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WO1996021665A1 - Turcasarines, nouvelles porphyrines expansees et utilisation desdites substances - Google Patents

Turcasarines, nouvelles porphyrines expansees et utilisation desdites substances Download PDF

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Publication number
WO1996021665A1
WO1996021665A1 PCT/US1995/000530 US9500530W WO9621665A1 WO 1996021665 A1 WO1996021665 A1 WO 1996021665A1 US 9500530 W US9500530 W US 9500530W WO 9621665 A1 WO9621665 A1 WO 9621665A1
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Prior art keywords
compound
substituted alkyl
alkyl
turcasarin
substituted
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PCT/US1995/000530
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English (en)
Inventor
Jonathan L. Sessler
Steven J. Weghorn
Eric A. Brucker
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Board Of Regents, The University Of Texas System
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Priority to PCT/US1995/000530 priority Critical patent/WO1996021665A1/fr
Priority to AU17266/95A priority patent/AU1726695A/en
Publication of WO1996021665A1 publication Critical patent/WO1996021665A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

Definitions

  • the present invention relates generally to the field of expanded porphyrins. More particularly, it concerns a decapyrrolic expanded porphyrin, named turcasarin, its characterization and its use as an anion chelating agent and as a photodynamic agent.
  • acyclovir (FIG. 7A, structure a; 9- [(2-hydroxyethoxy)methyl]-9H-guanine), is typical in that it is able to enter the cell only in its uncharged nucleoside-like form. Upon gaining entry to the
  • cytoplasm it is phosphorylated, first by a viral-encoded enzyme, thymidine kinase (FIG. 7A, structure b), and then by relatively nonspecific cellular enzymes to produce the active, ionic triphosphate nucleotide-like species (FIG. 7A, structure c). There, it functions both as an
  • antiviral agents including, for instance, the anti-HIV agent, Xylo-G (FIG. 7B, structure d; 9-( ⁇ -D-xylofuranosyl)guanine), on the other hand, are not phosphorylated by a viral enzyme and are, therefore, largely or completely inactive. If, however, the active monophosphorylated forms of these putative drugs (such as in FIG. 7B, structure e) could be transported into cells, it would be possible to fight viral infections with a large battery of otherwise inactive materials. If such specific into-cell transport were to be achieved, it would therefore greatly augment the treatment of such debilitating diseases as, for example, AIDS, herpes, hepatitis and measles. Given the fact that AIDS is currently a major national health problem of frightening proportions, and that something so nominally benign as measles still claims over 100,000 lives per year world-wide, treatment of these diseases would be particularly timely and worthwhile.
  • nucleobase nucleic acid base
  • nucleotide binding systems include acyclic, macrocyclic, and macrobicyclic polyaza systems; nucleotide-binding bis-intercalands; guanidinium-based receptors; and various rationally designed H-bonding receptors. These latter H-bonding receptors have been shown to be effective for the chelation of neutral nucleobase and/or nucleoside derived substrates but, without exception, have also all proved unsatisfactory for the important task of charged nucleotide recognition.
  • nucleotides particularly specifically-recognized nucleotides, to be transported across naturally lipophilic cellular
  • metal coordinating molecules may also find use in applications involving physiological (i.e., aqueous) environments.
  • physiological (i.e., aqueous) environments One such application is as a
  • the present invention provides a new class of expanded porphyrins containing 10 pyrrole units.
  • the present invention also provides uses of and a method of manufacture for this new class of macrocycles.
  • the present invention is a compound of formula I:
  • each of R 1 , R 2 or R 3 is a monoradical moiety of hydrogen, alkyl, alkyl halide, alkene, alkyne, aryl, amino, hydroxyl, alkoxy, carboxy, carboxamide, ester, amide, sulfonate, hydroxy substituted alkyl, glycol, polyglycol, alkoxy substituted alkyl, carboxy substituted alkyl, amino substituted alkyl, sulfonate substituted alkyl, ester substituted alkyl, amide substituted alkyl, substituted aryl, substituted alkyl, substituted ester, substituted ether, substituted amide, thiol, alkyl thiol, alkoxycarbonyl, aryloxycarbonyl, aldehyde, ketone, carboxylic acid, phosphate, phosphate substituted alkyl, phosphonate, phosphonate substituted alkyl, sulf
  • substituted alkyl or is of the formula (CH 2 ) m -A-(CH-) n -B wherein A is CH 2 , O, S, NH or NR 4 or wherein A is a diradical moiety selected from any of the R 1-3 groups oxy, sulfide, carbonyl, alkene, alkyne, alkyl halide, hydroxyalkyl, glycol, polyglycol, alkyl thiol,
  • R 4 may be alkyl, alkyl halide, hydroxyalkyl, glycol, polyglycol, or alkyl thiol; wherein B independently in each occurrence is any of the R 1-3 groups, nucleobase, saccharide, nucleotide, an expanded porphyrin, steroid, amino acid, peptide or polypeptide, turcasarin or polymeric or solid support matrix, wherein n is 0-10, wherein m is 0-10, and wherein the total number of carbon atoms in each of R 1-4 is less than or equal to 20, or salt thereof.
  • the present invention provides a new class of
  • FIG. 1 macrocycle 11 (FIG. 1) ( [40] decaphyrin- [1.0.1.0.0.1.0.1.0.0]).
  • This compound 11 is prepared by the acid catalyzed condensation of 4,4'-diethyl-5,5'-diformyl-3,3'-dimethyl-2,2'-bipyrrole 10 (Sessler,
  • Turcasarin 11 itself is a macrocycle which can be generally characterized by the presence of ten py rolic subunits contained within a 40 ⁇ -electron macrocyclic framework and by UV/VIS absorption bands that are
  • the turcasarins of the present invention may be prepared by acid catalyzed condensation of a 5,5'-diformyl-bipyrrole with a terpyrrole.
  • a generalized scheme of this condensation is shown in FIG. 3 wherein a substituted or unsubstituted 5, 5' -diformyl-bipyrrole 12 and a substituted or unsubstituted terpyrrole 13 are condensed in an acid catalyzed reaction to prepare a turcasarin 14 corresponding to a compound of formula I.
  • the condensation is typically run in an organic solvent such as an alcohol solution.
