WO2009023357A2 - Dérivés de la curcumine et leur utilisation en tant que radioprotecteurs - Google Patents

Dérivés de la curcumine et leur utilisation en tant que radioprotecteurs Download PDF

Info

Publication number
WO2009023357A2
WO2009023357A2 PCT/US2008/064872 US2008064872W WO2009023357A2 WO 2009023357 A2 WO2009023357 A2 WO 2009023357A2 US 2008064872 W US2008064872 W US 2008064872W WO 2009023357 A2 WO2009023357 A2 WO 2009023357A2
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
amino
compound
curcumin
Prior art date
Application number
PCT/US2008/064872
Other languages
English (en)
Other versions
WO2009023357A3 (fr
Inventor
Paul Okunieff
Lurong Zhang
Chaomei Liu
Weimin Sun
Shanmin Yang
Steven Swarts
Original Assignee
University Of Rochester
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University Of Rochester filed Critical University Of Rochester
Publication of WO2009023357A2 publication Critical patent/WO2009023357A2/fr
Publication of WO2009023357A3 publication Critical patent/WO2009023357A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/38—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom
    • C07C311/49—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/06—1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • GI injury is the second major cause of death after ionizing radiation (IR) exposure.
  • IR ionizing radiation
  • Amifostine the only drug for anti-IR, can effectively protect the GI injury, it has to be given before IR. Due to the unpredicted timing of accidental or intentional radiation exposure or nuclear terrorist attack, the urgent need is to develop mitigation agents that can effectively reduce the severity of GI injury after IR exposure.
  • this invention in one aspect, relates to a method of reducing radiation damage in a subject comprising administering to the subject an effective amount of an agent, wherein the agent is an analog, derivative, or metabolite of curcumin.
  • the invention relates to a method of reducing radiation damage in a subject comprising administering to the subject an effective amount of an agent, wherein the agent is administered after radiation exposure.
  • the invention relates to compositions capable or reducing radiation damage in a subject and methods of their synthesis.
  • the invention relates to compounds modified from curcumin, designed to have antioxidant properties to be capable of acting as radioprotective to the gastrointestinal tract and other tissues.
  • the invention relates to a compound comprising a structure:
  • Z is selected from CO, CH 2 CO, CH 2 CH 2 CO, CH(OH)CH 2 CO, CH(NH 2 )CH 2 CO, CH 2 CH(OH)CO, CH 2 CH(NH 2 )CO, SO, and SO 2 ; and wherein R is selected from substituted or unsubstituted aryl, amino acid residue, substituted or unsubstituted heterocycle, and fused bicyclic or heterobicyclic moiety, or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound comprising a structure:
  • R 51 is selected from: substituted or unsubstituted alkyl; substituted or unsubstituted sulphydrylalkyl having one or two sulphydryl group(s); substituted or unsubstituted alkaryl selected from benzyl and phenyl ethyl, having from one to three substituent(s) independently selected from one to three substituted or unsubstituted alkyl; from one to three substituted or unsubstituted alkoxyl; from one to three substituted or unsubstituted alkylthio; from one to three halogen; from one to three primary amino, secondary amino, tertiary amino; from one to two nitro; from one to two cyano; and from one to two acyl having a structure:
  • R 52 is selected from substituted or unsubstituted alkyl; substituted or unsubstituted alkoxyl; substituted or unsubstituted alkylthio; primary amino, secondary amino, tertiary amino; substituted or unsubstituted aryl; and substituted or unsubstituted heteroaryl; substituted or unsubstituted aryl having a structure:
  • R 53 is from one to three substituent(s) independently selected from substituted or unsubstituted alkyl; substituted or unsubstituted alkoxyl; substituted or unsubstituted alkylthio; halogen; primary amino, secondary amino, tertiary amino; from one to two nitro, with the proviso that R 53 is not 3-nitro; from one to two cyano; one to two carboxyl with the proviso that R 53 is not 4-carboxylic acid; and from one to two acyl having a structure:
  • R 54 is selected from substituted or unsubstituted alkyl; substituted or unsubstituted alkoxyl; and primary amino, secondary amino, or tertiary amino; substituted or unsubstituted heterocycle having a structure:
  • R 55 is from one to three substituent(s) independently selected from substituted or unsubstituted alkyl; substituted or unsubstituted alkoxyl; substituted or unsubstituted alkylthio; halogen; primary amino, secondary amino, tertiary amino; nitro; from one to two cyano; carboxyl; and acyl having a structure:
  • R 54 is selected from substituted or unsubstituted alkyl; substituted or unsubstituted alkoxyl; and primary amino, secondary amino, or tertiary amino; fused bicyclic or heterobicyclic moiety having a structure:
  • Fus is selected from aromatic, partially hydrogenated, and fully hydrogenated fused bicyclic or heterobicyclic moieties; and wherein R 57 is from one to three substituent(s) independently selected from substituted or unsubstituted alkyl; substituted or unsubstituted alkoxyl; substituted or unsubstituted alkylthio; halogen; primary amino, secondary amino, tertiary amino; nitro; cyano; carboxyl; and acyl having a structure:
  • R 54 is selected from substituted or unsubstituted alkyl; substituted or unsubstituted alkoxyl; and primary amino, secondary amino, or tertiary amino; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one of the disclosed compounds or disclosed products and a pharmaceutically acceptable carrier.
  • the invention relates to a method of preparing a curcumin derivative, the method comprising the step of reacting curcumin with a hydrazine derivative selected from a substituted or unsubstituted arylsulfonylhydrazide, a substituted or unsubstituted alkylcarbohydrazide, a substituted or unsubstituted sulphydrylalkylcarbohydrazide, a substituted or unsubstituted alkarylcarbohydrazide, a substituted or unsubstituted arylcarbohydrazide, a substituted or unsubstituted heterocyclic carbohydrazide, a substituted or unsubstituted carbohydrazide, a substituted or unsubstituted 2-aminoacetohydrazide, and a substituted or unsubstituted fused bicyclic or heterobicyclic carb
  • the invention relates to a product of the disclosed methods.
  • the invention relates to a method of mitigating radiation toxicity in a subject comprising the step of administering to the subject at least one of the disclosed compounds at least one of the disclosed pharmaceutical compositions, or at least one of the disclosed products in a dosage and amount effective to mitigate radiation toxicity in the subject.
  • the invention relates to a method of treating radiation-induced gastrointestinal syndrome in a subject comprising the step of administering to the subject at least one of the disclosed compounds at least one of the disclosed pharmaceutical compositions, or at least one of the disclosed products in a dosage and amount effective to treat gastrointestinal syndrome in the subject.
  • the invention relates to a method for the treatment of a disease of uncontrolled cellular proliferation comprising administering to a subject having a disease of uncontrolled cellular proliferation at least one of the disclosed compounds at least one of the disclosed pharmaceutical compositions, or at least one of the disclosed products in a dosage and amount effective to treat the disease of uncontrolled cellular proliferation.
  • Figure 1 shows a voltammeter analysis using neutral buffer with Ag/ AgCl as reference electrode and glassy carbon as working electrode.
  • Figure IA shows vehicle alone.
  • Figure IB shows compounds with low redox potential.
  • Figure 1C shows Curcumin.
  • Figure ID shows D13.
  • Figure IE shows D68.
  • Figure IF shows Vitamin C.
  • Figure IG shows D 12.
  • Figure IH shows HPLC analysis of D68.
  • Figure 2 shows GI protection of novel compounds D12, D13, and D68 relative to a control.
  • Figure 2 A shows GI protection of D12 in BALB/c mice.
  • Figure 2B shows GI protection of D 12 in BALB/c mice.
  • Figure 2C shows GI protection of D68 in BALB/c mice.
  • Figure 3 shows GI protection of novel compound D68 relative to a control in a different mouse model.
  • Figure 3 A shows GI protection of D68 in C57BL/6 mcie.
  • Figure 3B shows GI protection of D68 in C57BL/6 mice.
  • Figure 4 shows that the disclosed compounds can rescue a mouse following total body irradiation.
  • Figure 4 A shows TBI protection of D 12
  • 4B shows TBI protection of D13
  • 4C shows TBI protection of D68.
  • Figure 4D shows TBI protection of D68 following 7.0 Gy TBI.
  • Figure 5 shows a side-by-side comparison of the D12, D13, and D68 in rescuing a mouse from sub- TBI.
  • Figure 6 shows that compared with the normal, the numbers of proliferating crypts in all the segments of mice exposed to 10.5 Gy treated with vehicle alone were decreased dramatically.
  • Figure 6A shows that proliferating crypts in jejunum as seen by H&E staining.
  • Figure 6B shows increased crypts via BrdU staining.
  • Figures 6C-E show measured villi length in the jejunum, duodenum, and ileum by H&E and BrdU staining in Balb/C and C57BL/6 mice following treatment with D68 and sub-TDI.
  • Figure 6F shows the effects of different treatment on Proliferating crypts.
  • Figure 7 shows the stool hemoccult score differed among the groups.
  • Figure 7 A shows the hemoccult score.
  • Figure 7B and C shows the stools of IR and D68 treated mice.
  • Figure 7D and E show that Plasma endotoxin levels were reduced in D68 treated Balb/c (D) and C57BL/6 (E) mice.
  • Figure 7F shows loss and gain of body weight in D68 treated and control mice following IR.
  • Figure 8 shows that D68 restores GI endocrine and exocrine ability in mice with GI syndrome of ARS.
  • Figure 8 shows (A) plasma secretin levels, (B) Plasma CCK levels, (C) Plasma Insulin levels, and (D) Plasma Amylase levels 3.5 days following 10.5Gy sub-TBI in Balb/C mice.
  • Figure 9 shows the levels of various inflammatory molecules 3.5 days following exposure to 12Gy sub-TDI in Balb/C mice.
  • Figure 9 shows that, several IMs that were increased by the 12 Gy IR could be reduced by D68, including MCP-I (A), IL6 (B), KC (C), ILl ⁇ ( D), BLC (E), TNFa F), TCA-3 (G) and G-CSF (H).
  • Figure 91 shows alterations in plasma CD30 levels.
  • Figure 10 shows the results of our preliminary analysis of D68 in plasma as a function of time.
  • Figure 11 shows a typical chromatogram obtained for a SPE-extracted plasma sample where D68 and curcumin are measured at 327 ran and 430 ran (lower panel), respectively.
  • Figure 12 shows further analysis of the HPLC chromatograms from the PK studies shows the presence of additional peaks that are believed to be metabolites of D68.
  • Figure 13 shows that when a solution of DPPH is mixed with that of a substance that can donate a hydrogen atom (such as curcumin and the D-analogs thereof), this gives rise to the reduced form of DPPH.
  • a substance that can donate a hydrogen atom such as curcumin and the D-analogs thereof
  • Figure 14 shows IC50 values which were used to compare DPPH scavenging activity. Compared are curcumin, D12, 13, D68, and Trolox.
  • Figure 15 shows the total antioxidant capacity of D47 and D68 compared to curcumin.
  • Figure 16 shows that intracellular ROS were detected by FCM in SW 480 cell line.
  • A shows 5 Gy + Vehicle alone.
  • B shows 5 Gy + D68 micro-emulsion.
  • C shows the percentage of gate after 5 Gy IR and treatment.
  • D shows X mean alternation.
  • 5 Gy + E alone 5 Gy IR + Vehicle.
  • 5 Gy + D 68-E 5 Gy IR+ D68 microemulsion lOug/mL.
  • E shows alternation of percentage gate after treatment.
  • F shows a decrease of X mean after treatment with D68.
  • Figure 17 shows the kinetic plot for CytoC-Fe +3 ⁇ Cyto-Fe +2 .
  • Figure 18 shows a plot of competition kinetics - CytoC versus curcumin.
  • K cUr 1.19 ( ⁇ 0.12) x 10 5 M- 1 s "1 .
  • Ranges can be expressed herein as from “about” one particular value, and/or to "about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10" is also disclosed.
  • a “decrease” can refer to any change that results in a smaller amount of a symptom, condition, or disease such as radiation toxicity.
  • a “decrease” can refer to a reduction in an activity as well as a reduction in the effects of a disease or condition.
  • a decrease can be a change in the symptoms of a disorder such that the symptoms are less than previously observed.
  • a decrease in the toxic effects of ionizing radiation can include but is not limited to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% decrease in the symptoms associated with exposure to ionizing radiation.
  • An "increase" can refer to any change that results in a larger amount of a symptom, condition, or disease such as radiation toxicity.
  • an increase in the amount in toxic effects of ionizing radiation can include but is not limited to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% increase in the symptoms associated with exposure to ionizing radiation.
  • GI protectants Through extensive searching for GI protectants, agents were identified that mitigated the acute GI syndrome of acute radiation syndrome (ARS) and reduce the death rate of ARS within 7 days.
  • the approach was to chemically synthesize agents that derived from natural compounds.
  • the testing system was a sub-total body irradiation (sub-TBI) model in which one leg of animal was shielded from IR allowing the animal to tolerate a high IR dose that causes GI death within 5-7 days without bone marrow death.
  • sub-TBI sub-total body irradiation
  • agents After screen about a hundred of synthetic compounds, agents were identified that had a high potential of anti-oxidant (measured by Voltammetric analysis) and were capable of mitigating the acute GI syndrome of ARS.
  • the effectiveness of the radioprotector was demonstrated by several facts: 1) an increased a long-term survival of mice that received a GI death IR dose at LDioo /7 ; 2) an increased DMF for GI-IR death (about 1.16 with a potential to be higher after formulation optimization); 3) a higher than 50% prolonged the survival time for the mice received a high TBI dose that cause BM death (LD 1O o/ 3O ); 4) an increased proliferation of crypts; 5) an increased length and number of villi of small intestine; and 6) a reduced abnormalities of GI syndrome induced by IR, such as hemoccults, loose stool, decreased amylase and secretin and increased endotoximia. Beneficial effects were observed in other two strains of mouse, indicating that the new agent is effective on different genome backgrounds.
