a photolysis times of 5 s, 1 min and 5 min, respectively.
  • Protective group refers to a chemical group that exhibits the following
  • Fmoc fluorenylmethyloxycarbonyl - removed by base, such as piperidine.
  • Boc t-butyloxycarbonyl - removed by acid, such as HCI and CF 3 COOH.
  • Trt trityl - removed by acid, such as HCI and CF 3 COOH
  • Cbz carbobenzyloxy - removed by hydrogenolysis.
  • Bn benzyl - removed by hydrogenolysis.
  • SiR 3 where R can be combinations of different groups.
  • Common silyl protective groups are trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert- butyldimethylsilyl (TBS/TBDMS) and triisopropylsilyl (TIPS), [2- (trimethylsilyl)ethoxy]methyl (SEM) - removed with acids or fluorides such as HF and tetra-r?-butylammonium fluoride. Larger R-substituents increase resistance to hydrolysis.
  • Rink-linker 2-(4-(amino(2,4-dimethoxyphenyl)methyl)phenoxy)acetic acid
  • PEGA polyethylene glycol dimethyl acrylamide.
  • TBTU 0-(benzotriazol-l-yl)-/V,/V,/V',/V'-tetramethyluronium tetrafluorobrate
  • HATU 0-(7-azabenzotriazol-l-yl)-/V,/V,/V',/V'-tetramethyluronium
  • Physicochemical or biological response Any property that is measurable whose value describes a chemical or biological systems state.
  • the changes in the physicochemical or biological responses of a system can be used to describe its transformations.
  • the measurable values may include, but are not limited to :
  • fluorescence turn on/off fluorescence
  • chemiluminescence absorbance
  • concentration electric properties
  • pH pH
  • Chemical or biological system an integrated structure of components and subsystems capable of performing, in aggregate, one or more specific functions ⁇
  • a chemical or biological system may include, but are not limited to : binding of a ligand for a receptor of interest (e.g . GPCR), inhibition of an enzyme (e.g . HDAC), disruption of a protein/protein interaction (e.g . DNA replication), catalysis of a chemical transformation, and the like.
  • Activating group refers to a group which, when attached to a particular functional group, renders that site more reactive toward covalent bond formation with a second functional group.
  • the group of activating groups which are useful for a carboxylic acid include simple ester groups, anhydrides, and acid chlorides.
  • the ester groups include alkyl, aryl and alkenyl esters and in particular esters of 4- nitrophenol, N-hydroxysuccinimide, N-hydroxybenzotriazole, and
  • Chemical group a chemical entity for example a building block in the synthesis which, prior to attachment, has one reactive functional group appropriate for attachment to a chemical group on the solid support, and one or more optionally protected functional group appropriate for later further functionalization, e.g.
  • Combinatorial chemistry Ordered strategy for the synthesis of diverse compounds by sequential addition of reagents, which leads to the generation of large chemical libraries.
  • combinatorial chemistry refers to the systematic and repetitive, covalent connection of a set of different 'chemical entities' of varying structures to each other to yield large arrays of diverse molecular entities.
  • Chemical library An intentionally created collection of differing molecules which can be prepared either synthetically or biosynthetically and screened in a chemical or biological system for a physicochemical or biological response, e.g. a biological activity.
  • the present invention concerns a compound with the general formula I :
  • Ri and R 2 are the same or different and represent hydrogen, Ci-Cs alkyl, aryl, heteroaryl, Ci-Cs carboxyalkyl, carboxyaryl or arylalkyl,
  • R 3 is hydrogen, Ci-Cs alkyl, phenyl or mono- or multiply-substituted phenyl, wherein the substitutions are the same or different and represent hydrogen, Ci- alkyl, Ci-Cs alkoxy, halogen, nitrile or nitro,
  • R 4 and R 5 are the same or different and represent hydrogen, Ci-Cs alkyl, Ci-Cs alkoxy, aryl, heteroaryl, halogen, nitrile or nitro,
  • R 6 and R 7 are the same or different and represent Ci-Cs alkyl, aryl, heteroaryl or - (CH 2 -CH 2 -0)- n , where n is a integer from 1 to 100, and R 8 is hydrogen, Ci-Cs alkyl or aryl, which compound finds use as a unique photolabile linker for the solid phase synthesis of hydroxamic acid derivatives.