  • the present invention is a process for the production of turcasarins, comprising condensing a bipyrrole and a terpyrrole in the presence of an acid under conditions such that a turcasarin is formed.
  • the bipyrrole may be of formula II:
  • R 2-3 are as defined above; and wherein Z is H or -CHO, and the terpyrrole can be of formula III:
  • R 1 is as defined above.
  • the present invention provides a solution to the needs described above by providing a novel composition for use in specific anion binding and transport.
  • Turcasarin and turcasarin analogues are able to bind negatively charged substances, anions, at near-neutral pH, and would be expected to have the ability to
  • the turcasarin macrocyclic compounds of this invention are particularly contemplated for use in transporting
  • the compounds of this invention have a wide variety of uses.
  • the turcasarins may be useful as a chelating agent and as a photodynamic agent.
  • the turcasarins are useful as chelating agents of metal cations such as uranium oxide or zinc cations.
  • the use of turcasarin 11 to form a uranyl complex is demonstrated.
  • the turcasarin is capable of binding two uranyl cations. This provides another advantage of this invention since the chelating capacity is double that of most molecules.
  • the turcasarins may be used to treat solutions contaminated with uranium cations to thereby remove the uranium cations from solution.
  • uranium is diamagnetic and is itself useful in photodynamic therapy; therefore, one skilled in this art would expect that the turcasarin/uranyl complex would be useful in photodynamic therapy also.
  • both the red-shifted wavelength of the lower energy absorption and the high extinction coefficient for turcasarin 11 indicates that turcasarin is a likely candidate for use as a photodynamic agent and,
  • the turcasarins may have utility as
  • the macrocycles may also be useful as carriers for the through-membrane transport of nucleotide monophosphates such as guanosine-5' monophosphate.
  • Turcasarin and analogues thereof may be further characterized by the ability to undergo facile
  • turcasarin macrocycles may be either singly, doubly, triply or four- fold protonated.
  • R 1 , R 2 or R 3 is other than alkyl of 1 to 3 carbons.
  • the precursor molecules may be derivatized or the turcasarin macrocycle may be modified after condensation to yield turcasarins having a variety of substituents.
  • an R 1-3 group is an ester
  • the ester may be converted through well known synthetic procedures to produce a carboxylic acid which itself may be converted to a cyano group, an ether, another ester by transesterification, an aldehyde, an alcohol, a halide or an amide which itself can be
  • the of-positions of the starting bipyrroles may be carboxyl-, ester-, formyl-, and/or unsubstituted.
  • the alpha-position on the terpyrroles may be carboxyl-, ester-, formyl-, and/or unsubstituted.
  • turcasarin compounds are contemplated that contain the turcasarin macrocycle core for phosphate binding and also nucleobase "appendages" for specific nucleic acid recognition.
  • turcasarin-nucleobase conjugates which term is intended to include any conjugate formed by the covalent conjugation of any turcasarin macrocycle to any nucleic acid base ("nucleobase").
  • nucleobase nucleic acid base
  • turcasarin-nucleobase conjugates are exemplified in structures 51, 55, 59 and 63 of Schemes F through I.
  • nucleobase refers generally to any moiety that includes within its
  • nucleobase includes adenine, cytosine, guanine,
  • thymidine thymidine, uridine, inosine, and the like; bases, nucleotides or nucleosides, as well as any base,
  • nucleotide or nucleoside derivative based upon these or related structures Nucleotides can be readily coupled onto a turcasarin through manipulation of amide, ether and thioether linkages.
  • a turcasarin of formula I wherein R 1 , R 2 and/or R 3 contains a functional group of formula - Y-CO-CH 2 Br, wherein Y is NH or O may be reacted with an hydroxyl group of an oligonucleotide in the presence of a Lewis acid such as FeBr 3 to form an ether linkage between the turcasarin linker and the oligonucleotide.
  • oligonucleotide analogues containing one or more thiophosphate or thiol groups are selectively alkylated at the sulfur atom with an alkyl halide
  • Oligonucleotides are used to bind selectively compounds which include the complementary nucleotide or oligo- or poly- nucleotides containing substantially complementary sequences.
  • a substantially complementary sequence is one in which the nucleotides generally base pair with the complementary nucleotide and in which there are very few base pair mismatches.
  • the oligonucleotide may be large enough to bind probably at least 9 nucleotides of complementary nucleic acid.
  • a particular example of a useful nucleobase are the so-called antimetabolites that are based upon purine or pyrimidine structure. These structures typically exert their biological activity as antimetabolites through competing for enzyme sites and, thereby, inhibiting vital metabolic pathways.
  • antimetabolite nucleobase is used quite broadly to refer to any purine or
  • exemplary structures are shown in Table 1, and include the antimetabolites FU, AraC, AZT, ddl , xylo-GMP, Ara-AMP, PFA and LOMDP . It is contemplated that turcasarin-nucleobase conjugates will have a wide variety of applications, including their use as carriers for the delivery of antiviral drugs to a particular body or even subcellular locale.
  • nucleobase antimetabolites can not be readily employed in therapy due to the fact that their charged nature inhibits their uptake by target cells, or otherwise inhibits or suppresses their unencumbered movement across biological membranes.
  • this shortcoming is due to the presence of charged structures such as phosphates, phosphonates, sulfates or sulfonates on the nucleobase that, due to their charged nature, prevents or inhibits their crossing of a biological membrane.
  • the turcasarins of the present invention may be employed as transport agents for carrying such nucleobases across membranes, (whether the nucleobase is directly conjugated to the macrocycle or simply complexed with it). This point is elaborated in further detail in Sessler et al. (1992), (reference 8m) incorporated herein by reference.
  • nucleobase are termed “ditopic receptors", whereas those with two nucleobases are termed “tritopic receptors”.
  • the invention is not limited to compounds containing one or two nucleobase units, indeed, mono- or di-substituted turcasarin-nucleobase conjugates may have any number of nucleobases or nucleobase oligomers or polymers attached. The ultimate number of such residues that are attached will, of course, depend upon the application. One may employ a turcasarin derivative with 10 or so bases attached to bind and transport complementary oligo- or poly-nucleotides. Of course, there is no limitation to the particular position (s) within the turcasarin macrocycle to which the
  • nucleobase(s) may be attached to construct a conjugate.