  • novel GI radioprotectors including for example D 12, D13, and D68.
  • the disclosed compounds are: 1) effective when given after exposure to a GI death IR dose; 2) can be synthesized in a large quantity; 3) are small compounds that have non-antigenicity and can be used in a long-run without fear of host's developing resistance or immune reaction that is associated with most of protein regime; 4) their maximum tolerate dose (MTD) can be 15 higher than effective dose (ED 50 ), indicating that their is a big safety window (most radioprotector has a ratio of 5 to 10; 5) are stable at various hustle conditions, such as boil, and therefore they are portable by soldiers; 6) orally effective and can be self-administrated; 7) cheap to synthesize and therefore cost-effective compared with other biological regime, such as protein growth factors (G-CSF, KGF, FGF) which require a whole set of expensive processes for the production and purification.
  • G-CSF protein growth factors
  • KGF protein growth factors
  • compositions Disclosed are the components to be used to prepare the disclosed compositions as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular analogue, derivative or metabolite of curcumin is disclosed and discussed and a number of modifications that can be made, specifically contemplated is each and every combination and permutation of curcumin and the modifications that are possible unless specifically indicated to the contrary.
  • Curcumin [diferuloyl methane; l,7-bis-(4-hydroxy-3-methoxyphenyl)-l,6- heptadiene-3,5-dione; CR] is the major constituent in the rhizome of Curcuma longa ⁇ Zingiber aceae), commonly named turmeric.
  • the structure of curcumin can be divided into 3 parts A, B and C. Part A and C are same: jo ⁇ r ⁇ -phenol with a ortho- methoxyl group. B is a ⁇ , ⁇ -unsaturated 1,3-diketone.
  • Curcumin has been reported to possess various biological and pharmacological activities, including antioxidative (Dutta Sabari et al. Bioorganic & Medicinal Chemistry Letters 15 (2005) 2738-2744; Deng SX. et al. Food Chemistry 98 (2006) 112-119; Waylon M. Weber, Lucy A. Hunsaker, Steve F. Abcouwer, Lorraine M. Deck, and David L. Vander Jagt, Bioorg. Med. Chem. 13 (2005) 3811-3820; Venkateswarlu S. et al. Bioorganic & Medicinal Chemistry 13 (2005) 6374-6380; Daniel S. et al. J. of Inorganic Biochemistry 98 (2004) 266-275; Priyadarsini K.
  • both of curcumin' s hydroxyl groups attached to the aromatic rings (A and C parts) and the methylene CH 2 group of the ⁇ -l,3-diketone moiety (B part) are responsible for the formation of free radicals and protection of DNA, RNA, lipid and protein molecules.
  • the pair of 4- hydroxyl groups conjugated through a long olefmic double bond chain in the curcumin molecule is easily ionized to form radicals after absorption of energy from radiation. This is also facilitated by the formation of a hydrogen-bond between the 4- hydroxyl group and its neighboring 3-methoxy group in benzene rings.
  • the antioxidant activity and other biological properties of curcumin can be decreased if its hydroxyl groups in the aryl rings are methylated or if the olefinic bonds in the ⁇ -l,3-diketone moiety are hydrogenated to give the tetrahydro derivative of curcumin.
  • curcumin are important for antiinflammatory activity. This activity can be enhanced when, in combination with the para hydroxy groups, the meta positions are occupied with alkyl groups (AN Nurfina, MS Reksohadiprodjo, and H Timmerman et al. Eur J Med Chem (1997)32, 321-328). The presence of olefinic double bonds and 4-hydroxyl groups can be important for the antiinflammatory activity of curcumin.
  • the phenoxyl radical is the predominant species in the case of curcumin, while in the case of CRSC it is the imine carbonyl radical, which is the major species being formed in this reaction.
  • This specie is also more reactive, according to the reactions of three radicals, N 3 *, methyl, and halocarbon peroxyl radicals with both curcumin and CRSC.
  • Modification of the ⁇ -l,3-diketone moiety in curcumin can up-regulate its antioxidant property and free radical scavenging ability.
  • the curcumin semicarbazone theoretically has one more chemical mechanism as a radical scavenger than the curcumin itself.
  • the term "residue" of a chemical species refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species.
  • an ethylene glycol residue in a polyester refers to one or more -OCH 2 CH 2 O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester.
  • a sebacic acid residue in a polyester refers to one or more -CO(CH 2 ) 8 CO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described below.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms, such as nitrogen can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • substitution or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • a 1 ,” “A 2 ,” “A 3 ,” and “A 4 " are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.
  • alkyl as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, for example 1 to 12 carbon atoms or 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, w-butyl, isobutyl, s-butyl, t- butyl, M-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dode cyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like.
  • the alkyl group can also be substituted or unsubstituted.
  • the alkyl group can be substituted with one or more groups including, but not limited to, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • a "lower alkyl” group is an alkyl group containing from one to six carbon atoms.
  • alkyl is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group.
  • halogenated alkyl specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine.
  • alkoxyalkyl specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below.
  • alkylamino specifically refers to an alkyl group that is substituted with one or more amino groups, as described below, and the like.
  • alkyl is used in one instance and a specific term such as “alkylalcohol” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “alkylalcohol” and the like.
  • cycloalkyl as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like.
  • heterocycloalkyl is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted.
  • the cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • polyalkylene group as used herein is a group having two or more CH 2 groups linked to one another.
  • the polyalkylene group can be represented by the formula — (CH 2 ) a — , where "a" is an integer of from 2 to 500.
  • alkoxy and “alkoxyl” as used herein refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an "alkoxy” group can be defined as — OA 1 where A 1 is alkyl or cycloalkyl as defined above.
  • Alkoxy also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as — OA 1 - OA 2 or — OA 1 - (OA 2 ) a — OA 3 , where "a” is an integer of from 1 to 200 and A 1 , A 2 , and A 3 are alkyl and/or cycloalkyl groups.
  • alkenyl as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond.
  • the alkenyl group can be substituted with one or more groups including, but not limited to, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • groups including, but not limited to, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl,
  • Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like.
  • heterocycloalkenyl is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • alkynyl is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond.
  • the alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • cycloalkynyl as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound.
  • cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like.
  • heterocycloalkynyl is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted.
  • the cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • aryl as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, phenoxybenzene, and the like.
  • aryl also includes “heteroaryl,” which is defined as a group that contains an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus.
  • non-heteroaryl which is also included in the term “aryl,” defines a group that contains an aromatic group that does not contain a heteroatom.
  • the aryl group can be substituted or unsubstituted.
  • the aryl group can be substituted with one or more groups including, but not limited to, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • biasing is a specific type of aryl group and is included in the definition of "aryl.”
  • Biaryl refers to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.
  • amine or "amino” as used herein are represented by the formula NA 1 A 2 A 3 , where A 1 , A 2 , and A 3 can be, independently, hydrogen or substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • esters as used herein is represented by the formula — OC(O)A 1 or — C(O)OA 1 , where A 1 can be a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • polyester as used herein is represented by the formula — (A 1 O(O)C-A 2 - C(O)O) 3 - or — (A 1 O(O)C-A 2 -OC(O))a— , where A 1 and A 2 can be, independently, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and "a" is an interger from 1 to 500.
  • Polymer is the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.
  • ether as used herein is represented by the formula A 1 OA 2 , where A 1 and A 2 can be, independently, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein.
  • polyether as used herein is represented by the formula — (A 1 O- A 2 O) 3 — , where A 1 and A 2 can be, independently, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and "a" is an integer of from 1 to 500.
  • polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.
  • halide and "halo” as used herein refer to the halogens fluorine, chlorine, bromine, and iodine. It is also contemplated that, in certain aspects, pseudohalides (e.g., mesyl groups, brosyl groups, and tosyl groups) can be substituted for halides.
  • pseudohalides e.g., mesyl groups, brosyl groups, and tosyl groups
  • hydroxyl and "hydroxyl” as used herein is represented by the formula — OH.
  • ketone and “keto” as used herein is represented by the formula A 1 C(O)A 2 , where A 1 and A 2 can be, independently, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • nitro as used herein is represented by the formula — NO 2 .
  • silica as used herein is represented by the formula — SiA 1 A 2 A 3 , where A 1 , A 2 , and A 3 can be, independently, hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfo-oxo is represented by the formulas — S(O)A 1 , -S(O) 2 A 1 , -OS(O) 2 A 1 , or -OS(O) 2 OA 1 , where A 1 can be hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfonyl is used herein to refer to the sulfo-oxo group represented by the formula -S(O) 2 A 1 , where A 1 can be hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfone as used herein is represented by the formula A 1 S(O) 2 A 2 , where A 1 and A 2 can be, independently, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfoxide as used herein is represented by the formula A 1 S(O)A 2 , where A 1 and A 2 can be, independently, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • arylsulfonylhydrazide refers to a sulfonylhydrazide- functionalized aromatic compound. Such structure can be represented by the formula:
  • alkylcarbohydrazide refers to a carbohydrazide- functionalized alkyl compound. Such structure can be represented by the formula:
  • sulphydrylalkylcarbohydrazide refers to a sulphhydryl- (viz., sulfhydryl- or thiol-) functionalized alkylcarbohydrazide compound.
  • sulphhydryl- viz., sulfhydryl- or thiol-
  • alkylcarbohydrazide compound Such structure can be represented by the general formula:
  • Examples of a sulphydrylalkylcarbohydrazide include 2-mercaptopropanehydrazide and 3- mercaptopropanehydrazide.
  • alkarylcarbohydrazide refers to an aryl functionalized alkylcarbohydrazide compound. Such structure can be represented by the formula:
  • alkarylcarbohydrazide 2-phenylacetohydrazide.
  • arylcarbohydrazide refers to a carbohydrazide- functionalized aromatic compound. Such structure can be represented by the formula:
  • heterocyclic carbohydrazide refers to a carbohydrazide-functionalized heterocyclic compound. Such structure can be represented by the formula:
  • heterocyclic carbohydrazide examples include furan-2-carbohydrazide and 1- methylpiperidine-3-carbohydrazide.
  • 2-aminoacetohydrazide refers to a compound represented by the general formula:
  • 2-aminoacetohydrazide is l,7-bis-(4-hydroxy-3-methoxyphenyl)-l,6- heptadiene-3,5-dione L-tyrosine monohydrazone. It is also contemplated that the 2- aminoacetohydrazide can be further functionalized at the terminal amine with one or more additional amino acid residues, for example, as 2-amino-N-(2-(l-hydrazinyl-l-oxopropan-2- ylamino)-2-oxo-l-phenylethyl)-3-methylbutanamide:
  • an aminoacetohydrazide can be provided as oligopeptide- or polypeptide-functionalized carbohydrazide compounds.
  • the compounds can be provided in protected or unprotected forms, as appropriate.
  • fused bicyclic or heterobicyclic carbohydrazide refers to a carbohydrazide- functionalized fused bicyclic or heterobicyclic compound. Examples include 2-naphthohydrazide and bicyclo[2.1.1]hexane-2-carbohydrazide:
  • curcumin's semicarbazone molecule is replaced by benzene or other aromatic heterocycles. Accordingly, a series of substituted curcumin carbonyl hydrazones were designed and synthesized and their radiation protective effect and anticancer activities were screened.
  • BAECs bovine aortic endothelial cells
  • IC 50 520 nM
  • the invention relates to a compound comprising a structure:
  • Z is selected from CO, CH 2 CO, CH 2 CH 2 CO, CH(OH)CH 2 CO, CH(NH 2 )CH 2 CO, CH 2 CH(OH)CO, CH 2 CH(NH 2 )CO, SO, and SO 2 ; and wherein R is selected from substituted or unsubstituted aryl, amino acid residue, substituted or unsubstituted heterocycle, and fused bicyclic or heterobicyclic moiety, or a pharmaceutically acceptable salt thereof, hi a further aspect, Z is CO, SO, or SO 2 ; and wherein R is substituted or unsubstituted aryl having a structure:
  • R 1 ' is from one to three substituent(s) independently selected from one to three substituted or unsubstituted alkyl; from one to three substituted or unsubstituted alkoxyl; from one to three substituted or unsubstituted alkylthio; from one to three halogen; from one to three primary amino, secondary amino, tertiary amino; from one to two nitro; from one to two cyano; and from one to two acyl having a structure:
  • R 12 is selected from substituted or unsubstituted alkyl; substituted or unsubstituted alkoxyl; substituted or unsubstituted alkylthio; primary amino, secondary amino, tertiary amino; substituted or unsubstituted aryl; and substituted or unsubstituted heteroaryl.