  • Ri is an amino protecting group, such as Fmoc or Boc and R 2 is hydrogen.
  • Ci-Cs alkyl means a cyclic, branched, or straight chain chemical group containing 1-8 carbon atoms and containing only carbon and hydrogen. Examples are methyl, ethyl, propyl, iso-propyl, butyl and tert-butyl.
  • Ci-Cs alkoxy refers to the group alkyl-O, preferred examples are methoxy and ethoxy.
  • aryl means an aromatic carbocyclic group having a single ring (e.g . phenyl) or multiple condensed rings (e.g. naphthyl or anthracenyl), which can optionally be unsubstituted or substituted with amino, hydroxyl, Ci-C 8 alkyl, Ci-Cs alkoxy, aryloxy, halo, mercapto, and other substituents.
  • Preferred examples include phenyl, 1-naphthyl and 2-naphthyl.
  • heteroaryl means a monovalent unsaturated aromatic carbocyclic group having a single ring (e.g . pyridyl or furyl) or multiple condensed rings (e.g . indolizinyl or benzothienyl) and having at least one hetero atom, such as N, O or S, within the ring, which can optionally be unsubstituted or substituted with amino, hydroxyl, Ci- C 8 alkyl, alkoxy, halo, mercapto and other substituents, preferred examples are 2- pyridyl and 2-quinolinyl .
  • aryloxy means the group aryl-O, preferred examples are phenoxy and 2- naphthalenyloxy.
  • heteroaryloxy means the group heteroaryl-O, preferred examples are 2- pyridinyloxy and 2-quinolinyloxy.
  • Carboxy or “carboxyl” means the -R'(COOH) where R' is Ci-Cs alkyl, aryl, arylalkyl, heteroaryl .
  • Ci C 8 carboxyalkyl
  • R' is alkyl containing 1-8 carbon atoms.
  • carboxyaryl means the group -(CO)-R' where R' is aryl, heteroaryl, substituted aryl or substituted heteroaryl .
  • arylalkyl means the groups R'-aryl and R'-heteroaryl where R' is a cyclic, straight- chain or branched alkyl chain, examples are benzyl and furfuryl.
  • halogen means fluorine, chlorine, bromine or iodine.
  • the compounds according to the present invention may be prepared in many different ways following standard procedures in organic synthesis. The person skilled in the art would readily know how to synthesize compounds according to formula I.
  • preferred compounds of the present invention have the formula II :
  • Ri is a protecting group, such as Boc, Fmoc, Alloc, Cbz, Bn and R 8 is hydrogen or Ci-C 8 alkyl .
  • preferred compounds of the present invention have the formula III :
  • R 8 is hydrogen, methyl or ethyl .
  • one class of the compounds according to the present invention may be prepared starting from acetovanilone 1 from which ketone 2 can be prepared in a few high-yielding steps. Reduction of the ketone to the corresponding alcohol, followed by chlorination with thionylchloride in CH 2 CI 2 affords the key intermediate chloride 4.
  • Substitution of chloride can be effected by reaction with /V-hydroxyphthalimide to give 5.
  • Treatment of 5 with hydrazine removes the phthalimido group to give 6, which can then be protected with a protecting group Ri (e.g . Fmoc) to give the protected hydroxylamine-ester 7.
  • Ri e.g . Fmoc
  • Selective hydrolysis of the ester group R 8 may be accomplished by any suitable chemical or biological hydrolysis process, for example by use of an appropriate esterase, thus affording the Ri (e.g . Fmoc)-protected hydroxylamine-functionalized carboxylic acid linker 8.
  • Novozyme 435 is one example of a suitable esterase for a selective removal of the ester group R 8 .
  • the present invention concerns a method for producing a hydroxylamine-functionalized photolabile solid support comprising an attachment reaction and subsequent deprotection of the linker immobilized on a solid support.
  • Solid supports that can be functionalized with the linker may be of any shape or size, such as roughly spherical or a planer surface.
  • the solid supports need not necessarily be homogenous in size, shape or composition; although the solid supports usually and preferably will be uniform.