  • turcasarin derivatives or conjugates encompassed by the present invention are turcasarin saccharide derivatives, wherein the macrocycle is appended to a saccharide-based unit, such as a sugar, sugar derivative or polysaccharide.
  • a saccharide-based unit such as a sugar, sugar derivative or polysaccharide.
  • the synthesis of turcasarin-saccharide compounds is described in Example IX and specific turcasarin saccharide conjugates are represented by structures 66, 68, 76 and 84 in reaction schemes J, K, M and O, respectively.
  • a non-exhaustive, exemplary list of sugars which may be conjugated to turcasarin in this manner is set forth in Table 2.
  • any sugar or modified sugar may be employed including sugars having additional phosphate, methyl or amino groups, and the like.
  • compositions which are composed of a turcasarin
  • the second substance includes within its structure a negatively charged moiety. More particularly, the second substance will include a negatively charged component such as a chloride, phosphate, phosphonate, sulfate, or sulfonate moiety, of which, turcasarin-chloride ion complexes are a particular example.
  • a negatively charged component such as a chloride, phosphate, phosphonate, sulfate, or sulfonate moiety, of which, turcasarin-chloride ion complexes are a particular example.
  • the second substance will include a purine or pyrimidine, or an analog of either, within its structure.
  • these nucleobase structures include, for example, adenine, cytosine, guanine, thymidine, uridine and inosine;
  • Antimetabolic and antienzymatic compounds include those with antitumor, anticellular,
  • the invention concerns a method for forming a complex between a
  • the method involves preparing a turcasarin or turcasarin analogue or
  • the conjugate such as any one of the turcasarin derivatives as described above, and contacting this turcasarin or turcasarin derivative with a negatively charged substance or selected agent under conditions effective to allow the formation of a complex between the turcasarin macrocycle and the negatively charged substance.
  • complexing a range of negatively charged substances or selected agents, such as for example, chloride ions and other halides, pseudohalides such as azide or cyanide anions, and anionic clusters such as ferricyanide.
  • phosphate-containing compounds including, simple alkyl or aryl phosphates, nucleotides, oligo- and polynucleotides, such as DNA, RNA and anti-sense
  • nucleotide analogues is particularly contemplated. Even more preferable, is the complexing of antiviral compounds such as phosphonate derivatives and simple species such as the pyrophosphate derivatives PFA and COMDP; the antiviral agents of FIG. 7A, FIG. 7B, FIG. 7C, FIG. 7D, FIG. 7E and FIG. 7F and Table 1, and
  • embodiment is the high basicity of the turcasarin, which allows this class of compounds and its derivatives to act as vastly improved anion chelators or carriers in
  • Still further methodological embodiments concern methods for the cellular transport of a given substance, generally a negatively charged substance. This may be employed as a means of, for example, successfully
  • introducing a negatively charged substance into a cell or alternatively, as a means of facilitating the removal of a negatively charged substance from a cell.
  • a turcasarin macrocycle in accordance with the present invention, contact the macrocycle with the negatively charged substance under conditions effective to allow complex formation, and then simply contact the cell, either in vi tro or in vivo, with the macrocycle-bound substance.
  • oligonucleotides including anti-sense constructs, and nucleotide analogues, such as antiviral compounds, is particularly envisioned.
  • One example concerns the introduction of a turcasarin-complex composition which includes an antiviral antimetabolic or antienzymatic compound into a cell suspected of being a virally
  • an antitumor antimetabolic or antienzymatic compound into a cell suspected of being a tumor or proliferating cell.
  • target cells may be located within an animal or human patient, in which case an effective amount of the complex, in
  • compositions of the present invention will include the selected turcasarin derivative in a convenient amount that is diluted in a
  • pharmacologically or physiologically acceptable buffer such as, for example, phosphate buffered saline.
  • oligonucleotide or DNA fragment would be advantageous, such as in supplying a functioning gene, or in inhibiting an aberrant gene, for example, by employing an antisense DNA construct.
  • an antisense DNA construct As discussed above, the larger size, high basicity, and relative ease with which turcasarins may be protonated, renders them particularly effective molecules for use in anion transport.
  • certain turcasarins with advantageous chloride ion transporting properties may be employed as synthetic carriers capable of facilitating out-of-cell diffusion of chloride anions, and are therefore contemplated for use as therapeutic agents for the treatment of cystic fibrosis.
  • FIG. 1 shows a synthetic scheme for the synthesis of turcasarin 11.
  • FIG. 2 shows structures of expanded porphyrins described in the Background of the Invention.
  • FIG. 3 shows a generalized synthetic scheme for the synthesis of turcasarin macrocycles of the present invention.
  • FIG. 4 shows a schematic representation of the
  • FIG. 5 shows a two-dimensional H,H-correlated spectrum (H,H COSY) of the alkyl region of turcasarin 11 that allowed definitive peak assignments to be made. Paired sets of crosspeaks indicate near C 2 symmetry in the molecule and provide evidence for diastereotopic protons in the propyl side chains.
  • FIG. 7A, FIG. 7B, FIG. 7C, FIG. 7D, FIG. 7E and 7F show the structures for potential antiviral agents a through i.
  • the turcasarins of the present invention are of formula I shown hereinabove.
  • the structure has substituent groups R 1-3 , each of R 1-3 being defined as above.
  • alkanes used as such monoradicals include methane, ethane, straight-chain, branched or cyclic isomers of propane, butane, pentane, hexane, heptane, octane, nonaneand decane, with methane, ethane and propane being preferred.
  • alkenes useful as such monoradicals or diradicals include ethene, straight-chain, branched or cyclic isomers of propene, butene, pentene, hexene, heptene, octene, nonene and decene, with ethene and propene being preferred.
  • alkynes useful as such monoradicals or diradicals include ethyne, straight-chain, branched or cyclic isomers of propyne, butyne, pentyne, hexyne, heptyne, octyne, nonyne and decyne, with ethyne and propyne being preferred.
  • alkyl halides used in this invention include halides of methane, ethane, propane, butane, pentane, hexane, heptane, octane, nonane and decane, with halides,
  • hydroxyalkyls include alcohols of methane, ethane, straight-chain, branched or cyclic isomers of propane, butane, pentane, hexane, heptane, octane, nonane and decane, with alcohols of methane, ethane or propane being preferred.