  • Z can be CO, and R can be 3-pyridinyl, 4- pyridinyl, phenyl, or furanoyl.
  • Z and R together comprise a nicotinoyl, isonicotinoyl, benzoyl, or furanoyl moiety.
  • the disclosed compounds include those structures represented by a formula:
  • the compound can be l,7-bis-(4-hydroxy-3- methoxyphenyl)-l,6-heptadiene-3,5-dione monoisonicotinoylhydrazone (also referred to herein as D12); l,7-bis-(4-hydroxy-3-methoxyphenyl)-l,6-heptadiene-3,5-dione mononicotinoylhydrazone (also referred to herein as D13); l,7-bis-(4-hydroxy-3- methoxyphenyl)-l,6-heptadiene-3,5-dione benzoyl monohydrazone (also referred to herein as D68); and l,7-bis-(4-hydroxy-3-methoxyphenyl)-l,6-heptadiene-3,5-dione 2'-furoyl monohydrazone (also referred to herein as D56).
  • D12 l,7-bis-(4-hydroxy
  • Z is CO; and wherein Z and R together comprise an amino acid residue.
  • the amino acid residue can be selected from one or more of arginine, asparagine, cysteine, histidine, hydroxylysine, hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophane, tyrosine, and valine residues, hi a further aspect, the amino acid residue is an oligopeptide comprising from one to about ten, from one to about fifteen, from one to about twenty, or from one to about twenty five amino acid residues. In a yet further aspect, the amino acid residue is a polypeptide.
  • Z is CO, SO, or SO 2 ; and wherein R is substituted or unsubstituted heterocycle having a structure:
  • R .31 is from one to three substituent(s) independently selected from substituted or unsubstituted alkyl; substituted or unsubstituted alkoxyl; substituted or unsubstituted alkylthio; halogen; primary amino, secondary amino, tertiary amino; nitro; from one to two cyano; carboxyl; and acyl having a structure:
  • R is selected from substituted or unsubstituted alkyl; substituted or unsubstituted alkoxyl; substituted or unsubstituted alkylthio; primary amino, secondary amino, tertiary amino; substituted or unsubstituted aryl; and substituted or unsubstituted heteroaryl.
  • Het is selected from furan, thiophene, imidazole, thiazole, oxazole, thiadiazole, oxadiazole, triazole, pyridine, and pyrimidine.
  • R is a fused bicyclic or heterobicyclic moiety having a structure:
  • Fus is selected from aromatic, partially hydrogenated, and fully hydrogenated fused bicyclic or heterobicyclic moieties; and wherein R 31 is from one to three substituent(s) independently selected from substituted or unsubstituted alkyl; substituted or unsubstituted alkoxyl; substituted or unsubstituted alkylthio; halogen; primary amino, secondary amino, tertiary amino; nitro; from one to two cyano; carboxyl; and acyl having a structure:
  • R 42 is selected from substituted or unsubstituted alkyl; substituted or unsubstituted alkoxyl; substituted or unsubstituted alkylthio; primary amino, secondary amino, tertiary amino; substituted or unsubstituted aryl; and substituted or unsubstituted heteroaryl.
  • Fus is selected from aromatic, partially hydrogenated, or fully hydrogenated naphthalene, quinoline, isoquinoline, indole, benzothiophene, benzoimidazole, benzothiazole, benzoxazole, benzofuran, benzopyran, and 4H-[l]benzopyran[4,3-b]thiophene.
  • the invention relates to a compound comprising a structure:
  • R 51 is selected from substituted or unsubstituted alkyl; substituted or unsubstituted sulphydrylalkyl having one or two sulphydryl group(s); substituted or unsubstituted alkaryl selected from benzyl and phenyl ethyl, having from one to three substituent(s) independently selected from one to three substituted or unsubstituted alkyl; from one to three substituted or unsubstituted alkoxyl; from one to three substituted or unsubstituted alkylthio; from one to three halogen; from one to three primary amino, secondary amino, tertiary amino; from one to two nitro; from one to two cyano; and from one to two acyl having a structure:
  • R 52 is selected from substituted or unsubstituted alkyl; substituted or unsubstituted alkoxyl; substituted or unsubstituted alkylthio; primary amino, secondary amino, tertiary amino; substituted or unsubstituted aryl; and substituted or unsubstituted heteroaryl; substituted or unsubstituted aryl having a structure:
  • R 53 is from one to three substituent(s) independently selected from substituted or unsubstituted alkyl; substituted or unsubstituted alkoxyl; substituted or unsubstituted alkylthio; halogen; primary amino, secondary amino, tertiary amino; from one to two nitro, with the proviso that R 53 is not 3-nitro; from one to two cyano; one to two carboxyl with the proviso that R 53 is not 4-carboxylic acid; and from one to two acyl having a structure:
  • R 54 is selected from substituted or unsubstituted alkyl; substituted or unsubstituted alkoxyl; and primary amino, secondary amino, or tertiary amino; substituted or unsubstituted heterocycle having a structure:
  • R 55 is from one to three substituent(s) independently selected from substituted or unsubstituted alkyl; substituted or unsubstituted alkoxyl; substituted or unsubstituted alkylthio; halogen; primary amino, secondary amino, tertiary amino; nitro; from one to two cyano; carboxyl; and acyl having a structure:
  • R 54 is selected from substituted or unsubstituted alkyl; substituted or unsubstituted alkoxyl; and primary amino, secondary amino, or tertiary amino; fused bicyclic or heterobicyclic moiety having a structure:
  • Fus is selected from aromatic, partially hydrogenated, and fully hydrogenated fused bicyclic or heterobicyclic moieties; and wherein R 57 is from one to three substituent(s) independently selected from substituted or unsubstituted alkyl; substituted or unsubstituted alkoxyl; substituted or unsubstituted alkylthio; halogen; primary amino, secondary amino, tertiary amino; nitro; cyano; carboxyl; and acyl having a structure:
  • R 54 is selected from substituted or unsubstituted alkyl; substituted or unsubstituted alkoxyl; and primary amino, secondary amino, or tertiary amino; or a pharmaceutically acceptable salt thereof.
  • R 51 is substituted or unsubstituted alkyl having one or two hydroxyl groups, hi a further aspect, R 51 is 2-hydroxyethyl, 2-hydroxypropyl, 1- methyl-2-hydroxyethyl, or 3-hydroxybutyl. hi a further aspect, R 51 is selected from 2- sulphydrylethyl, 2-sulphydrylpropyl, l-methyl-2-sulphydrylethyl, and 3- sulphydrylbutyl.
  • compositions disclosed herein and the compositions necessary to perform the disclosed methods can be made using any method known to those of skill in the art for that particular reagent or compound unless otherwise specifically noted.
  • the invention relates to a method of preparing a curcumin derivative, the method comprising the step of reacting curcumin with a hydrazine derivative selected from a substituted or unsubstituted arylsulfonylhydrazide, a substituted or unsubstituted alkylcarbohydrazide, a substituted or unsubstituted sulphydrylalkylcarbohydrazide, a substituted or unsubstituted alkarylcarbohydrazide, a substituted or unsubstituted arylcarbohydrazide, a substituted or unsubstituted heterocyclic carbohydrazide, a substituted or unsubstituted carbohydrazide, a substituted or unsubstituted 2-aminoacetohydrazide, and a substituted or unsubstituted fused bicyclic or heterobicyclic carbohydr
  • the method produces a hydrazone:
  • the method produces a pyrazole:
  • the method further comprises the step of synthesizing the hydrazine derivative.
  • Hydrazine derivatives are well-known in the art; on of ordinary skill in the art of organic chemical synthesis can readily prepare hydrazines without undue experimentation with reference to published procedures and techniques.
  • the synthesizing step comprises reduction of an aryl diazonium salt to form a hydrazine derivative.
  • Aryl diazonium salts can be prepared, for example, by treatment of an amine with sodium nitrite in the presence of a mineral acid. Reduction can be accomplished, for example, by treatment with sulfite salts.
  • the synthesizing step comprises the steps of treating a carbonyl compound with at least two molar equivalents of hydrazine to form a hydrazone, and reducing the hydrazone to form a hydrazine derivative.
  • the hydrazone can be reduced under common reducing conditions, including sulfite salts.
  • the hydrazine derivative is a substituted or unsubstituted arylsulfonylhydrazide selected from benzenesulfonohydrazide and p- toluenesulfonohydrazide.
  • the hydrazine derivative is a substituted or unsubstituted carbohydrazide selected from benzohydrazide, nicotinohydrazide, isonicotinohydrazide, aminobenzohydrazide, hydroxybenzohydrazide, furancarbohydrazide, and thiophenecarbohydrazide.
  • the hydrazine derivative is a substituted or unsubstituted 2-aminoacetohydrazide 2- aminoacetohydrazide comprising a residue of arginine, asparagine, cysteine, histidine, hydroxylysine, hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophane, tyrosine, or valine.
  • the invention relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one of the disclosed compounds or at least one of the disclosed products and a pharmaceutically acceptable carrier.
  • Compounds disclosed herein and compositions thereof can be administered by various methods including, for example, orally, intravenously, enterally, parenterally, topically, nasally, vaginally, opthalinically, sublingually or by inhalation for the treatment of diseases related to uncontrolled proliferative diseases such as, Routes of administration and dosages known in the art can be found in Comprehensive Medicinal Chemistry, Volume 5, Hansch, C. Pergamon Press, 1990; incorporated herein by reference in its entirety.
  • the compounds described herein can be administered as pure chemicals either singularly or plurally, it is preferable to present the active ingredient as a pharmaceutical composition.
  • compositions comprising one or more compounds and/or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers thereof and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carrier(s) should be "acceptable” in the sense of being compatible with the other ingredients of the composition and not overly deleterious to the recipient thereof.
  • the pharmaceutical composition is administered to an animal diagnosed as in need of treatment for a disease of uncontrolled cellular proliferation, in an amount effective to treat the disease of uncontrolled cellular proliferation, such as the various cancers and precancerous conditions described herein.
  • the amount of the compound, or an active salt or derivative thereof (i.e. a prodrug), required for effective use in treatment of a disease of uncontrolled cellular proliferation will vary not only with the particular compound and/or salt selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient.
  • An effective amount of a compound provided herein is a substantially nontoxic but sufficient amount of the compound to provide a clinically useful degree inhibition of the growth or progression of the disease of uncontrolled cellular proliferation.
  • the active compounds of the invention are administered to achieve peak plasma concentrations of the active compound of from typically about 0.1 to about 100 ⁇ M, about 1 to 50 ⁇ M, or about 2 to about 30 ⁇ M. This can be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 0.5-500 mg of the active ingredient. Desirable blood levels can be maintained by continuous infusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusions containing about 0.4-15 mg/kg of the active compounds of the invention.
  • compositions include those suitable for oral, enteral, parental (including intramuscular, subcutaneous and intravenous), topical, nasal, vaginal, ophthalinical, sublingually or by inhalation administration.
  • the compositions can, where appropriate, be conveniently presented in discrete unit dosage forms and can be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with liquid carriers, solid matrices, semi-solid carriers, finely divided solid carriers or combination thereof, and then, if necessary, shaping the product into the desired delivery system.
  • compositions can be adapted to provide sustained release of the active ingredient employed, e.g., by combination thereof with certain hydrophilic polymer matrices, e.g., comprising natural gels, synthetic polymer gels or mixtures thereof.
  • the compounds of the invention can have oral bioavailability as exhibited by blood levels after oral dosing, either alone or in the presence of an excipient. Oral bioavailability allows oral dosing for use in chronic diseases, with the advantage of self-administration and decreased cost over other means of administration.
  • compositions suitable for oral administration can be presented as discrete unit dosage forms such as hard or soft gelatin capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or as granules; as a solution, a suspension or as an emulsion.
  • the active ingredient can also be presented as a bolus, electuary or paste.
  • Tablets and capsules for oral administration can contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
  • the tablets can be coated according to methods well known in the art., e.g., with enteric coatings.
  • Oral liquid preparations can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or can be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations can contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which can include edible oils), or one or more preservative.
  • the compounds can also be formulated for parenteral administration
  • compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient can be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • the compounds can be formulated as ointments, creams or lotions, or as the active ingredient of a transdermal patch.
  • Suitable transdermal delivery systems are disclosed, for example, in Fisher et al. (U.S. Patent (No. 4,788,603, incorporated herein by reference) or Bawas et al. (U.S. Patent No. 4,931,279, 4,668,504 and 4,713,224; all incorporated herein by reference).
  • Ointments and creams can, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions can be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • the active ingredient can also be delivered via iontophoresis, e.g., as disclosed in U.S. Patent Nos. 4,140,122, 4383,529, or 4,051,842; incorporated herein by reference.
  • compositions suitable for topical administration in the mouth include unit dosage forms such as lozenges comprising active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; mucoadherent gels, and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • unit dosage forms such as lozenges comprising active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; mucoadherent gels, and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • the above-described compositions can be adapted to provide sustained release of the active ingredient employed, e.g., by combination thereof with certain hydrophilic polymer matrices, e.g., comprising natural gels, synthetic