  • Solid supports may consist of many materials, limited primarily by capacity for derivatization to attach any of a number of chemically reactive groups and compatibility with the synthetic chemistry used for linker attachment and/or synthesis. Suitable solid support materials typically will be the type of material commonly used in peptide and polymer synthesis. They include polymeric organic substrates, for example polystyrene, polypropylene, polyethylene glycol,
  • the solid support is preferably composed by polymeric beads, limited primarily by capacity for swelling, light permeability and the capacity for derivatization to attach any of a number of chemically reactive groups as well as compatibility with the synthetic chemistry used for linker attachment and/or synthesis.
  • Suitable solid support materials typically will be the type of material commonly used in peptide and polymer synthesis.
  • resins, or other supports work well and are often preferable.
  • Particularly preferred materials include polystyrene, polypropylene, polyethylene glycol and polyacrylamide resins, e.g. TentaGel® or Chemmatrix®.
  • Immobilization The choice of functionality used for binding the linker to the solid support will depend on the type of solid support. Conditions for coupling monomers to solid supports through a wide variety of functional groups are known. For example, the carboxyl group of the linker can be activated by converting it to the corresponding -COP group wherein P is an activating group as defined above. This can then be coupled to an amino or hydroxyl group of the solid support.
  • the hydroxylamine-functionalized photolabile solid support has the following formula :
  • Ri is a protecting group, e.g. Alloc, Cbz, Bn, Boc or Fmoc
  • linker(s) represents a solid support, optionally including a spacer and/or functionalized with one or more secondary cleavable linkers.
  • additional linker(s) is/are either chemically or photolytically cleavable.
  • Two or more differently cleavable linkers may be used to release portions of the synthesized compounds in subsequent cleaving steps to allow testing in one or more chemical or biological systems for one or more physicochemical and/or biological responses followed by release of remaining compounds for identification of the compound(s) immobilized on positive solid support.
  • Such linker(s) used in addition to the linker of the present invention are known in the art and chosen either from a commercial source or synthesized for this particular purpose.
  • the hydroxylamine-functionalized photolabile solid support can be obtained by chemical coupling to immobilize the hydroxamic acid- releasing linker 8 to a suitable amino-functionalized solid support, such as a bead Said solid support may be amino-functionalized by way of a Rink linker and/or N- terminal peptide sequences, including bromo-substituted amino acid residues.
  • the Rink linker can be attached to the commercially available amino solid support (PEGA 80 o) in an 0-(benzotriazol- l-yl)-/V,/V,/V',/V'- tetramethyluroniumtetra-fluorobrate(TBTU)-mediated coupling, followed by Fmoc deprotection and coupling of linker 8, to afford the hydroxylamine-functionalized photolabile solid support 9.
  • PEGA 80 o commercially available amino solid support
  • Photolytic cleavage is carried out on the hydroxamate-functionalized photolabile solid support suspended in appropriate solvents by irradiation for an amount of time to allow the desired cleavage to take place.
  • illumination from 0 to 100 % of the photolabile bonds are cleaved.
  • the present invention may be desirable to release as much as possible in one step by choosing a sufficiently long time-length of illumination. A quality check of the synthesized compound may be incorporated by release of a small portion before release of the whole lot.
  • the present invention is used in synthesis and screening of a library, it is desirable to control the amount of cleavage taking place in each of two or more consecutive cleavage steps. If more tests on the same synthesized hydroxamic acid derivatives are desired, sequential release provides a good opportunity for such testing or screening.
  • the present invention provides a unique tool for such multiple
  • a first step less than 90% is released, for example 1-90%, 5-50% or 5-30% of the hydroxamic acid derivatives are released from the solid support, e.g. inside beads for use in screening the library for physiochemical or biological responses by adding a (first) chemical or biological system to the solid support (the beads).
  • Subsequent portions of the compounds in the library may be released in a second or further step for a second or further testing in a second or further chemical or biological system and finally for
  • Each piece of solid support e.g . bead may contain a sufficient amount of compounds for a post-screening hit
  • Photolytic release of compounds from active (positive) beads may for example also be used for a dose-response assay to validate the activity observed in a primary screening .