  • Representative examples of useful glycols of this invention include diols of ethane, straight -chain, branched or cyclic isomers propane, butane, pentane, hexane, heptane, octane, nonane and decane, with diols of ethane or propane being preferred.
  • Representative examples of polyglycols include polyethylene glycol, polypropylene glycol and polybutylene glycol as well as polyalkylene glycols containing combinations of ethylene, propylene and butylene.
  • Representative examples of alkyl thiols include thiols of ethane, thiols of
  • substituted alkyls include alkyls substituted by two or more functional groups described herein.
  • phosphates include phosphate or polyphosphate groups .
  • Representative examples of phosphate substituted alkyls include alkyls as described above substituted by one or more phosphate or polyphosphate groups.
  • Representative examples of phosphonate substituted alkyls include alkyls as described above substituted by one or more phosphonate groups.
  • Sulfate substituted alkyls include alkyls as described above substituted by one or more sulfate groups, a representative example of which is diethyl sulfate ((C 2 H 5 ) 2 SO 4 ).
  • Representative examples of carboxy groups include carboxylic acids of the alkyls described above as well as aryl carboxylic acids such as benzoic acid.
  • Representative examples of carboxyamides include primary carboxyamides (CONH 2 ), secondary (CONHR 4 ) and tertiary (CONR 4 R 4 ) R 4 carboxyamides where R 4 is a
  • useful amines include a primary, secondary or tertiary amine of an alkyl as described hereinabove.
  • oligonucleotides include nucleotides, oligonucleotides and polynucleotides composed of adenine, cytosine, guanine, thymine or uracil bases. It is understood that the term nucleotide as used herein refers to both naturally-occurring and synthetic nucleotides, poly- and oligonucleotides and to analogs and derivatives thereof such as methylphosphonates, phosphotriesters, phosphorothioates and phosphoramidates.
  • useful steroids include any of the steroid hormones of the following five categories: progestins (e.g.
  • progesterone glucocorticoids
  • cortisol mineralocorticoids
  • aldosterone mineralocorticoids
  • estrogens e.g., estradiol
  • useful amino acids include amino acids with simple aliphatic side chains (e.g., glycine, alanine, valine, leucine, and isoleucine), amino acids with aromatic side chains (e.g., phenylalanine, tryptophan, tyrosine, and histidine), amino acids with oxygen and sulfur-containing side chains (e.g., serine, threonine, methionine, and cysteine), amino acids with side chains containing carboxylic acid or amide groups (e.g., aspartic acid, glutamic acid, asparagine, and glutamine), and amino acids with side chains containing strongly basic groups (e.g., lysine and arginine), and proline.
  • useful peptides include any of both naturally occurring and synthetic di-, tri-, tetra-, and pentapeptides derived from any of the above described amino acids .
  • useful polypeptides include both naturally occurring and synthetic polypeptides
  • polymeric or solid support matrixes include resin-type polystyrene derived solid support matrixes, aminopropyl-functionalized silica gel or natural polymers such as polysaccharides.
  • nucleobases useful in this invention include those shown in Table 1 hereinbelow.
  • sugars useful in the practice of this invention include those shown in Table 2
  • Representative examples of useful chelates include EDTA, EGTA, DTPA, DOTA, ethylene diamine, bipyridine, 1,10-phenanthralene, crown ether, aza crown and catechols.
  • the bipyrroles that are used in the practice of this invention to prepare turcasarins contain two formyl groups at the alpha positions.
  • the R 2-3 substituents may be introduced on the pyrrole ring before or after the condensation reaction to synthesize a turcasarin
  • the substituent may be incorporated after the
  • bipyrroles are well known compounds which can be readily prepared by conventional techniques well known to those of skill in the art.
  • terpyrroles used in this invention are well known materials which can be readily prepared by conventional techniques well known to those skill in the art .
  • One method of terpyrrole preparation involves the synthesis as shown in Example 2.
  • Other methods include those described by Chierici et al., Gaz. Chim. Ital.. volume 86, pages 1278-1283 (1956).
  • the most preferred acid is hydrogen chloride.
  • Suitable solvents for the condensation include ethanol or methanol with cosolvents such as chloroform or methylene chloride. The condensation is generally run at room temperature.
  • the turcasarin and turcasarin analogues of the present invention are characterized by the capacity to bind anions and yet retain overall supramolecular charge neutrality. A particular advantage to turcasarin
  • Example VII A range of compounds with a wide variety of alkyl and/or aryl substituents in the meso and/or
  • turcasarins of the present invention will be of use as drug delivery agents. It is contemplated that they will find utility in mediating the cross-membrane transport of negatively charged compounds or molecules, including halides, pseudohalides, such as azide or cyanide anions, or anionic clusters such as ferricyanide.
  • halides pseudohalides, such as azide or cyanide anions
  • anionic clusters such as ferricyanide.
  • Phosphate-containing compounds which may be transported in this manner include, for example, simple alkyl or aryl phosphate, nucleotides such as AMP or GMP, oligonucleotides and DNA or RNA, including anti-sense DNA or RNA constructs, and more particularly, antiviral compounds such as those depicted in FIG. 7A, FIG. 7B, FIG. 7C, FIG. 7D, FIG. 7E and FIG. 7F structures b,e,f,g,h,i, Table 1, and equivalents thereof.
  • any one of a variety of antiviral agents may be delivered to a cell using turcasarin or a turcasarin analogue in accordance herewith.
  • these agents include, for example, the anti-HSV and anti-HIV agents acyclovir monophosphate, Xylo-GMP, Ara-AMP, and/or phosphonate derivatives that also have documented anti-HSV and anti-HIV activity in vi tro (e.g., FIG. 7F and FIG. 7G), and simple species such as the pyrophosphate derivatites PFA (FIG. 7E) and COMDP (FIG. 7F) that have demonstrated anti-HIV reverse transcriptase activity in cell-free media.
  • PFA pyrophosphate derivatites PFA
  • COMDP FIG. 7F
  • the turcasarin compounds of the present invention may be rendered useful as nucleotide transporters if one or more nucleobase recognition units were to be "appended" directly onto the phosphate-chelating macrocyclic core. This would impart a further degree of nucleotide specificity to binding and transport reactions. Accordingly, turcasarin-nucleobase conjugates which have been derivatized by the addition of one or more nucleobase compounds form an important aspect of the present invention.