  • compositions according to the invention can also contain other adjuvants such as flavorings, coloring, antimicrobial agents, or preservatives.
  • the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • a suitable dose will, in alternative embodiments, typically be in the range of from about 0.5 to about 10 mg/kg/day, or from about 1 to about 20 mg/kg of body weight per day, or from about 5 to about 50 mg/kg/day.
  • the desired dose can conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose as necessary by one skilled in the art, can itself be further divided, e.g., into a number of discrete loosely spaced administrations.
  • compositions of matter useful for the treatment of cancer contain, in addition to the aforementioned compounds, an additional therapeutic agent.
  • agents can be chemotherapeutic agents, ablation or other therapeutic hormones, antineoplastic agents, monoclonal antibodies useful against cancers and angiogenesis inhibitors.
  • chemotherapeutic agents can be chemotherapeutic agents, ablation or other therapeutic hormones, antineoplastic agents, monoclonal antibodies useful against cancers and angiogenesis inhibitors.
  • angiogenesis inhibitors can be chemotherapeutic agents, ablation or other therapeutic hormones, antineoplastic agents, monoclonal antibodies useful against cancers and angiogenesis inhibitors.
  • DES diethylstilbestrol
  • leuprolide a hormone which can be used in combination with the present inventive compounds
  • flutamide a hormone which can be used in combination with the present inventive compounds
  • cyproterone acetate a hormone which can be used in combination with the present inventive compounds
  • ketoconazole amino glutethimide
  • antineoplastic and anticancer agents that can be used in combination with the inventive compounds, 5-fluorouracil, vinblastine sulfate, estramustine phosphate, suramin and strontium-89.
  • Other chemotherapeutics useful in combination and within the scope of the present invention are buserelin, chlorotranisene, chromic phosphate, cisplatin, cyclophosphamide, dexamethasone, doxorubicin, estradiol, estradiol valerate, estrogens conjugated and esterified, estrone, ethinyl estradiol, floxuridine, goserelin, hydroxyurea, melphalan, methotrexate, mitomycin, prednisone and tamoxifen.
  • compositions can also be administered in vivo in a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject, along with the nucleic acid or vector, without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
  • the carrier would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art.
  • compositions may be administered orally, parenterally (e.g., intravenously), by intramuscular injection, by intraperitoneal injection, transdermally, extracorporeal ⁇ , topically or the like, including topical intranasal administration or administration by inhalant.
  • topical intranasal administration means delivery of the compositions into the nose and nasal passages through one or both of the nares and can comprise delivery by a spraying mechanism or droplet mechanism, or through aerosolization of the nucleic acid or vector.
  • Administration of the compositions by inhalant can be through the nose or mouth via delivery by a spraying or droplet mechanism. Delivery can also be directly to any area of the respiratory system (e.g., lungs) via intubation.
  • compositions required will vary from subject to subject, depending on the species, age, weight and general condition of the subject, the severity of the allergic disorder being treated, the particular nucleic acid or vector used, its mode of administration and the like. Thus, it is not possible to specify an exact amount for every composition. However, an appropriate amount can be determined by one of ordinary skill in the art using only routine experimentation given the teachings herein.
  • Parenteral administration of the composition is generally characterized by injection.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution of suspension in liquid prior to injection, or as emulsions.
  • a more recently revised approach for parenteral administration involves use of a slow release or sustained release system such that a constant dosage is maintained. See, e.g., U.S. Patent No. 3,610,795, which is incorporated by reference herein.
  • the materials may be in solution, suspension (for example, incorporated into microparticles, liposomes, or cells). These may be targeted to a particular cell type via antibodies, receptors, or receptor ligands.
  • the following references are examples of the use of this technology to target specific proteins to tumor tissue (Senter, et al., Bioconjugate Chem., 2:447-451, (1991); Bagshawe, K.D., Br. J. Cancer, 60:275-281, (1989); Bagshawe, et al., Br. J. Cancer, 58:700-703, (1988); Senter, et al., Bioconjugate Chem., 4:3-9, (1993); Battelli, et al., Cancer Immunol.
  • Vehicles such as "stealth” and other antibody conjugated liposomes (including lipid mediated drug targeting to colonic carcinoma), receptor mediated targeting of DNA through cell specific ligands, lymphocyte directed tumor targeting, and highly specific therapeutic retroviral targeting of murine glioma cells in vivo.
  • the internalization pathways serve a variety of functions, such as nutrient uptake, removal of activated proteins, clearance of macromolecules, opportunistic entry of viruses and toxins, dissociation and degradation of ligand, and receptor-level regulation. Many receptors follow more than one intracellular pathway, depending on the cell type, receptor concentration, type of ligand, ligand valency, and ligand concentration. Molecular and cellular mechanisms of receptor-mediated endocytosis has been reviewed (Brown and Greene, DNA and Cell Biology 10:6, 399- 409 (1991)).
  • compositions including antibodies, can be used therapeutically in combination with a pharmaceutically acceptable carrier.
  • Suitable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy (19th ed.) ed. A.R. Gennaro, Mack Publishing Company, Easton, PA 1995.
  • an appropriate amount of a pharmaceutically- acceptable salt is used in the formulation to render the formulation isotonic.
  • the pharmaceutically-acceptable carrier include, but are not limited to, saline, Ringer's solution and dextrose solution.
  • the pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5.
  • Further carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, liposomes or microparticles. It will be apparent to those persons skilled in the art that certain carriers may be more preferable depending upon, for instance, the route of administration and concentration of composition being administered.
  • compositions can be administered intramuscularly or subcutaneously. Other compounds will be administered according to standard procedures used by those skilled in the art.
  • compositions may include carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice.
  • Pharmaceutical compositions may also include one or more active ingredients such as antimicrobial agents, antiinflammatory agents, anesthetics, and the like.
  • the pharmaceutical composition may be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated. Administration may be topically (including ophthalmically, vaginally, rectally, intranasally), orally, by inhalation, or parenterally, for example by intravenous drip, subcutaneous, intraperitoneal or intramuscular injection.
  • the disclosed antibodies can be administered intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally.
  • Preparations for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.
  • Formulations for topical administration may include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets. Thickeners, flavorings, diluents, emulsifiers, dispersing aids or binders may be desirable..
  • compositions may potentially be administered as a pharmaceutically acceptable acid- or base- addition salt, formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases such as mono-, di-, trialkyl and aryl amines and substituted ethanolamines.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, glyco
  • Effective dosages and schedules for administering the compositions may be determined empirically, and making such determinations is within the skill in the art.
  • the dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the symptoms of the disorder are effected.
  • the dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like.
  • the dosage will vary with the age, condition, sex and extent of the disease in the patient, route of administration, or whether other drugs are included in the regimen, and can be determined by one of skill in the art.
  • the dosage can be adjusted by the individual physician in the event of any counterindications.
  • Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days.
  • Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.
  • guidance in selecting appropriate doses for antibodies can be found in the literature on therapeutic uses of antibodies, e.g., Handbook of Monoclonal Antibodies, Ferrone et al., eds., Noges Publications, Park Ridge, NJ., (1985) ch. 22 and pp. 303-357; Smith et al., Antibodies in Human Diagnosis and Therapy, Haber et al., eds., Raven Press, New York (1977) pp. 365- 389.
  • a typical daily dosage of the antibody used alone might range from about 1 ⁇ g/kg to up to 100 mg/kg of body weight or more per day, depending on the factors mentioned above.
  • compositions for treating, inhibiting, or preventing a GI syndrome, BM syndrome, or inflammation of ARS
  • the efficacy of the therapeutic compositions can be assessed in various ways well known to the skilled practitioner. For instance, one of ordinary skill in the art will understand that a composition, disclosed herein is efficacious in treating or inhibiting a GI syndrome, BM syndrome, or inflammation of ARS in a subject by observing that the composition reduces death, cytokine levels, or increases the health of the subject.
  • IR IR-induced local damage of normal tissue
  • radiation therapy does cause IR-induced local damage of normal tissue (radiation toxicity), leading to a temporary or persistent impairment of irradiated tissues, which lowers the life quality of cancer patients.
  • Some severe side effects such as the acute radiation syndrome conditions of gastrointestinal syndrome and bone marrow syndrome can even result in the discontinuation of the life-saving radiation therapy (Johansen et al. Radiother Oncol. 40: 101-9 (1996), Niemierko et al. IntJRadiat Oncol Biol Phys.
  • the radiation damage can be caused by radiation therapy, such as that used to treat cancer.
  • the radiation damage can also be caused by nuclear radiation, or by a weapon, such as a bomb, terrorist agent.
  • the compositions herein can be admininstered prior to, after, or during exposure to radiation.
  • compositions can be used to prevent gastroinstestinal (GI) syndrome or bone marrow (BM) syndrome, acute radiation syndrome (ARS), lethal brain bleeding, or the effects associated with any of the above conditions. It is further understood that the disclosed compositions can be administered one, two, three, or four times every 24 hours. It is further understood that the agent of the disclosed methods can be administered every 24 hours for 1, 2, 3, 4, 5, 6, 7, 14, or 21 days or at any time point in between.
  • mitigate means to reduce the damage associated with a symptom, disease, or condition relative to the untreated state. It is also understood that “mitigation” can be in reference to a symptom, disease, or condition, in addition to or alternatively to damage associated with the symptom, disease, or condition. It is understood and herein contemplated that the reduction is not limited to the complete ablation of the damage, symptom, disease, or condition, but may include, for example, a 10% reduction in the activity, response, condition, or disease as compared to the native or control level. Thus, the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to untreated, native, or control levels.
  • a composition or treatment method would be understood to mitigate the damage from radiation toxicity even if the damage from radiation toxity increased (e.g., X+10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%) provided untreated controls increased more (e.g., X+15%, 25%, 35%, 45%, 55%, 65%, 75%, 85%, 95%).
  • “Inhibit,” “inhibiting,” and “inhibition” mean to decrease an activity, response, condition, disease, or other biological parameter. This can include but is not limited to the complete ablation of the activity, response, condition, or disease. This may also include, for example, a 10% reduction in the activity, response, condition, or disease as compared to the native or control level. Thus, the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to native or control levels.
  • Treatment means a method of reducing the effects of a disease or condition.
  • Treatment can also refer to a method of reducing the disease or condition itself rather than just the symptoms.
  • the treatment can be any reduction from native levels and can be but is not limited to the complete ablation of the disease, condition, or the symptoms of the disease or condition. Therefore, in the disclosed methods, treatment” can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an established disease or the disease progression.
  • a disclosed method for reducing the effects of radiation toxicity, gastrointestinal syndrome, bone marrow syndrome, inflammation, or uncontrolled cellular proliferation is considered to be a treatment if there is a 10% reduction in one or more symptoms of the disease in a subject with the disease when compared to native levels in the same subject or control subjects.
  • the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to native or control levels. It is understood and herein contemplated that "treatment” does not necessarily refer to a cure of the disease or condition, but an improvement in the outlook of a disease or condition.
  • the invention relates to a method of mitigating radiation toxicity in a subject comprising the step of administering to the subject at least one of the disclosed compounds at least one of the disclosed pharmaceutical compositions, or at least one of the disclosed products in a dosage and amount effective to mitigate radiation toxicity in the subject.
  • the subject is a mammal, for example, a human.