  • one or more additional linkers may be included in the hydroxylamine- functionalized photolabile solid support for additional chemical or photolytic cleavage.
  • additional linkers comprise base-labile, acid-labile, metal-labile, safety-catch and photolabile linkers, known to persons skilled in the art.
  • Other linkers may also be included in order to optimize and verify the attachment chemistry.
  • Such linkers such as for example the Rink linker, are known is the art.
  • spacers such as a 4-bromophenylalanine spacer may be positioned in connection with the linker.
  • spacers are known in the art.
  • the energy needed in the photolysis step to cleave the linker according to the present invention is provided by a 360 nm light source, for example a 400W LED UV-lamp.
  • Figure 1 illustrates an experimental setup used in photolysis reactions.
  • hydroxamate-functionalized photolabile solid support 9 For the release of synthesized compounds, e.g. from a library of functionalized small molecules, photolytic cleavage is carried out on a hydroxamate-functionalized photolabile solid support.
  • the hydroxamate-functionalized photolabile solid support 9 is suspended in appropriate solvents and cleaved by irradiating for a certain time at room
  • hydroxamic acid 11 and the carboxamide 12 result from C-0 and N-0 cleavage, respectively.
  • the hydroxamic acid is the predominant product.
  • the photolytic cleavage may result in a mixture of hydroxamic acid and
  • HFIP hexafluoroisopropanol
  • Apolar solvents favor formation of the carboxamide product 12. Inspection of the product pattern reveals that selectivity increases in the order mesitylene > xylene > toluene. Carrying out the reaction in mesitylene exclusively provides
  • the o-nitroveratryl derivative 15 was synthesized as a model compound for studying the photolysis in solution. In this way it was possible to identify the nature of by-products formed in the photolysis of a hydroxamate-functionalized o-nitroveratryl compound, illustrative of the compounds with general formula I, to gain a deeper mechanistic understanding . In this way, solution-phase photolysis experiments provide opportunities for studying the photolysis of hydroxamate-functionalized I compounds according to the present invention without the potential influence of swelling and solvation properties of the solid support.
  • the UV spectra of the model derivative 15 were measured in a broad range of polar and apolar solvents and in solutions with either high or low acidity (Figure 2). In all cases, the typical absorption of the nitro-veratryl moiety with its characteristic maxima around 350 nm was observed. The differences in absorbance and extinction coefficients at the photolysis wavelength of 360 nm are only minor, which indicates that the absorbance of the nitroveratryl moiety is not substantially influenced by the nature of the solvent. This indicates that it is not the primary photo-excitation of the nitro group which determines the product ratios but more probably the kinetics and equilibrium position of the presumed intermediate aci- nitro compounds.
  • the present invention concerns a method, a production platform for synthesizing a hydroxamic acid derivative comprising : a) coupling a compound/linker according to the present invention to a solid support, b) coupling a chemical group to the immobilized compound/linker, and c) releasing said hydroxamic acid derivative from said solid support by photolytic cleavage.
  • the coupling of a chemical group may involve one or more steps in a synthesis of the desired hydroxamic acid derivative, i.e. one or more building blocks in the form of chemical groups may be coupled together during the synthesis on the photolabile linker of the present invention which again is coupled to the solid support in the first step.
  • Multistep solid-phase peptide synthesis may in this way be carried out on the present photolabile linker, and the resulting peptide hydroxamic acid be released by photolysis.
  • multistep solid-phase oligonucleotide, oligosaccharide and other polymers may be synthesized by the present invention as derivatives and released by photolysis.
  • the product platform may be used to produce desired hydroxamic acid derivatives of small molecules.
  • Synthesis of a specific hydroxamic acid compound may follow is this way and provides for an easy and reproducible synthesis of a desired product in high purity under neutral reaction conditions.
  • the present invention further concerns a hydroxylamine-functionalized compound immobilized on solid support through a photolabile linker having the formula :
  • R is a chemical entity, i.e. the compound to be converted into a
  • hydroxamine acid derivative and O represents a solid support, optionally including a spacer and/or a second cleavable linker.
  • the hydroxylamine linker having the general formula I may serve as the starting point for the combinatorial synthesis of hydroxamic acid libraries.