  • Turcasarin mononucleobase derivatives may include any of the naturally-occurring purine or pyrimidine nucleobases, namely, cytosine, guanine, thymidine, adenine, uridine or inosine. Equally, they may include modified versions of any of these, such as the
  • Turcasarin-nucleobase conjugates with protected bases include, for example, conjugates wherein one or more base has a protecting group, such as 9-fluorenylmethylcarbonyl,
  • benzyloxycarbonyl 4-methoxyphenacyloxycarbonyl, t-butyloxycarbonyl, 1-adamantyloxycarbonyl, benzoyl, N- triphenylmethyl or N-di- (4-methoxyphenyl)phenylmethyl on the amino group of the nucleobase.
  • oligomethylene bridges with terminal amino, or hydroxy function which allow formation of an amide or ester bond for the connection of the turcasarin and nucleobase units.
  • This bridge may also be modified, for example, by the reduction of the amide bond to give the amine function.
  • Turcasarin nucleobase conjugates would be useful as antiviral agents, capable of binding and solubilizing nucleotides and of effecting their selective through- membrane transport at or near physiologic pH.
  • Turcasarin nucleobase conjugates with appended oligonucleotides are also contemplated by the present invention, and would be of use in binding and transporting oligo- or
  • polynucleotides including antisense constructs, into cells.
  • turcasarins may conceivably be employed in the treatment of any disease in which the delivery of an oligonucleotide or DNA fragment would be advantageous, such as in supplying a functioning gene, or in inhibiting an aberrant gene, for example, by employing an antisense DNA construct.
  • the conjugates contemplated are the turcasarin saccharide derivatives which comprise a turcasarin macrocycle conjugated to a sugar, sugar derivative or
  • Example IX The synthesis of turcasarin-saccharide compounds, as represented by structures 66, 68, 76 and 84 in reaction schemes J, K, M and O, respectively, is described in Example IX. It will be understood that any one of a variety of individual sugar units, such as those set forth in Table 2, or polymers thereof, may be
  • Table 2 is intended to include modified versions of the sugar units, such as sugars having additional phosphate, methyl or amino groups and the like, and also includes D- and L-isomers and ⁇ and ⁇ forms.
  • turcasarin conjugates includes, for example: metal chelator moieties such as EDTA, EGTA, 1,10-phenanthralene, DTPA, DOTA, crown ether, azacrown, catecholate and ethylene diamine; alkylating agents such as ethylene diamine, epoxide and bromoacetamide; steroids and steroid derivatives; amino acids, peptides and polypeptides; other turcasarins, turcasarin derivatives, polymeric turcasarin, or other macrocyclic compounds such as sapphyrins, texaphyrins or derivatives thereof; and polymeric matrices or solid supports such as polymers, glasses, agarose, polyacrylamide , controlled pore glass, silica gel, polystyrene and sepharose.
  • metal chelator moieties such as EDTA, EGTA, 1,10-phenanthralene, DTPA, DOTA, crown ether, azacrown,
  • terpyrrole tetraester 8 (FIG. l) was carried out as follows. Dipyrroylbutanedione 7 (23.54 g., 40m mol), prepared according to the procedure of Johnson et al . (1992), ammonium acetate (vacuum dried at 50°C, 91. lg, 1 mol), acetic anhydride (32 mL, 0.33 mol) and glacial acetic acid (150 mL) were held at reflux under argon for 18 hours, poured into stirred ice water (400 mL), and stirred for 1 hour. The solid was
  • terpyrrole 9 (FIG. 1) was carried out as follows. Terpyrrole tetraester 8 (5.7 g, 10 mmol), NaOH (10 g, 400 mmol), and ethylene glycol (100 mL) were placed in a three-necked 250 mL round bottomed flask equipped with an argon inlet, thermometer,
  • the flask contents were heated for another 30 minutes and cooled.
  • the flask contents were diluted with water (70 mL, degassed by the freeze-pump-thaw method) and allowed to cool to room temperature.
  • the flask contents were diluted to 400 mL with ice water.
  • the solid so obtained was separated by filtration under an argon blanket (an aluminum foil cover and a pipette blower works fine), washed with water, and dried in vaeuo to give the pure product as a tan to light green powder (2.62 g, 9.3 mmole, 93%).
  • the first major purple band was collected using CH 2 Cl 2 as the eluent placed in a separatory funnel, and washed first with water (2 ⁇ 25 mL) and then 1N HCl (3x 25 mL). The organic layer was then separated, dried over Na 2 SO 4 , and taken to dryness in vaeuo .
  • FIG. 6 shows top and side views of turcasarin 11, the views derived from the crystallographic data. Data were collected on a Nicolet R3 diffractometer at -90°C, equipped with a Nicolet LT-2 low-temperature device, using the omega scan technique at 5 - 12°/min out to a 2q limit of 45°. A total of 12144 reflections were collected, of which 10699 were unique.
  • the R for averaging symmetry equivalent reflections was equal to 0.034.
  • Data were corrected for L p effects and decay but not for absorption.
  • the structure was solved by the direct methods and refined by full-matrix least- squares using SHELXTL-Plus (Sheldrick, 1991).
  • the hydrogen atoms were calculated in ideal positions, with Uiso set to 1.2 ⁇ U eq of the relevant atom.
  • One molecule of n-hexane and one of methylene chloride are disordered.
  • the twist observed in the solid state also serves to define two pentaphyrin-like "hemi-macrocycles" as well as found smaller “pockets.” Occupying each of these latter pockets are two chloride anions held within hydrogen bonding distance to the nitrogens. These hydrogen bonding interactions, as implied above, are currently considered to account for the slow conformational
  • Turcasarin 11 may be considered as being a 40 T ⁇ - electron annulene. Thus, turcasarin should not be aromatic as predicted by the (4n + 2) rule for aromatic systems. However, it displays a Soret-like absorption in the visible portion of the electronic spectrum that is considerably red-shifted compared to that of the
  • the 13 C NMR spectrum shows, for instance, apparent C 2 symmetry in the macrocycle frame as judged by the number of observable peaks.
  • the 1 H NMR spectrum is also consistent with C symmetry as judged by the number of signals in the interior NH and exterior b- pyrrolic and meso-proton region.
  • the signals in thealkyl region proved more complex, with no clear assignment of symmetry or structure being possible from immediate inspection.