  • the subject has been diagnosed with a need for mitigating radiation toxicity prior to the administering step, hi a yet further aspect, the administering step is performed before the subject acquires radiation toxicity.
  • the invention relates to a method of treating radiation- induced gastrointestinal syndrome in a subject comprising the step of administering to the subject at least one of the disclosed compounds at least one of the disclosed pharmaceutical compositions, or at least one of the disclosed products in a dosage and amount effective to treat gastrointestinal syndrome in the subject.
  • the subject is a mammal, for example, a human
  • the subject has been diagnosed with a need for treatment of gastrointestinal syndrome
  • the administering step is performed after the subject is exposed to irradiation.
  • the invention relates to a method for the treatment of a disease of uncontrolled cellular proliferation comprising administering to a subject having a disease of uncontrolled cellular proliferation at least one of the disclosed compounds at least one of the disclosed pharmaceutical compositions, or at least one of the disclosed products in a dosage and amount effective to treat the disease of uncontrolled cellular proliferation,
  • the subject is a mammal, for example, a human, hi a further aspect, the subject has been diagnosed with a need for treatment of a disease of uncontrolled cellular proliferation, hi a further aspect, the disease of uncontrolled proliferation is a carcinoma, lymphoma, leukemia, or sarcoma.
  • the disease of uncontrolled cellular proliferation treated can be a carcinoma, lymphoma, leukemia, or sarcoma.
  • the types of cancer treated by methods of the invention include but are not limited to Hodgkin's Disease, meyloid leukemia, polycystic kidney disease, bladder cancer, brain cancer, head and neck cancer, kidney cancer, lung cancer, myeloma, neuroblastoma/glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, liver cancer, melanoma, colon cancer, cervical carcinoma, breast cancer, epithelial cancer, and leukemia.
  • compositions can also be used as regulators in diseases of uncontrolled proliferation and/or precancerous conditions such as cervical and anal dysplasias, other dysplasias, severe dysplasias, hyperplasias, atypical hyperplasias, and neoplasias.
  • the compounds disclosed herein can be either used singularly, or plurally, in mixtures of one or more compounds, tautomers, isomers, or enantiomers, and in pharmaceutical compositions thereof, for the treatment of mammalian diseases of uncontrolled cellular proliferatio, particularly those diseases related to humans.
  • Disclosed herein are methods of treating, preventing, or reducing radiation- induced gastrointestinal syndrome, radiation toxicity, or the damaging effects associate with either condition comprising administering to a subject and effective amount of an agent, wherein the agent is a derivative, analogue, or metabolite of curcumin. It is understood and herein contemplated that the agent can be administered one, two, three, or four times every 24 hours. It is further understood that the agent of the disclosed methods can be administered every 24 hours for 1, 2, 3, 4, 5, 6, 7, 14, or 21 days. Also disclosed are methods further comprising the administration of a therapy that reduces the effects of ionizing radiation.
  • the therapy can comprise any procedure or composition known by those of skill in the art to reduce the effects of ionizing radiation. It is further understood that the therapy can comprise a second agent. It is contemplated herein that the agent can be administered before or after the exposure to ionizing irradiation. It is further contemplated that the agent is an amifostine. Thus, for example, disclosed herein are methods wherein the second agent is an amifostine administered prior to exposure to IR.
  • sub-TBI sub-total body irradiation
  • the appendage can be any appendage comprising a bone comprising bone marrow.
  • the appendage can be an arm or a leg.
  • the dose of radiation can be any dose between 5 and 15 Gy.
  • the dose of radiation is between 8 and 12 Gy.
  • the dose of radiation is between 8 and 10.5 Gy.
  • the radiation dose is between 8.9 and 9.1 Gy.
  • the subject can be any animal that is effected by radiation.
  • the subject can be a mouse.
  • the disclosed methods of administering sub total body irradiation can be used to make a model for radiation induced gastrointestinal syndrome. It is further understood that such a model can be used to screen for an agent or test a known agent for effectiveness in treating, reducing, preventing, or inhibiting gastrointestinal syndrome. It is further understood that such a model can be used to screen for an agent or test an known agent for efficacy in treating, reducing, preventing, inhibiting, or mitigating radiation toxicity.
  • Screening for agents that mitigate radiation toxicity can be useful for subjects exposed to ionizing radiation. Therefore, disclosed herein are methods of screening for an agent that mitigate, inhibit, treat, or reduce radiation toxicity comprising administering a lethal dose of ionizing radiation (IR) to a subject, wherein on appendage of the subject is shielded and kept out of the IR field during IR exposure and administering the agent following IR exposure, wherein a reduction in the toxic effects of IR relative to a control indicate an agent that treats radiation toxicity. It is understood that the same methods can be used to screen for agents effective against GI syndrome.
  • IR ionizing radiation
  • IR ionizing radiation
  • methods of screening for an agent that mitigate, inhibit, treat, or reduce radiation toxicity comprising administering a lethal dose of ionizing radiation (IR) to a subject, wherein on appendage of the subject is shielded and kept out of the IR field during IR exposure and administering the agent following IR exposure, wherein a reduction in the toxic effects of IR relative to a control indicate an agent that treats gastrointestinal syndrome.
  • IR ionizing radiation
  • IR ionizing radiation
  • Radiation toxicity can be divided into two main stages: early toxicity and late toxicity (MacKay et al. Radioiher Oncol. 46:215-6 (1998), Rubin et al. Radiother Oncol. 35: 9-10, (199?), Dubray et al. Cancer Radiother. 1: 744-52 (1997), Vozenin- Brotons et al. Radiat Res. 152: 332-7 (1999), Lefaix et al. Br J Radiol Suppl. 19: 109- 13 (1986), Lefaix et al. Soc Biol FiI. 191: 777-95 (1997), Verola et al. Br J Radiol Suppl. 19: 104-8 (1986)).
  • IR kills cell through the production of free radicals.
  • the IR toxicity is a result of counteraction of host defense system that responds to IR physical insult.
  • the cells are damaged by free radicals, and undergo either repair or apoptosis/death, which initiates the cascade of signal transduction pathways (such as Nuclear factor- ⁇ B (NFK/3), etc.).
  • signal transduction pathways such as Nuclear factor- ⁇ B (NFK/3), etc.
  • IR up-regulates the expression of inflammatory mediators (such as cytokines, lymphokines and chemokines) and immunomodulatory molecules (MHC, co-stimulatory molecules, adhesion molecules, death receptors, heat shock proteins) in irradiated tumor, stromal, and vascular endothelial cells (Friedman et al.).
  • inflammatory mediators such as cytokines, lymphokines and chemokines
  • MHC immunomodulatory molecules
  • adhesion molecules adhesion molecules
  • death receptors heat shock proteins
  • NO and the signaling of DNA breakage directly activate NF-k/3, which induces IL1/3.
  • the ELI/3 binds to its receptors, which again triggers NFk/3 and P38 pathways to enhance its production, a positive feed-back to amplify the inflammation signaling.
  • ILl ⁇ is a key cytokine in the IR inflammation process.
  • IL1/3 enhances the expression of COX-2, and together they markedly induce inflammatory angiogenesis (Kuwano et al. FASEB J.
  • IL-IB- induced activation of the COX-2 gene is modulated by NF-k/3 (Kirtikara et al. (2000), Crofford et al. Arthritis Rheum. 40,226-236 (1997)).
  • the COX-2 selective inhibitors can block IL 1/3 induced angiogenesis but only partially block VEGF-induced angiogenesis.
  • the ILl /3 induced angiogenesis is much less in the COX-2 knockout mice than wild-type mice (Kuwano et al. (2004)).
  • Overexpression of COX-2 also is accompanied by up-regulation of nitric oxide synthases (Tsuji et al. Nippon Rinsho. 56: 2247-2252 (1998)), which can intensify local damage.
  • Cyclooxygenase is the rate-limiting step in the conversion of arachidonic acid to prostaglandins.
  • COX-I is constitutively expressed at low levels in many cell types. Specifically, COX-I is known to be essential for maintaining the integrity of the gastrointestinal epithelium. COX-2 expression is stimulated by growth factors, cytokines, and endotoxins.
  • the cyclooxygenase 2 isoform (COX-2) is not expressed in most tissues (e.g., liver) under physiological conditions but is highly upregulated in inflammatory processes and cancer, for example. Up-regulation of COX-2 is responsible for the increased formation of prostaglandins associated with inflammation.
  • Inflammation is a complex stereotypical reaction of the body expressing the response to damage of its cells and vascularized tissues.
  • the discovery of the detailed processes of inflammation has revealed a close relationship between inflammation and the immune response.
  • the main features of the inflammatory response are vasodilation, i.e. widening of the blood vessels to increase the blood flow to the infected area; increased vascular permeability, which allows diffusible components to enter the site; cellular infiltration by chemotaxis, or the directed movement of inflammatory cells through the walls of blood vessels into the site of injury; changes in biosynthetic, metabolic, and catabolic profiles of many organs; and activation of cells of the immune system as well as of complex enzymatic systems of blood plasma.
  • Acute inflammation can be divided into several phases. The earliest, gross event of an inflammatory response is temporary vasoconstriction, i.e. narrowing of blood vessels caused by contraction of smooth muscle in the vessel walls, which can be seen as blanching (whitening) of the skin. This is followed by several phases that occur over minutes, hours and days later. The first is the acute vascular response, which follows within seconds of the tissue injury and lasts for several minutes. This results from vasodilation and increased capillary permeability due to alterations in the vascular endothelium, which leads to increased blood flow ⁇ hyperemia) that causes redness ⁇ erythema) and the entry of fluid into the tissues ⁇ edema).
  • Examples of chronic inflammatory diseases include tuberculosis, chronic cholecystitis, bronchiectasis, rheumatoid arthritis, Hashimoto's thyroiditis, inflammatory bowel disease (ulcerative colitis and Crohn's disease), silicosis and other pneumoconiosis, and implanted foreign body in a wound.
  • Activated cells can also be identified at the site of inflammation.
  • Activated cells are defined as cells that participate in the inflammatory response. Examples of such cells include, but are not limited to, T-cells and B-cells , macrophages, NK cells, mast cells, eosinophils, neutrophils, Kupffer cells, antigen presenting cells, as well as vascular endothelial cells.
  • Macrophages release cytokines (e.g. , tumor necrosis factor, interleukin- 1 ), which heighten the intensity of inflammation by stimulating inflammatory endothelial responses; these endothelial changes help recruit large numbers of T cells to the inflammatory site.
  • cytokines e.g. , tumor necrosis factor, interleukin- 1
  • Damaged tissues release pro-inflammatory mediators e.g., Hageman factor (factor X ⁇ ) that trigger several biochemical cascades.
  • the clotting cascade induces fibrin and several related fibrinopeptides, which promote local vascular permeability and attract neutrophils and macrophages.
  • the kinin cascade principally produces bradykinin, which promotes vasodilation, smooth muscle contraction, and increased vascular permeability.
  • Dislcosed herein are methods of treating inflammation in a subject by administering to the subject an effective amount of a derivative, analogue, or metabolite of curcumin.
  • “Inflammation” or “inflammatory” herein is defined as the reaction of living tissues to injury, infection, or irritation. Anything that stimulates an inflammatory response is said to be inflammatory.
  • Inflammatory disease is defined as any disease state associated with inflammation.
  • the inflammation can be associated with an inflammatory disease.
  • inflammatory disease include, but are not limited to, asthma, systemic lupus erythematosus, rheumatoid arthritis, reactive arthritis, spondyarthritis, systemic vasculitis, insulin dependent diabetes mellitus, multiple sclerosis, experimental allergic encephalomyelitis, Sjogren's syndrome, graft versus host disease, inflammatory bowel disease (including Crohn's disease and ulcerative colitis) and scleroderma, myasthenia gravis, Guillain-Barre disease, primary biliary cirrhosis, hepatitis, hemolytic anemia, uveitis, Grave's disease, pernicious anemia, thrombocytopenia, Hashimoto's thyroiditis, oophoritis, orchitis, adrenal gland diseases, anti-phospholipid syndrome, Wegener's granulomato
  • primary mediators of inflammation include cytokines.
  • cytokines include cytokines.
  • methods of inhibiting cytokines in a subject exposed to radiation include by are not limited to ILl ⁇ , IL6, KC, TNFo, TGF/3, VEGF, TCA-3, G-CSF, and MCPl or any combination thereof.
  • Inflammation can be associated with a number of different diseases and disorders. Examples of inflammation include, but are not limited to, inflammation associated with hepatitis, inflammation associated with the lungs, and inflammation associated with an infectious process. Inflammation can also be associated with liver toxicity, which can be associated in turn with cancer therapy, such as apoptosis induction or chemotherapy, or a combination of the two, for example.
  • cancer therapy such as apoptosis induction or chemotherapy, or a combination of the two, for example.
  • the infectious process can be associated with a viral infection.
  • viral infections include, but are not limited to, Herpes simplex virus type-1, Herpes simplex virus type-2, Cytomegalovirus, Epstein-Barr virus, Varicella-zoster virus, Human herpesvirus 6, Human herpesvirus 7, Human herpesvirus 8, Variola virus, Vesicular stomatitis virus, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis D virus, Hepatitis E virus, Rhinovirus, Coronavirus, Influenza virus A, Influenza virus B, Measles virus, Polyomavirus, Human Papilomavirus, Respiratory syncytial virus, Adenovirus, Coxsackie virus, Dengue virus, Mumps virus, Poliovirus, Rabies virus, Rous sarcoma virus, Yellow fever virus, Ebola virus, Marburg virus, Lassa fever virus, Eastern Equation