  • hydroxylamine linker 8 was synthesized and employed for the parallel synthesis of a library of putative HDAC inhibitors (Table 3).
  • a Rink linker was positioned between the solid support and the photolabile linker unit to optimize and verify attachment chemistry of linker 8 on the solid support.
  • Orthogonal and quantitative cleavage of the acid-labile Rink linker indicates the ratio of hydroxamate to unconverted photolabile hydroxylamine-linker, thus providing a measure of the loading efficiency.
  • Photolytic cleavage was carried out on an amount of solid support suspended in appropriate solvent by irradiating for 0.5-3 h at room temperature with 360 nm light using a 400W LED UV-lamp.
  • Photolytic cleavage was carried out for 2 h with an LED UV-lamp 400W (360 nm). Cleavage of the Rink linker was carried out with TFA CH 2 CI 2 (1 :1) for 2 h. a Purities were determined by RP-HPLC (254 nm). b Isolated yields after photolysis in HFIP.
  • the present invention discloses a novel method for synthesizing a library of hydroxamic acid derivatives, comprising: a) coupling a compound/linker according to the present invention to a solid
  • step c) providing two or more different chemical groups and coupling them to the one or more chemical groups coupled to the solid support in step c), and e) repeating the coupling step as many times as desired/necessary to obtain the desired library.
  • the steps of coupling different groups on the solid support are performed in a way to obtain coupling of the different chemical groups in a combinatorial fashion.
  • OBOC one-bead-one- compound
  • the synthesis of one-bead-one- compound (OBOC) combinatorial libraries is useful for the discovery of bioactive compounds.
  • the method is particularly attractive since hundreds of thousands of chemical compounds can be generated via split-pool synthesis within a short time.
  • each compound is localized on an identifiable solid support such as an individual bead and therefore spatially addressable during hit identification. For example, to provide a mixture of a high number of different compounds in the library, the so-called "split-and-mix" synthesis may conveniently be used.
  • the "split-and-mix" synthesis is illustrated in Figure 4.
  • a large assembly of beads is suspended in a suitable solvent in a parent container.
  • the beads are provided with a photocleavable linker having a reactive site.
  • the reactive site is protected by an optional protecting group.
  • the beads are divided for coupling into separate containers.
  • the protecting groups are then removed and a first portion of the molecule to be synthesized is added to the various containers.
  • the number of containers will be limited to three and the chemical entities denoted as A, B, C, D, E, and F.
  • the protecting groups are then removed and a first portion of the molecule to be synthesized, i.e., the first chemical group, is added to each of the three containers (i.e., A is added to container 1, B is added to container 2 and C is added to container 3). Thereafter, the various beads are washed of excess reagents as appropriate, and remixed in a parent container. Again, it will be recognized that by virtue of the large number of beads utilized at the outset, there will similarly be a large number of beads randomly dispersed in the parent container, each functionalized with a particular first chemical group. Thereafter, the various beads are again divided for coupling in another group of three containers.
  • the beads in the first container are deprotected and exposed to a second chemical group (D), while the beads in the second and third containers are coupled to chemical groups E and F respectively. Accordingly, molecules AD, BD, and CD will be present in the first container, while AE, BE, and CE will be present in the second container, and molecules AF, BF, and CF will be present in the third container. Each bead, however, will only display a single compound structure. Thus, all of the possible compounds formed from the first portions A, B, C, and the second portions, D, E, F are formed . The beads are then recombined into one container and additional steps such as are conducted to complete the synthesis of the combinatorial library.
  • linker 8 While the linker 8 has been demonstrated to be stable towards both acidic and basic conditions, the utility of the linker for the synthesis of acid labile substrates has also been tested. Both hydroxamic acid-functionalized amino acid derivatives containing Fmoc- (20) and Boc- (21) protected a-amino groups and Trt-protected amide (20) and Pbf-protected guanidinium (21) side groups were successfully synthesized on the linker immobilized on a solid support and released,
  • linker 8 to generate a hydroxamic acid-functionalized Doxorubicin (Dox) derivative.