  • complex splitting patterns for the methylene protons of the alkyl sidechains were observed.
  • the complex splitting patterns mentioned above lead to the suggestion that the macrocycle may exist in two limiting conformations.
  • Turcasarin 11 could therefore exist as a pair of enantiomers. It would thus be dissymmetric even though it possesses no formal stereogenic centers. Such a postulate of conformational chirality, even though unexpected for a fully conjugated macrocycle, would, of course, account for the observed complex splitting patterns which would arise as the result of an imposed diastereotopicity on the alkyl side chains.
  • This solid can be recrystallized from diffusion of isopropyl ether into a CH 2 Cl 2 solution of 2 (or from hexanes layered on a CHCl 3 solution of 2) to afford fine green needles. Yield: 5.7 mg (69%). M.p.: dec.
  • compounds of formula I may be prepared where R 1 , R 2 or R 3 is hydroxy substituted methyl, ethyl, or propyl; carboxy or ester substituted methyl, ethyl or propyl; polyglycol substituted methyl, ethyl, or propyl, by employing the appropriate substituted bipyrroles and terpyrroles.
  • R 1 , R 2 or R 3 is hydroxy substituted methyl, ethyl, or propyl
  • polyglycol substituted methyl, ethyl, or propyl by employing the appropriate substituted bipyrroles and terpyrroles.
  • the turcasarins may be used as receptors for anions, cations or neutral molecules provided the turcasarin is of appropriate charge.
  • anionic turcasarin may be prepared for use as a metal cation chelant by removing protons from the secondary amine groups in the macrocycle in organic solution using strong bases such as butyl lithium.
  • meso substituted compounds may be prepared to test the extent to which the presence of different groups, such as, for example, 4'-phenyl and/or 2'-phenyl donating groups may augment effective nitrogen lone pair basicity and/or enhance higher pH phosphate transport capability. Extensions to systems bearing two (or more) meso substituents are also contemplated within the scope of the invention. In any event, it is
  • This procedure involves the condensation of a bis- ⁇ -free bipyrrole (e.g., 25) with an ⁇ , ⁇ -free bis(pyrrolyl)-pyrrole (e.g., 26) in the presence of benzaldehyde or substituted benzaldehyde under turcasarin forming conditions, as described herein, which will afford bisarylturcasarin 27.
  • a range of other macrocyclic and non- macrocyclic products may also be obtained.
  • turcasarin-forming conditions such as those described in Example 3, affords a turcasarin with each of its four "meso" positions substituted with aryl groups (e.g., 27).
  • substituents in the starting compounds such as those groups represented by R 1-3 may be varied as desired.
  • a turcasarin product may be produced in which groups R 1-3 (as represented by structure 27) may be substituted with any of the R 1-3 groups listed above.
  • R 1-3 as represented by structure 27
  • Extensions of known methods may also be used that would allow one of skill in the art, in light of the present disclosure, to prepare functionalized turcasarins bearing one or more non-alkyl substituents in the ⁇ positions.
  • carboxyalkyl substituted turcasarins may also be used as the basis for obtaining other, more complex, functionalized systems.
  • carboxyalkyl-bearing turcasarins may be activated using standard reagents (such as, for example, thionyl chloride or DCC) and used to prepare either ester- or amide-linked conjugates.
  • standard reagents such as, for example, thionyl chloride or DCC
  • Said conjugates could include compounds that contain one or more nucleic acid base (“nucleobase”) or sugar ("saccharide”) subunits, as is described in detail in the following Examples.
  • nucleobase nucleic acid base
  • sugar saccharide
  • the carboxyalkyl substituted turcasarins may be prepared by several routes. For example, as shown in Scheme C, condensation of bipyrrole 36 with terpyrrole 37 may be used to obtain, following debenzylation,
  • bipyrrole 44a (3,3'-bis(methoxycarbonylethyl)-5,5'-bis(benzyloxycarbonyl)-4,4'-dimethyl-2,2'-bipyrrole) via sulfuryl chloride oxidation to acid 42, followed by standard iodination (43), and copper bronze mediated Ullman coupling.
  • terpyrrole 46 of reaction Scheme E under turcasarin- forming conditions will provide a turcasarin containing at least four carboxyalkyl substituents protected as their corresponding methyl esters, structure 47.
  • turcasarin-based dibasic phosphate chelators may be modified so as to obtain ditopic binding systems that display high inherent specificity for a given purine or pyrimidine derived nucleotide. This may be achieved by adding a synthetic appendage of a nucleobase moiety.
  • the known aminobutyl cytosine derivative may be employed with an acid-catalyzed detritylation procedure.
  • the mode of base attachment may be varied, for example, at the level of coupling, protecting group, precursors, and the length, nature, and
  • transport capability may then be determined and any adjustments made accordingly.
  • R groups may be changed, or secondary amides converted to tertiary amides.
  • nucleobase "chelation" may be achieved via complementary Watson-Crick type base-pairing interactions. These compounds should display base-selective transport capability. This may be specifically examined by various structural, static binding, and dynamic transport analyses. In particular, it will be determined whether the cytosine-for-guanine selectivity holds in the case of suitably designed synthetic
  • nucleobase selectivity in the case of adenine-thymine pairing.
  • doubly functionalized systems may be synthesized for use in the selective binding of dinucleotides, some of which have interesting antiviral properties, as well as for the recognition and transport of mononucleotides. In the latter case, the possible combination of both
  • the doubly functionalized turcasarin system could serve as a viable antiviral adjuvant, capable not only of binding and solubilizing the phosphate portion of a nucleotide monophosphate, but also of effecting its selective through-membrane transport at or near physiologic pH.
  • Reaction Schemes F through I represent examples of the synthesis of turcasarin nucleobase conjugates.
  • the synthetic methodology represented in these reaction schemes may be straightforwardly adapted for the
  • reaction Scheme F An example of the preparation of a turcasarin nucleobase conjugate is shown in reaction Scheme F.
  • a tetracarboxyalkyl bearing turcasarin, tetra (ethoxycarbonylethyl)-turcasarin 40 (as prepared hereinabove in Scheme C) is saponified to its diacid form 49 by treatment with a 1:1 mixture of HCl and
  • the amide linked bis (aminoethyl) guanosine turcasarin conjugate 55 is prepared by DDC coupling of turcasarin diacid 49 with benzoyl-protected aminoethyl guanosine 54 in DMF at 0°C followed by deprotection with TFA.