  • the infectious process can also be associated with a bacterial infection.
  • bacterial infections include, but are not limited to, M. tuberculosis, M. bovis, M. bovis strain BCG, BCG substrains, M. avium, M. intracellulare, M. africanum, M. kansasii, M. marinum, M. ulcerans, M.
  • avium subspecies paratuberculosis Nocardia asteroides, other Nocardia species, Legionella pneumophila, other Legionella species, Salmonella typhi, other Salmonella species, Shigella species, Yersinia pestis, Pasteurella haemolytica, Pasteurella multodda, other Pasteurella species, Actinobacillus pleuropneumoniae, Listeria monocytogenes, Listeria ivanovii, Brucella abortus, other Brucella species, Cowdria ruminantium, Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydia psittaci, Coxiella burnetii, other Rickettsial species, Ehrlichia species, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus agalactiae, Bac
  • the infectious process can also be associated with a parasitic infection.
  • parasitic infections include, but are not limited to, Toxoplasma gondii, Plasmodium species such as Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, and other Plasmodium species, Trypanosoma brucei, Trypanosoma cruzi, Leishmania species such as Leishmania major, Schistosoma such as Schistosoma mansoni and other Shistosoma species, and Entamoeba histolytica.
  • the infectious process can also be associated with a fungal infection.
  • fungal infections include, but are not limited to, Candida albicans, Cryptococcus neoformans, Histoplama capsulatum, Aspergillus fumigatus, Coccidiodes immitis, Paracoccidiodes brasiliensis, Blastomyces dermitidis, Pneumocystis carnii, Penicillium marneffi, and Alternaria alternata.
  • the inflammation can be associated with cancer.
  • types of cancer include, but are not limited to, lymphoma (Hodgkins and non-Hodgkins) B-cell lymphoma, T-cell lymphoma, leukemia such as myeloid leukemia and other types of leukemia, mycosis fungoide, carcinoma, adenocarcinoma, sarcoma, glioma, blastoma, neuroblastoma, plasmacytoma, histiocytoma, melanoma, adenoma, hypoxic tumor, myeloma, AIDS-related lymphoma or AIDS-related sarcoma, metastatic cancer, bladder cancer, brain cancer, nervous system cancer, squamous cell carcinoma of the head and neck, neuroblastoma, glioblastoma, ovarian cancer, skin cancer, liver cancer, squamous cell carcinomas of the mouth, throat, larynx, and lung, colon cancer, cervical cancer,
  • compositions can be used to treat any disease where uncontrolled cellular proliferation occurs such as cancers.
  • a non-limiting list of different types of cancers is as follows: lymphomas (Hodgkins and non-Hodgkins), leukemias, carcinomas, carcinomas of solid tissues, squamous cell carcinomas, adenocarcinomas, sarcomas, gliomas, high grade gliomas, blastomas, neuroblastomas, plasmacytomas, histiocytomas, melanomas, adenomas, hypoxic tumours, myelomas, AIDS-related lymphomas or sarcomas, metastatic cancers, or cancers in general.
  • a representative but non-limiting list of cancers that the disclosed compositions can be used to treat is the following: lymphoma, B cell lymphoma, T cell lymphoma, mycosis fungoides, Hodgkin's Disease, myeloid leukemia, bladder cancer, brain cancer, nervous system cancer, head and neck cancer, squamous cell carcinoma of head and neck, kidney cancer, lung cancers such as small cell lung cancer and non-small cell lung cancer, neuroblastoma/glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, liver cancer, melanoma, squamous cell carcinomas of the mouth, throat, larynx, and lung, colon cancer, cervical cancer, cervical carcinoma, breast cancer, and epithelial cancer, renal cancer, genitourinary cancer, pulmonary cancer, esophageal carcinoma, head and neck carcinoma, large bowel cancer, hematopoietic cancers; testicular cancer; colon and rectal cancers, prostatic cancer,
  • Compounds disclosed herein may also be used for the treatment of precancer conditions such as cervical and anal dysplasias, other dysplasias, severe dysplasias, hyperplasias, atypical hyperplasias, and neoplasias.
  • Inflammation is associated with transplant rejection in a transplant recipient.
  • antibodies are formed against foreign antigens on the transplanted material.
  • the transplantation can be, for example, organ transplantation, such as liver, kidney, skin, eyes, heart, or any other transplantable organ of the body or part thereof.
  • Transplantation immunology refers to an extensive sequence of events that occurs after an allograft or a xenograft is removed from a donor and then transplanted into a recipient. Tissue is damaged at both the graft and the transplantation sites. An inflammatory reaction follows immediately, as does activation of biochemical cascades. A series of specific and nonspecific cellular responses ensues as antigens are recognized. Antigen-independent causes of tissue damage (i.e., ischemia, hypothermia, reperfusion injury) are the result of mechanical trauma as well as disruption of the blood supply as the graft is harvested. In contrast, antigen-dependent causes of tissue damage involve immune-mediated damage.
  • tissue damage i.e., ischemia, hypothermia, reperfusion injury
  • Rejection is the consequence of the recipient's alloimmune response to the nonself antigens expressed by donor tissues.
  • transplant subjects are serologically presensitized to alloantigens (i.e., graft antigens are recognized as nonself).
  • PMNs polymorphonuclear leukocytes
  • Hyperacute rejection manifests within minutes to hours of graft implantation. Hyperacute rejection has become relatively rare since the introduction of routine pretransplantation screening of graft recipients for antidonor antibodies.
  • graft antigens are recognized by T cells; the resulting cytokine release eventually leads to tissue distortion, vascular insufficiency, and cell destruction. Histologically, leukocytes are present, dominated by equivalent numbers of macrophages and T cells within the interstitium. These processes can occur within 24 hours of transplantation and occur over a period of days to weeks.
  • Transplant rej ection may occur within 1-10 minutes of transplantation, or within 10 minutes to 1 hour of transplantation, or within 1 hour to 10 hours of transplantation, or within 10 hours to 24 hours of transplantation, within 24 hours to 48 hours of transplantation, within 48 hours to 1 month of transplantation, within 1 month to 1 year of transplantation, within 1 year to 5 years of transplantation, or even longer after transplantation.
  • the subject can include domesticated animals, such as cats, dogs, etc., livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.) and birds.
  • livestock e.g., cattle, horses, pigs, sheep, goats, etc.
  • laboratory animals e.g., mouse, rabbit, rat, guinea pig, etc.
  • the subject is a mammal such as a primate such as a monkey or chimpanzee, and, more preferably, a human.
  • compositions can be used in a variety of ways as research tools.
  • the disclosed compositions such as D68, D 12, and Dl 3 can be used to study the effects of ionizing radiation, and in particular the effects of ionizing radiation in the onset of gastroinstestinal injury (GI) syndrome or bone marrow (BM) syndrome of acute radiation syndrome (ARS).
  • GI gastroinstestinal injury
  • BM bone marrow
  • ARS acute radiation syndrome
  • compositions can be used as discussed herein as either reagents in micro arrays or as reagents to probe or analyze existing microarrays to identify genes or proteins critical to the formation of ARS, GI syndrome, or BM syndrome.
  • the compositions can also be used in any known method of screening assays, related to chip/micro arrays.
  • the compositions can also be used in any known way of using the computer readable embodiments of the disclosed compositions, for example, to study relatedness or to perform molecular modeling analysis related to the disclosed compositions.
  • kits that are drawn to reagents that can be used in practicing the methods disclosed herein.
  • the kits can include any reagent or combination of reagent discussed herein or that would be understood to be required or beneficial in the practice of the disclosed methods.
  • the kits could include analogues, derivatives, or metabolites of curcumin, such as, for example D 12, D 13, or D68, to perform the methods disclosed herein.
  • a kit for preventing GI syndrome or BM syndrome of ARS following exposure to IR is disclosed.
  • compositions disclosed herein have certain functions, such as inhibiting COX-2.
  • Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures which can perform the same function which are related to the disclosed structures, and that these structures will ultimately achieve the same result, for example, preventing or delaying the onset of GI syndrome or BM syndrome or ARS.
  • Example 1 Preparation of l,7-bis-(4-hydroxy-3-methoxyphenyl)-l,6- heptadiene-3,5-dione mono-p-toluenesulfonylhydrazone
  • Example 9 Preparation of l,7-bis-(4-hydroxy-3-methoxyphenyl)-l,6- heptadiene-3,5-dione 4'-methyl-l',2',3'-thiadiazole-5'-carboxyl monohydrazone
  • Example 10 Preparation of l,7-bis-(4-hydroxy-3-methoxyphenyl)-l,6- heptadiene-3,5-dione 4'-tert-butylbenzoyI monohydrazone
  • Example 12 Preparation of l,7-bis-(4-hydroxy-3-methoxyphenyl)-l,6- heptadiene-3,5-dione benzoyl monohydrazone
  • Example 13 Preparation of l,7-bis-(4-hydroxy-3-methoxyphenyl)-l,6- heptadiene-3,5-dione 4'-methylbenzoyl monohydrazone
  • Example 14 Preparation of l,7-bis-(4-hydroxy-3-methoxyphenyl)-l,6- heptadiene-3,5-dione 4'-nitrobenzoyl monohydrazone
  • Example 15 Preparation of l,7-bis-(4-hydroxy-3-methoxyphenyl)-l,6- heptadiene-3,5-dione 3'-hydroxybenzoyl monohydrazone
  • Example 17 Preparation of l,7-bis-(4-hydroxy-3-methoxyphenyl)-l,6- heptadiene-3,5-dione 4'-chlorobenzoyl monohydrazone
  • Example 19 Preparation of l,7-bis-(4-hydroxy-3-methoxyphenyl)-l,6- heptadiene-3,5-dione 2'-hydroxy-4'-methoxybenzoyl monohydrazone
  • Example 20 Preparation of l,7-bis-(4-hydroxy-3-methoxyphenyl)-l,6- heptadiene-3,5-dione 4'-trifluoromethylitrobenzoyl monohydrazone
  • Example 22 Preparation of 3,5-bis-(4-hydroxy-3-methoxyphenyl)-ethyIene-l- methylpyrazole
  • Curcumin (3.68g, lOmmol) and methylhydrazine (0.88g, 20mmol) were added to absolute ethanol (80ml) containing some concentrated hydrochloric acid (0.4ml).
  • the reaction mixture was stirred at room temperature for 1 hour, then heated under refluxing for 20 hours.
  • the mixture was allowed to cool to room temperature and then concentrated using a rotary evaporator under reduced pressure.
  • the residue was purified by silica gel column chromatography with the elute of combination of n- heptane and ethyl acetate to give a light yellow powder (0.40g), 10.58% yield, mp 228-30°C.
  • Example 27 Preparation of 3,5-bis-(4-hydroxy-3-methoxyphenyl)-ethylene-l- (2-nitrophenyl) pyrazole
  • Example 29 Preparation of 3,5-bis-(4-hydroxy-3-methoxyphenyl)-ethylene-l- (4-methylphenyl) pyrazole
  • Example 30 Preparation of 3,5-bis-(4-hydroxy-3-methoxyphenyl)-ethylene-l- (2-methylphenyl) pyrazole
  • Example 31 Preparation of 3,5-bis-(4-hydroxy-3-methoxyphenyl)-ethylene-l- (2-pyridyl) pyrazole
  • Example 32 Preparation of 3,5-bis-(4-hydroxy-3-methoxyphenyl)-ethylene-l- (2,4-dinitrophenyl) pyrazole
  • Example 34 Preparation of 3,5-bis-(4-hydroxy-3-methoxyphenyl)-ethylene-l- (2,6-dichloro-4-trifluoromethylphenyi) pyrazole
  • Example 36 Preparation of 3,5-bis-(4-hydroxy-3-methoxyphenyI)-ethyIene-l- (benzothiazol-2-yl) pyrazole
  • Example 38 Preparation of 3,5-bis-(4-hydroxy-3-methoxyphenyl)-ethylene-l- (4-trifluoromethoxyphenyl) pyrazole
  • Example 39 Preparation of 3,5-bis-(4-hydroxy-3-methoxyphenyl)-ethylene-l- benzyl pyrazole
  • Example 40 Preparation of 3,5-bis-(4-hydroxy-3-methoxyphenyl)-ethylene-l- (3-trifluoromethylphenyl) pyrazole
  • Example 42 Preparation of amorphous crystal form of 3,5-bis-(4-hydroxy-3- methoxyphenyl)-ethylene-l -(4-methylphenyl) pyrazole
  • Example 43 Characterization and synthesis of anti-oxidants derived from natural compounds
  • the starting compound library for screening the anti-radiation /oxidants is the purified compound from naturally existing plants. This idea is based on the fact that the majority of anti-cancer drug is originally discovered from natural products (such as Taxol, Mitomysin C, Adrimycin, etc), and therefore, mother "nature" should give a birth of anti-radiation compounds since the earth might experience some period of high radiation exposure and many livings have adapted to the irradiated environment via producing their own anti-oxidants. For example, some plants that survive from high dose IR environment (such as plants from very high attitude mountain exposed to extensive UV, or plants growing in the high level of underground radiation area) might contain some components that are resistant to radiation. More than 20 compounds were collected that were purified (>95%) from different plants grown in different areas and attitudes, and then screen for their antioxidant activity.
  • natural products such as Taxol, Mitomysin C, Adrimycin, etc
  • the easy and fast in vitro method to characterize the anti-oxidant property was to use the electronic chemical detector (model CHI830B from CH Instruments me, Austin, TX). It is a voltammeter analysis using neutral buffer with Ag/ AgCl as reference electrode and glassy carbon as working electrode, which can sensitively determine if the agent releases electronics under un-trigged conditions (ready to against free radices) or under voltage-trigged condition (anti-free radices under certain circumstance).
  • the background redox potential for the vehicle alone is shown in Fig IA. After screening more than 20 purified compounds from different plants with electronic chemical detector, it was found that most of them had a low potential of redox as represented in Fig IB (which required the voltage >0.6 V to release electronics).
  • curcumin a spice food namely curcumin
  • a low voltage about 0.2 V
  • curcumin a spice food namely curcumin
  • Amifostine is activated in vivo with enzymatic reaction.
  • the compounds disclosed herein have a similar redox potential to Amifostine, and higher than Vitamin C. Table 1
  • Example 44 In vivo mitigation effect of the synthetic agents on GI syndrome of acute radiation syndrome (ARS) a) Capability of rescuing mice from death of GI syndrome of ARS
  • BM is much more sensitive to IR than GI.
  • the TBI is not a good model to study agents that mitigate the lethal GI IR damage.