  • Dox is a highly potent anticancer agent. However, its application is limited by significant cardiotoxic side effects. Considerable work has therefore been undertaken to chemically modify Dox with the goal of reducing its systemic toxicity. Synthetic efforts in this context are hampered by the sensitivity of Dox to acidic and basic reaction conditions. Therefore, the efficient synthesis and release of a modified Dox derivative on the linker shows the potential of the linker for the generation of more elaborate structures in a combinatorial library format.
  • linker 8 for the generation of a hydroxamic acid-functionalized Dox derivative was demonstrated by treating a hydroxylamine-functionalized photolabile solid support in a standard solid-phase peptide synthesis (SPPS) with mono-tert- butyl malonate.
  • SPPS solid-phase peptide synthesis
  • the tert-butyl protecting group was removed with TFA/CH 2 CI 2 (1 : 1) and the carboxylic acid functionalized photolabile solid support was treated with Dox in a 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyl- uroniumhexafluorophosphate (HATU)-mediated coupling to give 23.
  • HATU 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyl- uroniumhexafluorophosphate
  • OBOC one-bead-one-compound
  • the novel "in-bead” screening is based on the observation that products covalently released from polymeric beads by photolysis remain inside the beads, when they are swelled in aqueous buffer. Such compounds readily leave the beads upon washing with organic solvents. A measure for this phenomenon is given by the partition coefficient between the aqueous buffer and the organic environment provided by the bead.
  • each bead comprises a spatially separated "micro-compartment” into which a compound can be released .
  • a further aspect of the present invention thus concerns a method for screening a library of hydroxamic acid derivatives for their physicochemical or biological response in a chemical or biological system, comprising : a) obtaining a library of immobilized hydroxamic acid derivatives according to the method of the present invention, b) releasing said hydroxamic acid derivatives by photolytic cleavage in an aqueous media, c) adding said chemical or biological system to said library in an aqueous solution, and d) detecting solid support, e.g. beads, showing a physiochemical or biological response, and e) identifying hydroxamic acid derivatives immobilized on solid support,, e.g .
  • Step b) may be performed before step c) or step c) may be performed before step b) in the method for screening a library of hydroxamic acid derivatives for their physicochemical or biological response in a chemical or biological system.
  • the screening method may include two or more rounds of releasing compounds and testing them in different assays, i.e. different chemical or biological systems, before the identification step.
  • the HDAC reaction was developed by the addition of a developer solution containing the known inhibitor TSA to simultaneously quench any further deacetylation reaction.
  • a blue coloration of beads upon inspection of the plates under a fluorescence microscope indicates that no inhibition of HDAC activity has taken place.
  • beads remaining colorless indicate that HDAC activity was inhibited by the compounds released inside these beads (see Figure 5 for a graphical illustration of the in-bead HDAC assay).
  • beads suspended in substrate solution were isolated and surrounding aqueous buffer-solution removed by a pipette.
  • the beads were washed twice with buffer followed by CH 3 CN.
  • HPLC- analysis of combined buffer- and CH 3 CN-wash, respectively, showed no substrate in the buffer-wash, while the CH 3 CN wash contained a mixture of light-released compound and substrate.
  • a 4- bromophenylalanine spacer was positioned between a Rink-linker functionalized solid support and the photolabile linker unit ( Figure 6). Orthogonal cleavage of the acid-labile Rink linker (see Figure 6) provides a cleavage product with sufficient mass to be out of range of low-mass noise and matrix ions typically seen in the MALDI-TOF MS analysis.
  • the 4-bromophenylalanine spacer generates mass peaks with a characteristic bromine isotope pattern, so that the relevant peaks of the library products are readily identified by the presence of two peaks of equal intensity [M + Na] + (for the 79 Br-capped fragments) and [M + 2+Na] + (for the corresponding 81 Br-capped fragments).
  • beads functionalized with SAHA 25c
  • SAHA an approved drug and known inhibitor of histone deacetylases
  • the colourless beads isolated from the assay were washed with aqueous buffer and CH 3 CN to remove assay components before manually transferring one bead to a MALDI target.
  • the active bead was swollen in TFA/CH 2 CI 2 on the MALDI target and left to react before being subjected to MALDI-TOF MS analysis, which showed the expected mass of the H 2 N-(4Br)Phe-PLL-SAHA-fragment.