  • tetra (methoxycarbonylethyl) -turcasarin 47 is saponified to diacid 57 by treatment with a 1:1 mixture of HCl and trifluoroacetic acid.
  • DCC coupling of turcasarin diacid 57 with trityl-protected aminoethyl cytosine 58 in methylene chloride at 0°C followed by deprotection with TFA affords the amide linked bis (aminoethyl) cytosine turcasarin conjugate 59.
  • the amide linked bis (aminoethyl) guanosine turcasarin conjugate 63 of Scheme I is prepared by DDC coupling of turcasarin diacid 61 with benzoyl-protected aminoethyl guanosine 62 in DMF at 0°C followed by deprotection with TFA.
  • Turcasarin derivatives or conjugates including one or more saccharide units may be prepared according to the synthetic methodology described hereinbelow.
  • the sugar units (represented originally by structures 65 and 75) in Schemes J through O are intended to represent any one or more saccharide units
  • individual sugar or sugar derivative such as those set forth in Table 2, or polymers thereof, and include modified sugars, such as methyl, amino, and phosphate sugars, and D-, L-, ⁇ and ⁇ forms of said sugars.
  • amide-linked turcasarin saccharide conjugates such as those represented by structure 66b, are prepared by coupling diacid chloride substituted turcasarin 64 (prepared by treating its respective diacid turcasarin with thionyl chloride) with the acetoxy protected HBr salt of amino saccharide 65 in methylene chloride and pyridine, and deprotecting with KOH in methanol.
  • the amide- linked bis(saccharide) turcasarin 68b may be prepared by coupling turcasarin diacid chloride 67 with the acetoxy protected HBr salt of amino saccharide 65 in methylene chloride and pyridine, followed by deprotection with KOH in methanol.
  • the dihydroxy functionalized turcasarins such as those represented by structure 73b in Scheme L, may be prepared. For example, reduction of the methyl esters of macrocycle 69 with borane-THF to the
  • Dihydroxyturcasarins formed as described above (Scheme L), can be coupled with acetoxy- and/or benzoyl-protected bromo-substituted saccharide units, such as structure 75 as shown in Scheme M, in methylene chloride with a catalyst such as silver triflate and barium carbonate. This results in the production of acetoxy- and/or benzoyl-protected bis (saccharide) turcasarin conjugates such as 76a in Scheme M. Treatment of the acetoxy and/or benzoyl protected
  • the dihydroxyturcasarin thus formed can be coupled with acetoxy- and/or benzoyl-protected bromo-substituted saccharide units, such as structure 75, in methylene chloride with silver triflate and barium carbonate to afford the acetoxy- and/or benzoyl-protected bis(saccharide)turcasarin conjugate 84a.
  • acetoxy and/or benzoyl protected bis(saccharide)turcasarin 84a with KOH in methanol will yield the corresponding deprotected
  • diprotonated turcasarin systems will act as effective receptors for a variety of anions. For instance, it is contemplated that
  • diprotonated turcasarin may bind both fluoride and phosphate anions in a strong and non-labile manner.
  • thermodynamics and kinetics of anion binding under a range of conditions and with an array of different anions may be determined.
  • the structure and function of the most promising turcasarin compounds may then be optimized such that they bind either
  • phosphate-bearing nucleotides or chloride ions, with high affinity and selectivity at neutral pH.
  • .pK ' values for various turcasarins may be determined by employing the methods previously used to determine the pK a ' values for sapphyrin and anthraphyrin.
  • K S for [H 6 Tur 2+ ⁇ GMP 2- ] formation in a variety of solvent systems may be measured in a similar manner to that for the hydrohalide salts of sapphyrin and anthraphyrin.
  • Standard methods as quantitative UV/vis titrations and concentration dependent NMR chemical shift analyses may be used, along with more sophisticated techniques such as those involving static and time-resolved fluorescence.
  • the latter methods offer considerable advantages and are particularly useful for measuring high affinity constants (i.e. those in the K s ⁇ 10 6 M -1 range).
  • receptor-anion complex formation through-membrane carrier-complex diffusion, product release, and/or rate of carrier back-diffusion.
  • On- and off-rates for complex formation may be measured, for example, by dynamic NMR, UV/vis, or time-resolved fluorescence, in, e.g., simple water-saturated dichloromethane solutions. More precise analyses of receptor-mediated transport may also be made, again with a mind to determining the dynamics of
  • the U-tube model system may be employed, and when appropriate, more sophisticated membrane analogues such as mixed phosphatidylcholine- cholesterol liposomes may be used.
  • membrane analogues such as mixed phosphatidylcholine- cholesterol liposomes
  • it may prove most convenient to prepare nucleotide or halide encapsulating liposomes and then determine the kinetics of anion extrusion as a function of carrier concentration and/or external
  • turcasarin will be found to be capable of effecting through-membrane transport of GMP and other nucleotides at near-neutral pH (i.e. in the pH 6.0 to 6.5 regime).
  • the effective transport by turcasarin a larger, more basic system, may derive from lower in-core
  • transport effected by this latter turcasarin carrier could be made somewhat nucleobase selective by adding the appropriate complementary TIPS derivative to the organic membrane phase.
  • this latter turcasarin carrier could be made somewhat nucleobase selective by adding the appropriate complementary TIPS derivative to the organic membrane phase.
  • Turcasarin compounds of the present invention are contemplated to be of use as anion transporters in various embodiments relating to human treatment.
  • the turcasarins are particularly contemplated for use as delivery agents for antiviral compounds and may thus be employed to combat a variety of diseases including AIDS, herpes, hepatitis and measles.
  • Turcasarin compounds optimized for chloride transport are also contemplated for use in the treatment of cystic fibrosis.
  • Vero cells sapphyrin and several other expanded porphyrins.
  • a monolayer of Vero cells will be infected with HSV-1, coated with an overlay culture medium, and then exposed to various relative and absolute concentrations of both putative carrier and known active antiviral.
  • adjuvant efficacy will be determined by counting the number of plaque forming units (PFU) obtained in the presence and absence of a given carrier.