  • a sub-TBI model was created in which one leg of mouse was shielded and out of the IR field, hi this system, 8.5 Gy were delivered to BALB/c mice without any death.
  • sub-TBI IR dose was increased to 9 Gy, around half of IR mice died, and at 10.5 Gy, 66-100% mice died within 5-7 days with devastating gut damage observable under microscope.
  • mice The total body exposure to radiation is the most likely scenario in radiation exposure events, since the enormous IR energy will penetrate all barriers to some extent. Therefore, the ability of the agents to prolong the life of mice after their total body irradiation (TBI) to a 100% lethal IR dose (LDioo/io-3o, a death due to BM failure) was investigated. The agents that rescued host from GI death also prolong the life from BM and other tissue injury, when working as an anti-oxidant. To test this, the TBI in BALB/c mouse model was used. As indicated before, the LD 5 o /3 o for BALB/c mouse was about 5.5 Gy. The cutoff for MDF >1.2 was 6.0 Gy.
  • Dl 3 120 mg/kg, Fig 4B.
  • D68 120 mg/kg rescued mice from death after 7Gy TBI (Fig 4C, up to now 4 months).
  • Example 45 Direct effect of D68 on GI tract a) Enhanced proliferation of crypts in small intestine
  • the epithelium lying on the small intestine has a rapid turnover, approximately 3-5 days.
  • the stem cells in the bottom of villi actively divide, especially when IR causes a serious damage that triggers a very active process of repair, manifesting as a strong staining of hemotoxilin in the nuclear-enriched crypts.
  • mice exposed to 10.5 Gy sub-TBI were randomly divided into two group and orally given either NS alone or D68 (120 mg/kg) 10 minutes after IR and thereafter once a day for 2 days.
  • the BrdU 120 mg/kg was i.p.
  • mice were sacrificed and the duodenal, jejunal and ileal segments (3-4 pieces/segment) were harvested, fixed in formalin, processed in paraffin blocks, cut in transverse sections of the full segment circumference (5 ⁇ m thick) and stained with H&E or anti-BrdU following the standard immunochemistry procedure with antigen retrieve.
  • the proliferating crypts were defined as containing 10 or more adjacent chromophilic non-Paneth cells and a lumen. The circumference of a transverse cross-section of the intestine was used as a unit. The number of proliferating crypts was counted in each circumference.
  • D68 partially restores the GI physiological function of mice with GI syndrome of deadly ARS
  • the IR damaged GI has a loose stool or diarrhea, which were pictured at day 3.5 post-PR; 3) endotoximia: the lost of normal GI barrier and function results in the overgrowth of GI bacterial and their penetration into circulation causing sepsis, a major cause of GI death of ARS.
  • the level of plasma endotoxin on 3.5 days post-IR was measured with a commercialized kit that utilized tachypleus amebocyte lysate to sensitively quantitate endotoxin even ⁇ 0.01 EU/ml; and 4) body weight (BW): the loss of nutrition and water due to GI IR-damage reduces the body weight. The survivor can gradually re-gain their body weights, reflecting the restoring GI function.
  • the results are summarized as follows: The stool hemoccult score differed among the groups (Fig 7A). The higher score (more bloody stool) was detected in mice receiving 12 Gy sub-TBI with vehicle mock treatment as compared to normal mice. The irradiated mice that treated with D68 and Amifostine (positive control) had a reduced hemoccult score in their stool (P ⁇ 0.05), indicating that D68 is capable to reduce the GI bleeding induced by IR. Similar results were obtained from second strain of mice. [00249] A more serious loose (diarrhea) and bloody stool was observed in vehicle group than that in D68 group (Fig 7B and C).
  • the plasma endotoxin level of BALB/c mice exposed to 10.5 Gy in vehicle treated groups was elevated significantly compared to normal mice (mean 0.45 v.s. 3.32), while the IR mice treated with D68 had a reduced endotoxin (mean 2.12, Fig 7D).
  • the Amifostine (as positive control) that was delivered via i.v. injection 30 min before 10.5 Gy IR resulted in a relatively low level of plasma endotoxin (mean 0.93), suggesting that it protected the integrity of gut and prevented the accumulation of bacterial and their entry into blood.
  • it is well-known that it must be used before IR even 10 min post-IR delivery resulted in a high endotoxin level (mean 2.87).
  • mice body weight indicated that in the first 6 days after 10.5Gy sub-TBI, the injury was overweighing the repair, and all mice had a similar BW loss up to 1/3 of original BW. However, if the mice did not die on 5-7 days due to the individual resistance to IR (33% in control) or the treatment with D68 (83%), their BW gradually re-gained. The mice that treated with D68 had a relatively quick re-gaining compared to that of a few survivors from controls, although BW finally reached similar level (Fig 7F). BW does not predict the death or not, but its regain indicates a good recovery.
  • D68 partially restores the GI endocrine and exocrine ability in mice with deadly GI syndrome of ARS
  • pancreas Due its anatomy position, the pancreas is likely to exposed to radiation when GI tract is irradiated.
  • amylase that is secreted by epithelial cells along the GI system, including pancreas. All these endocrine and exocrine molecules are affected when the GI tract is injured by radiation.
  • ELISA kits were used for most of above biomarkers, since ELISA kits are sensitive enough to detect any settle change in plasma.
  • the protein sequence of cholecystokinin (CCK) is 100% conserved among all the species, therefore, the kit (Peninsula Laboratories, cat# S- 1205) for human can be used for this purpose.
  • secretin sequence HDGTFTSELSRLQDSARLQRLLQGLV (SEQ ID NO: I)
  • M vs. T at position 5 there is one amino acid change (M vs. T at position 5).
  • the kit for human secretin (Peninsula Laboratories, cat# S- 1229) has been tested and it recognizes mouse form.
  • the mouse insulin kit is available in the market (Linco Inc. Cat# EZRMI- 13 K).
  • the EnzChek Ultr Amylase Assay kit (Molecular Probes, Cat # E33651) can be used for all species, since it measures for the enzymatic activity.
  • the blood glucose level is measured with Sigma kits based on enzymatic activity (Cat# GAGO-20 and GAHK-20), which is universal to all species too.
  • Luminex bead array was used.
  • the paired monoclonal antibodies, highly-purified standard protein and more than 50 different regions of bead were purchased.
  • the unlabeled antibodies were covalently conjugated onto surface of beads according to manufacture's instruction.
  • Luminex bead array The advantages of using techniques of Luminex bead array are: 1) it allows a high- throughput screen of a panel of biomarker; 2) it takes only 2.5—3.5 hours to finish the assay; 3) it requires only 25-50 ⁇ l of plasma which can be easily obtained from figure of IR victim; and 4) the equipment is portable, reliable and durable. Biomarkers, identified from this project, can be easily translated into human use, which provides a good window to monitor the ARS course and to guide the treatment protocol for individual victim.
  • curcumin is the major component of curry, spice food sold in grocery stores worldwide.
  • the purified curcumin is very safe for human use, up to 8 g/day with no detectable toxicity. It is in clinical trail for cancer prevention and treatment as well as other anti-oxidation and anti-inflammation purposes.
  • HPLC high-LC or radiolabled ( 3 H or 14 C) D68.
  • the advantages of HPLC are: 1) the assay can be used in human clinical trials; and 2) avoids the special handling and disposal requirements for use of long-lived radioisotopes in the laboratory.
  • Radiolabeled D68 can sensitively trace the movement of D68 in animal models, but cannot be used in human studies.
  • HPLC was used first and if needed, alternative radiolabel assays were used to confirm the results obtained from HPLC -based studies in animal models.
  • the current approach to quantifying D68 in plasma and tissues is a single stage extraction method using solid phase extraction (SPE) techniques followed by HPLC analysis.
  • SPE solid phase extraction
  • Recoveries of D68 from human plasma spiked at concentrations of 0.04, 0.2, 1 or 5 ⁇ g/mL D68 ranged from 74.6-98.1% for D68.
  • the recoveries of D68 from spiked human plasma increased with decreasing D68 concentration.
  • the percent relative standard deviation (RSD) in the inter-day recovery of D68 from spiked plasma (5 ⁇ g/mL) on three separate days was 1.13.
  • FIG. 11 shows a typical chromatogram obtained for a SPE-extracted plasma sample where D68 and curcumin are measured at 327 nm (upper panel) and 430 nm (lower panel), respectively.
  • human plasma is spiked with D68 and curcumin at concentrations of 0.2 and 1.0 ⁇ g/mL, respectively.
  • Li the upper panel, the chromatogram shows D68 eluting at 7.2 min, whereas in the lower panel curcumin elutes at 16.2 min.
  • the limits of detection (LOD), as calculated from the calibration-design- dependent approach, for D68 in plasma are defined as 5 and 10 times of the background in the chromatograms, respectively.
  • the LOD and LOQ for D68 in spiked plasma are 0.05 ⁇ g/ml and 0.10 ⁇ g/ml, respectively.
  • the peak height for this concentration is 5 times greater than the LOQ for the current assay.
  • the LOD/LOQ of the D68 quantitative assay is expected to improve by an order of magnitude as the wash steps in the SPE extraction phase of the assay are optimized.
  • glururonide and glucuronide/sulfate conjugates of D68 are consistent with what is known about the metabolism of D68's parent compound, curcumin.
  • curcumin conjugation at one or both of the phenoxy groups is known to be a major metabolic pathway for the compound. Curcumin also undergoes reduction of the heptatrienone chain and cleavage at or near the diketone function. Whether these additional metabolic processes occur in the metabolism of D68 has yet to be established.
  • the sub- TBI mouse (BM of leg was shielded, which allow a high dose that cause GI death without BM death) was good to study mitigation agent for GI syndromes of ARS; 2) the agents disclosed herein and in particular D68 have a high redox potential as measured with electronic chemical detector, which rendered the agents with a strong anti-oxidant property; 3) unlike Amifostine, the agents disclosed herein exerted its mitigation effect after IR exposure; 4) D68 agent was administrated via p.o.
  • D68 and the other agents disclosed herein can be pocketed by warfighter since it is a dried small stable molecule; 5) the agents, especially D68, rescued mice from GI syndromes of ARS after exposure to an IR dose of LD 50/7 (83%) and LD 100 / 7 (43%).
  • D68 partially restores the GI endocrine and exocrine ability in mice with deadly GI syndrome of ARS, as evidenced by the low stool hemoccult score, reduced severity of loose and bloody stool and endotoximia; 9) D68 partially restores the GI endocrine and exocrine ability in mice with deadly GI syndrome of ARS; 10) several EVIs that were increased by the 12 Gy IR were reduced by D68, including MCP-I, IL6, KC, ILl ⁇ , BLC, TNF ⁇ , TCA-3 and G-
  • Example 48 DPPH (2,2-Diphenyl-l-PicrylhydrazyI ) Free Radical Scavenging Activity
  • DPPH (1 , below left) is characterized as a stable free radical.
  • the method used to evaluate TAC was the phosphomolybdenum method. This method is based on the reduction of Mo(VI) / Mo(V) by the sample analyte and subsequent formation of green phosphate/Mo(V) complex with a maximal absorption at 695 nm.
  • D12, D13, D47, D68, D71, D72, D73, D75, D76 and D81 showed more antioxidant ability in both of these two assays.
  • D12, D13 and D68 showed protective effects in the in vivo animal study.
  • D47 was remarkably much more potent than curcumin in vitro.
  • Table 3 Total Antioxidant Capacity of Ds (Equivalent of ascorbic acid ⁇ mol/g sample).
  • Example 50 Intracellular ROS measurement
  • ROS reactive oxygen species
  • Curcumin and the D-compounds described herein have many useful properties. This includes lipophilic properties. Protective effects can be found in membranes, and good radical scavengers can also be found in cytosolic compartments. Curcumin and D-compounds contain conjugated pi-bonding systems, which provides an advantage by stabilizing free radicals formed in scavenging reactions. Redox potentials are within a range where these compounds function as antioxidants; reducing ROS.
  • Curcumin possesses a pro-oxidant activity as mitigation agent. It has been shown to increase ROS-mediated cellular damage (nDNA, mtDNA, proteins, membranes); and this has been shown to be effective at 20-40 ⁇ g/mL, with a 1-6 hour exposure time in tumor cell lines. Pro-oxidant activity is mediated through production of superoxide radicals; this reduces thioredoxin reductase activity through alkylation of protein; and induction of NAPDH oxidase activity takes place. Normal tissues show some elevation in ROS when treated with curcumin. This is offset by increased antioxidant capacity (i.e. thiols, catalase, SOD, etc.)
  • Curcumin and derivatives thereof have been shown to have radical scavenging activity - hydroxyl radical, lipid radicals (carbon radicals, peroxyl, alkoxyl). The rate constants are > 10 7 M "1 s "1 . Curcumin has + O 2 ⁇ ; 4.7 x 10 5 M “1 s "1 . Oxidation of O 2 ⁇ to form O 2 .
  • D47 The D-compounds (i.e. D47) are comparable to curcumin as oxidizing agents of O 2 ⁇ . Direct oxidation occurs as follows:
  • Example 52 Cytochrome C Assay
  • the cytochrome C assay is a way to indirectly measure O 2 .
  • Reaction buffer 50 niM Tris-HCl (pH 7.4), 600 ⁇ M EDTA, 100 ⁇ M xanthine with 37.5% DMSO. Cytochrome C (horse heart) at 190 ⁇ M in 50 mM Tris'HCl (pH 7.4), 600 ⁇ M EDTA. Xanthine oxidase (bovine milk) at 0.2 units/mL 50 mM Tris ⁇ Cl (pH 7.4), 600 ⁇ M EDTA.
  • Reaction mixture 96-well microtiter plate; 3 blank replicates (270 ⁇ L reaction buffer + 30 ⁇ L cytoC); 3 sample replicates (250 ⁇ L reaction buffer + 30 ⁇ L cytoC + 15 ⁇ L xanthine oxidase + 5 ⁇ L test compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des compositions à base d'analogues, de dérivés, et de métabolites de la curcumine, ainsi que des procédés pour synthétiser et pour utiliser lesdites compositions. Le présent abrégé concerne un outil de balayage proposé à des fins de recherches dans l'art particulier et n'est pas destiné à être restreint à la présente invention.
PCT/US2008/064872 2007-05-25 2008-05-27 Dérivés de la curcumine et leur utilisation en tant que radioprotecteurs WO2009023357A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US94039607P 2007-05-25 2007-05-25
US60/940,396 2007-05-25
US94062107P 2007-05-29 2007-05-29
US60/940,621 2007-05-29