  • each bead (60-180pmol per PEGA bead) contains a sufficient amount of compound for more than one assay, a two-tiered release strategy may be incorporated. After identifying and isolating active beads in a primary screening assay, a second photolytic release of compounds from active beads for a dose- response assay may verify the activity observed in the primary screening, or indicate another biological activity. Furthermore each bead contains sufficient amount of compound for a post-screening hit identification.
  • the "in-bead" screening technology provides a rapid, convenient, and efficient primary screening tool for bead-based combinatorial libraries. Regarding the ease of this method as a primary screening tool, the approach is relatively rapid in that a library can be screened in less than 1 h.
  • Another significant advantage of this method is the low cost of the screening format in that it does not rely on costly robotics or automation instruments and only uses small amounts of biological and chemical reagents.
  • the screening results of the HDAC inhibitor library show that this screening method is capable of providing and identifying high-affinity inhibitors from combinatorial bead-based libraries. Rapid and unambiguous sequencing of selected beads by MALDI-TOF MS may be facilitated by a combined acid- and photolabile cleavage construct.
  • the described "in-bead" technology is a generally applicable method for evaluating other biological targets by adaptation to many other chemical or biological assay systems.
  • ketoester lb (10.0 g, 35.7 mmol) in 30 mL acetic anhydride was slowly added to a solution of 70% HN0 3 (200 mL) and acetic anhydride (40 mL) at 0 °C. After stirring for 3 h the reaction mixture was poured into ice-cooled water. The precipitate was immediately collected by filtration (we found that leaving the mixture for a longer time reduced the yield due to hydrolysis of the ester). The precipitate was washed extensively with water before being dried under vacuum to afford 10.8 g of 2 (82%) as a pale yellow solid .
  • Ethyl 4-(4-(l-(aminooxy)ethyl)-2-methoxy-5-nitrophenoxy)butanoate (6) (1.9 g, 5.5 mmol) was dissolved in dioxane (lOmL) and 10% aq. Na 2 C0 3 (20ml_) was added . The reaction mixture was cooled to 0 °C.
  • Fmoc-Rink linker to amino functionalized PEGA 8 oo beads
  • Fmoc-Rink linker (3 eq .), NEM (4 equiv.) and TBTU (2.88 equiv.) were mixed in DMF, and shaken for 5 min at rt.
  • the solution was then added to amino- functionalized PEGA 8 oo beads pre-swelled in DMF and allowed to react for 2 hours, followed by washing with DMF (x 6). Full conversion was judged by conventional Kaiser test.
  • Fmoc-4-bromophenylalanine (3 equiv.) was dissolved in DMF, and NEM (4 equiv.) followed by TBTU (2.88 equiv.) were added .
  • the mixture was shaken for 5 min at room temperature before being added to the Rink-functionalized beads pre-swelled in DMF.
  • the mixture was shaken for 2 h at room temperature.
  • the solid support was washed with DMF ( x 6). Full conversion was judged by conventional Kaiser test. Fmoc deprotection was accomplished as noted above before.
  • the solid support was finally washed with DMF (x 8), MeOH (x 6), CH 2 CI 2 ( ⁇ 6) before being lyophilized .
  • Resin sample (5-30 mg) was immersed in appropriate solvent (500 ⁇ _) and irradiated for lh. The beads were filtered and washed with CH 3 CN . The combined filtrates were analyzed by RP-HPLC.
  • Fmoc deprotection of Fmoc- protected hydroxylamine-functionalized photolabile PEGA-beads 9 was accomplished as noted above.