  • the turcasarin compounds whether used in antiviral delivery, or for chloride transport in cystic fibrosis treatment, may be modified further if required. They might, for instance, be modified to overcome poor water solubility or
  • the turcasarins could be enveloped within a bio-compatible liposome (made, e.g. from
  • Cremophor Cremophor
  • intravenously Such an approach has previously resulted in good in vivo murine adenocarcinoma photodynamic tumor killing with a water- insoluble texaphyrin-type expanded porphyrin.
  • the "Trojan Horse” method could also be employed to deliver the turcasarin antiviral carrier in vivo to the desired locus of biological activity.
  • the idea would be to use non-infectious viral membrane material to produce liposomes and then use these in turn as transport
  • Toxicity studies will also be carried out at this stage. The methods for determining both acute and chronic toxicity will be known to those of skill in the art. Available evidence indicates that turcasarins, like sapphyrins, will be relatively nontoxic. Toxicity can be investigated in relation to solubility, net charge at physiologic pH, and changes in appended ⁇ -pyrrolic and/or meso substituents.
  • phosphate-binding turcasarin compounds of the present invention may act as receptors and transporters for other biologically important
  • polynucleic acids such as DNA, RNA and oligonucleotides.
  • Another dimension to the invention concerns the possibility of using turcasarins in the transport of DNA molecules, such as antisense DNA constructs, into cells for use in so-called gene therapy programs.
  • TFA trifluoroacetic acid
  • compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the composition, methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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Composés de formule (I) dans laquelle R?1, R2 et R3¿ peuvent être alkyle ou une variété de groupes fonctionnels et leur utilisation en tant que sensibilisants aux rayonnements.
PCT/US1995/000530 1995-01-13 1995-01-13 Turcasarines, nouvelles porphyrines expansees et utilisation desdites substances WO1996021665A1 (fr)

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WO1998006440A3 (fr) * 1996-08-16 1998-06-25 Innovir Lab Inc Transformation phenotypique de cellules induite par des sequences guide externes
US6610478B1 (en) 1996-08-16 2003-08-26 Yale University Phenotypic conversion of cells mediated by external guide sequences
US6984734B2 (en) 2002-02-26 2006-01-10 Board Of Regents, The University Of Texas System Cyclo[n]pyrroles and methods thereto
US8133474B2 (en) 2006-09-15 2012-03-13 Massachusetts Institute Of Technology Sensors for fluorescence and magnetic resonance imaging
WO2014130869A1 (fr) * 2013-02-22 2014-08-28 Samumed, Llc Gamma-dicétones en tant qu'activateurs de la voie de signalisation wnt/β-caténine
US8921413B2 (en) 2010-08-18 2014-12-30 Samumed, Llc β- and γ-diketones and γ-hydroxyketones as WNT/ β-catenin signaling pathway activators
US9795550B2 (en) 2014-08-20 2017-10-24 Samumed, Llc Gamma-diketones for treatment and prevention of aging skin and wrinkles

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Publication number Priority date Publication date Assignee Title
WO1998006440A3 (fr) * 1996-08-16 1998-06-25 Innovir Lab Inc Transformation phenotypique de cellules induite par des sequences guide externes
US6610478B1 (en) 1996-08-16 2003-08-26 Yale University Phenotypic conversion of cells mediated by external guide sequences
US6984734B2 (en) 2002-02-26 2006-01-10 Board Of Regents, The University Of Texas System Cyclo[n]pyrroles and methods thereto
US8133474B2 (en) 2006-09-15 2012-03-13 Massachusetts Institute Of Technology Sensors for fluorescence and magnetic resonance imaging
US9884053B2 (en) 2010-08-18 2018-02-06 Samumed, Llc β- and γ-diketones and γ-hydroxyketones as WNT/β-catenin signaling pathway activators
US8921413B2 (en) 2010-08-18 2014-12-30 Samumed, Llc β- and γ-diketones and γ-hydroxyketones as WNT/ β-catenin signaling pathway activators
US9303010B2 (en) 2010-08-18 2016-04-05 Samumed, Llc β- and γ-diketones and γ-hydroxyketones as Wnt/β-catenin signaling pathway activators
US9493437B2 (en) 2010-08-18 2016-11-15 Samumed, Llc β- and γ-diketones and γ-hydroxyketones as Wnt/ β-catenin signaling pathway activators
US10314832B2 (en) 2010-08-18 2019-06-11 Samumed, Llc β- and γ-diketones and γ-hydroxyketones as Wnt/β-catenin signaling pathway activators
US9951053B2 (en) 2013-02-22 2018-04-24 Samumed, Llc γ-diketones as Wnt/β-catenin signaling pathway activators
WO2014130869A1 (fr) * 2013-02-22 2014-08-28 Samumed, Llc Gamma-dicétones en tant qu'activateurs de la voie de signalisation wnt/β-caténine
RU2680716C2 (ru) * 2013-02-22 2019-02-26 СЭМЬЮМЕД, ЭлЭлСи γ-ДИКЕТОНЫ В КАЧЕСТВЕ АКТИВАТОРОВ WNT/β-КАТЕНИНОВОГО СИГНАЛЬНОГО ПУТИ
US9533976B2 (en) 2013-02-22 2017-01-03 Samumed, Llc γ-diketones as WNT/β-catenin signaling pathway activators
US10457672B2 (en) 2013-02-22 2019-10-29 Samumed, Llc γ-diketones as Wnt/β-catenin signaling pathway activators
US11034682B2 (en) 2013-02-22 2021-06-15 Samumed, Llc Gamma-diketones as wnt/β-catenin signaling pathway activators
US11673885B2 (en) 2013-02-22 2023-06-13 Biosplice Therapeutics, Inc. γ-diketones as Wnt/β-catenin signaling pathway activators
US9795550B2 (en) 2014-08-20 2017-10-24 Samumed, Llc Gamma-diketones for treatment and prevention of aging skin and wrinkles
US10434052B2 (en) 2014-08-20 2019-10-08 Samumed, Llc Gamma-diketones for treatment and prevention of aging skin and wrinkles
US11077046B2 (en) 2014-08-20 2021-08-03 Biosplice Therapeutics, Inc. Gamma-diketones for treatment and prevention of aging skin and wrinkles
US11839679B2 (en) 2014-08-20 2023-12-12 Biosplice Therapeutics, Inc. Gamma-diketones for treatment and prevention of aging skin and wrinkles

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