Publications (2)

Publication Number Publication Date
WO2009023357A2 true WO2009023357A2 (fr) 2009-02-19
WO2009023357A3 WO2009023357A3 (fr) 2009-04-30

Family

ID=40351397

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/064872 WO2009023357A2 (fr) 2007-05-25 2008-05-27 Dérivés de la curcumine et leur utilisation en tant que radioprotecteurs

Country Status (1)

Country Link
WO (1) WO2009023357A2 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014071389A1 (fr) * 2012-11-05 2014-05-08 Veech Richard L Corps cétoniques destinés à protéger les tissus des lésions par rayonnement ionisant
US9211275B2 (en) 2008-01-04 2015-12-15 Isis Innovation Ltd. Ketone bodies and ketone body esters as blood lipid lowering agents
US10051880B2 (en) 2008-08-21 2018-08-21 Oxford University Innovation Limited Hydroxybutyrate ester and medical use thereof
CN108976279A (zh) * 2017-05-31 2018-12-11 首都医科大学 茶氨酰氨基酸苄酯修饰的姜黄素，其合成，活性和应用
CN109134595A (zh) * 2017-06-16 2019-01-04 首都医科大学 茶氨酰氨基酸苄酯修饰的姜黄素，其合成，活性和应用
US10660958B2 (en) 2010-02-22 2020-05-26 Tdeltas Limited Nutritional composition
CN111253282A (zh) * 2020-03-31 2020-06-09 南京解风堂健康管理有限公司 一种经姜黄素改造的增强抗菌活性的化合物及其制备方法和应用
US10821062B2 (en) 2013-03-12 2020-11-03 Tdeltas Limited Compound for use in protecting skin
US11230722B2 (en) 2003-06-03 2022-01-25 Oxford University Innovation Limited Nutritional supplements and therapeutic compositions comprising (r)-3-hydroxybutyrate derivatives
US11566268B2 (en) 2013-03-14 2023-01-31 Government Of The Usa, As Represented By The Secretary, Department Of Health And Human Services Process for producing (R)-3-hydroxybutyl (R)-3-hydroxybutyrate

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030153512A1 (en) * 2000-06-30 2003-08-14 Manfred Hergenhahn Curcumin derivatives with improved water solubility compared to curcumin and medicaments containing the same
US7060733B2 (en) * 2002-08-15 2006-06-13 The Regents Of The University Of California Methods for treating pancreatitis with curcumin compounds and inhibitors of reactive oxygen species

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030153512A1 (en) * 2000-06-30 2003-08-14 Manfred Hergenhahn Curcumin derivatives with improved water solubility compared to curcumin and medicaments containing the same
US7060733B2 (en) * 2002-08-15 2006-06-13 The Regents Of The University Of California Methods for treating pancreatitis with curcumin compounds and inhibitors of reactive oxygen species

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHIM ET AL.: 'Hydrazinocurcumin, a novel synthetic curcumin derivative, Is a potent inhibitor of endothelial cell proliferation .' BIOORGANIC AND MEDICINAL CHEMISTRY vol. 10, no. 8, August 2002, pages 2439 - 2444 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11230722B2 (en) 2003-06-03 2022-01-25 Oxford University Innovation Limited Nutritional supplements and therapeutic compositions comprising (r)-3-hydroxybutyrate derivatives
US10154982B2 (en) 2008-01-04 2018-12-18 Oxford University Innovation Limited Ketone bodies and ketone body esters as blood lipid lowering agents
US9211275B2 (en) 2008-01-04 2015-12-15 Isis Innovation Ltd. Ketone bodies and ketone body esters as blood lipid lowering agents
US11311509B2 (en) 2008-01-04 2022-04-26 Oxford University Innovation Limited Ketone bodies and ketone body esters as blood lipid lowering agents
US10051880B2 (en) 2008-08-21 2018-08-21 Oxford University Innovation Limited Hydroxybutyrate ester and medical use thereof
US10660958B2 (en) 2010-02-22 2020-05-26 Tdeltas Limited Nutritional composition
US11571479B2 (en) 2010-02-22 2023-02-07 Tdeltas Nutritional composition
US10478415B2 (en) 2012-11-05 2019-11-19 Tdeltas Limited Ketone bodies to protect tissues from damage by ionizing radiation
WO2014071389A1 (fr) * 2012-11-05 2014-05-08 Veech Richard L Corps cétoniques destinés à protéger les tissus des lésions par rayonnement ionisant
EP3659595A1 (fr) * 2012-11-05 2020-06-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Corps cétoniques destinés à protéger les tissus des lésions par rayonnement ionisant
US11234953B2 (en) 2012-11-05 2022-02-01 Tdeltas Limited Ketone bodies to protect tissues from damage by ionizing radiation
US9579302B2 (en) 2012-11-05 2017-02-28 Tdeltas Ketone bodies to protect tissues from damage by ionizing radiation
US10821062B2 (en) 2013-03-12 2020-11-03 Tdeltas Limited Compound for use in protecting skin
US11566268B2 (en) 2013-03-14 2023-01-31 Government Of The Usa, As Represented By The Secretary, Department Of Health And Human Services Process for producing (R)-3-hydroxybutyl (R)-3-hydroxybutyrate
CN108976279A (zh) * 2017-05-31 2018-12-11 首都医科大学 茶氨酰氨基酸苄酯修饰的姜黄素，其合成，活性和应用
CN109134595A (zh) * 2017-06-16 2019-01-04 首都医科大学 茶氨酰氨基酸苄酯修饰的姜黄素，其合成，活性和应用
CN109134595B (zh) * 2017-06-16 2022-02-08 首都医科大学 茶氨酰氨基酸苄酯修饰的姜黄素，其合成，活性和应用
CN111253282A (zh) * 2020-03-31 2020-06-09 南京解风堂健康管理有限公司 一种经姜黄素改造的增强抗菌活性的化合物及其制备方法和应用

Also Published As

Publication number Publication date
WO2009023357A3 (fr) 2009-04-30

Similar Documents

Publication Publication Date Title
WO2009023357A2 (fr) Dérivés de la curcumine et leur utilisation en tant que radioprotecteurs
Thakkar et al. Benzothiazole analogues: Synthesis, characterization, MO calculations with PM6 and DFT, in silico studies and in vitro antimalarial as DHFR inhibitors and antimicrobial activities
RU2705548C2 (ru) Лечение или профилактика пролиферативных состояний
Hay et al. DNA-targeted 1, 2, 4-benzotriazine 1, 4-dioxides: potent analogues of the hypoxia-selective cytotoxin tirapazamine
US9714249B2 (en) Pyrazolo-pyrrolidin-4-one derivatives and their use in the treatment of disease
JP2019048833A (ja) Ｆａｓｎを阻害するための新規化合物および組成物
US20130237523A1 (en) Acrylamide derivatives as fab i inhibitors
US20090118503A1 (en) Faah inhibitors
US20090137681A1 (en) Sirtuin Inhibiting Compounds
US11066370B2 (en) Kinase inhibitor compounds, compositions, and methods of treating cancer
US20100286190A1 (en) Certain substituted ureas, as modulators of kinase activity
US20200190097A1 (en) Selective proton coupled folate transporter and folate receptor, and garftase inhibitor compounds and methods of using the same
Yao et al. Identification of a potent oridonin analogue for treatment of triple-negative breast cancer
Elebiju et al. Recent advances in functionalized quinoline scaffolds and hybrids—Exceptional pharmacophore in therapeutic medicine
El Malah et al. Click synthesis, anticancer activity and molecular docking studies on pyridazinone scaffolds
TW201625610A (zh) 萘啶二酮（ｎａｐｈｔｈｙｒｉｄｉｎｅｄｉｏｎｅ）衍生物
KR20150058441A (ko) 고형 종양의 치료 수단 및 방법
WO2009017874A9 (fr) Dérivés innovants de la curcumine et leurs utilisations pharmaceutiques
Liu et al. Discovery of novel tacrine derivatives as potent antiproliferative agents with CDKs inhibitory property
JP2021533164A (ja) イミダゾテトラジン化合物
US8748626B2 (en) Oxazole and thiazole compounds as KSP inhibitors
US20180305330A1 (en) Materials and method for inhibiting replication protein a and uses thereof
US8236827B2 (en) Compounds
EP3275881B1 (fr) Composé de 5-hydroxyle-1,7-naphtyridine substitué par un groupe aryloxy ou hétérooxy, son procédé de préparation et son utilisation pharmaceutique
KR20150041786A (ko) 암치료 및 면역억제를 위한 조합요법

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08827376

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08827376

Country of ref document: EP

Kind code of ref document: A2