  • Fmoc-4-(aminomethyl)benzoic acid (3 equiv.) was dissolved in DMF, and NEM (4 equiv.) followed by TBTU (2.88 equiv.) were added . The mixture was shaken for 5 min at room temperature before being added to the Fmoc-deprotected
  • Fmoc-4-(aminomethyl)benzoic acid (3 equiv.) was dissolved in DMF, and NEM (4 equiv.) followed by TBTU (2.88 equiv.) were added . The mixture was shaken for 5 min at room temperature before being added to the Fmoc-deprotected
  • Boc-Arg(Pbf)-OH (3 equiv.) was dissolved in DMF, and NEM (4 equiv.) followed by TBTU (2.88 equiv.) were added . The mixture was shaken for 5 min at room temperature before being added to the beads pre-swelled in DMF. The mixture was shaken for 2 h at room temperature. The beads were washed with DMF (x 6), MeOH (x 6) and CH 2 CI 2 ( ⁇ 6) before being lyophilized. Full conversion was judged by conventional Kaiser test. Bead sample (30 mg) was immersed in HFIP (500 ⁇ _) and irradiated for 30min. The beads were filtered and washed with CH 3 CN . The combined filtrates were analyzed by RP-HPLC, showing release of 21 in >95% purity. UPLC/MS (ESI) m/z 676.7
  • Fmoc deprotection of Fmoc- protected hydroxylamine-functionalized photolabile PEGA-beads 9 was accomplished as noted above. Mono-tert-butyl malonate (3 equiv.) was dissolved in DMF, and NEM (4 equiv.) followed by TBTU (2.88 equiv.) were added . The mixture was shaken for 5 min at room temperature before being added to the Fmoc-deprotected hydroxylamine- functionalized photolabile PEGA-beads pre-swelled in DMF. The mixture was shaken for 2 h at room temperature. The solid support was washed with DMF (x 6), MeOH (x 6) and CH 2 CI 2 ( ⁇ 6) before being lyophilized. Full conversion to 22 was judged by conventional Kaiser test.
  • the tert-butyl protecting group was removed with TFA/CH 2 CI 2 (1 : 1) and the carboxylic acid functionalized photolabile beads were washed with CH 2 CI 2 ( ⁇ 6), MeOH ( ⁇ 6) and DMF ( ⁇ 6).
  • Doxorubicin (3 equiv.) was dissolved in DMF, and DIPEA (5 equiv.) followed by HATU (2.88 equiv.) were added. The mixture was shaken for 5 min at room temperature before being added to the carboxylic acid functionalized photolabile beads pre-swelled in DMF. The mixture was shaken for 2 h at room temperature. The solid support was washed with DMF (x 6), MeOH (x 6), CH 2 CI 2 ( ⁇ 6) before being lyophilized .

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Abstract

La présente invention a trait à un coupleur hydroxamate photolabile basé sur le groupe o-nitrovératryle et à son application en synthèse en phase solide multi-étapes et à la libération photolytique contrôlée d'acides hydroxamiques. L'invention a également trait à un procédé de production d'un support solide comprenant un coupleur photolabile fonctionnalisé par une hydroxylamine et au support solide photolabile fonctionnalisé par une hydroxylamine ainsi produit. L'invention a en outre trait à un procédé de synthèse d'une bibliothèque de dérivés d'acide hydroxamique, une bille permettant d'obtenir un composé, sur un coupleur photolabile, ainsi qu'à un procédé de criblage d'une bibliothèque de dérivés d'acide hydroxamique.
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EP2826769A1 (fr) * 2013-07-18 2015-01-21 Institut de Recherche pour le Développement ( IRD) Nouveaux composés pour le traitement et/ou la prévention de maladies parasitaires et procédé de production de ceux-ci
WO2022109456A1 (fr) * 2020-11-23 2022-05-27 Francis Lee Procédés de fabrication et d'utilisation de plateformes pour la synthèse de peptides et compositions associées

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2826769A1 (fr) * 2013-07-18 2015-01-21 Institut de Recherche pour le Développement ( IRD) Nouveaux composés pour le traitement et/ou la prévention de maladies parasitaires et procédé de production de ceux-ci
WO2015007870A1 (fr) * 2013-07-18 2015-01-22 Institut De Recherche Pour Le Developpement (I.R.D.) Nouveaux composés pour le traitement et/ou la prévention de maladies parasitaires et leur procédé de production
US10106493B2 (en) 2013-07-18 2018-10-23 Institut De Recherche Pour Le Developpement (I.R.D.) N-hydroxybenzamides as HDAC inhibitors for the treatment of parasitic diseases
WO2022109456A1 (fr) * 2020-11-23 2022-05-27 Francis Lee Procédés de fabrication et d'utilisation de plateformes pour la synthèse de peptides et compositions associées

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