US20090253707A1 - Heteroannelated anthraquinone derivatives and the synthesis method thereof - Google Patents

Heteroannelated anthraquinone derivatives and the synthesis method thereof Download PDF

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US20090253707A1
US20090253707A1 US12/193,564 US19356408A US2009253707A1 US 20090253707 A1 US20090253707 A1 US 20090253707A1 US 19356408 A US19356408 A US 19356408A US 2009253707 A1 US2009253707 A1 US 2009253707A1
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Hsu-Shan Huang
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Priority to US13/325,852 priority patent/US8772321B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/10—Radicals substituted by halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • 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
    • C07D285/14—Thiadiazoles; Hydrogenated thiadiazoles condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to heteroannelated anthraquinone derivatives for inhibiting a proliferation activity of a cancer cell, and more particularly to a series of heteroannelated anthraquinone derivatives and the synthesis method thereof.
  • telomere In normal somatic cells, the telomere, which is located at the end of a chromosome, gets shortened at each time of cell mitosis. When the telomere is shortened to some level, the cell will lose the ability of replication and go into apoptosis stage. Telomerase, which is a ribonucleoprotein, acts on the telomere in a eukaryocyte, so as to prolong or maintain the length of the telomere.
  • a telomerase mainly includes two portions; one is a protein sub-unit with activity of reverse transcription, i.e.
  • telomerase reverse transcriptase i.e. the human telomerase reverse transcriptase (hTERT)
  • hTERT human telomerase reverse transcriptase
  • the other one is an RNA template for synthesizing repeated sequences of the telomerase, i.e. the human telomerase RNA component (hTR), wherein the RNA template includes the single RNA sequence, -AAUCCC, which is complementary to the telomerase sequence.
  • Telomerase activity is rarely detected in normal human somatic cells, but is usually detected in the cells that keep proliferating, such as hematopoietic cells, embryogenic cells, stem cells, etc.
  • telomere activity It is estimated that about 85-90% of human tumor cells have telomerase activity, and that is the reason why tumor cells do not go into apoptosis like a normal cell and can keep proliferating (Urquidi et al., Annu. Rev. Med. 2000, 51, 65-79). Reductions in hTERT mRNA expression level and telomerase activity are observed during the processes of cell going aged or immortalized (Bestilny et al., Cancer Res. 1996, 56, 3796-802).
  • telomerase activity of a somatic cell that should not express the telomerase activity could be reproduced by introduction of the hTERT cDNA thereinto for a high level expression of telomerase activity (Bodnar et al., Science. 1998, 279, 349-52).
  • the telomere at chromosome ends of eukaryotic cells is guanine-rich.
  • the G-quadruplex structure includes two portions, wherein one is a small loop composed of TTA, and the other one is a guanine-tetrad composed of four guanines formed by cyclic hydrogen bonds.
  • an alternative besides the direct inhibition to telomerase activity is to stabilize the G-quadruplex structure for inhibiting its reaction with the complementary single strand RNA (AAUCCC), so as to prevent the telomerase from extending the telomere.
  • Chromosome replications of tumor cells may be inhibited by the mentioned method, so as to achieve the anti-caner effect directly or indirectly (Smogorzewska et al., Annu. Rev. Biochem. 2004, 73, 177-208).
  • the present invention provides heteroannelated anthraquinone derivatives and the synthesis method thereof, which is accomplished by preserving the chromophore group with plane tri-cyclic structure and the carbonyl groups at 9 and 10, which have better binding ability, then changing the tri-cyclic structure into tetra-cyclic structure and adding various side chains derived from different modified substituents, so as to synthesize a series of heteroannelated anthraquinone derivatives.
  • the present invention provides a series of heteroannelated anthraquinone derivatives for inhibiting the proliferation activity of cancer cells, which facilitate the study and application regarding cancer cells.
  • a heteroannelated anthraquinone derivative compound is provided.
  • the compound is represented by a formula (I):
  • the halogen is one selected from a group consisting of a fluorine, a chlorine, a bromine and an iodine.
  • the second substituent is one selected from a group consisting of a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a pentyl group, an isopentyl group, a cyclopentyl group, a heptyl group, an isoheptyl group, a cycloheptyl group, an octyl group, an isooctyl group, a cyclooctyl group, a straight alkyl group with a branch substituted by a straight C 1 ⁇ C 5 alkyl group, a nephthenic group with a branch substituted by a straight C 1 ⁇ C 5 alkyl group, alkoxyl derivatives of the mentioned alkyl groups, and halogenated derivatives of the mentioned alkyl groups.
  • the third substituent is one selected from a group consisting of a vinyl group, a propenyl group, a butenyl group, an isobutenyl group, a pentenyl group, an isopentenyl group, a cyclopentenyl group, a hexenyl group, a cyclohexenyl group, a heptenyl group, an cycloheptenyl group, a straight alkyl group with a branch substituted by a straight C 1 ⁇ C 3 alkyl group, a nephthenic group with a branch substituted by a straight C 1 ⁇ C 3 alkyl group, alkoxyl derivatives of the mentioned groups, and halogenated derivatives of the mentioned groups.
  • the heteroannelated anthraquinone derivative compound is used as an effective component together with an excipient to provide a pharmaceutic composition for inhibiting one selected from a group consisting of a growth of a cancer cell, a disease of cell proliferation, and a growth of cell telomere.
  • a heteroannelated anthraquinone derivative compound is provided.
  • the compound is represented by a formula (II):
  • the heteroannelated anthraquinone derivative compound is used as an effective component together with an excipient to provide a pharmaceutic composition for inhibiting one selected from a group consisting of a growth of a cancer cell, a disease of cell proliferation, and a growth of cell telomere.
  • a heteroannelated anthraquinone derivative compound is provided.
  • the compound is represented by a formula (III):
  • R 2 and R 3 is one of i) a first substituent being one of a hydryl group and a sulfuryl-group, and ii) a second substituent being one selected from a group consisting of a C 1 ⁇ C 8 alkyl group, a C 1 ⁇ C 8 alkoxyl group, a C 3 ⁇ C 8 nephthenic group, and a C 3 ⁇ C 8 cyclic alkoxyl group, a straight alkyl group with a branch substitutent, a nephthenic group with a branch substitutent by a straight C 1 ⁇ C 5 alkyl group and halogenated derivatives of the mentioned substitent groups.
  • the second substituent is one selected from a group consisting of a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a pentyl group, an isopentyl group, a cyclopentyl group, a heptyl group, an isoheptyl group, a cycloheptyl group, an octyl group, an isooctyl group, a cyclooctyl group, a phenyl group, a benzyl group, a phenethyl group, a straight alkyl group with a branch substituted by a straight C 1 ⁇ C 3 alkyl group, a nephthenic group with a branch substituted by a straight C 1 ⁇ C 3 alkyl group, alkoxyl derivatives of the mentioned substituent groups, and halogenated derivatives of the mentioned substituent groups.
  • the heteroannelated anthraquinone derivative is used as an effective component together with an excipient to provide a pharmaceutic composition for inhibiting one selected from a group consisting of a growth of a cancer cell, a disease of cell proliferation, and a growth of cell telomere.
  • a heteroannelated anthraquinone derivative compound is provided.
  • the compound is represented by a formula (IV):
  • R 4 is one selected from a group consisting of a hydryl group, a C 1 ⁇ C 4 alkyl group, a C 1 ⁇ C 4 alkoxyl group, a C 1 ⁇ C 4 ketone group, a straight alkyl group with a branch substituted by a straight C 1 ⁇ C 3 alkyl group, a halogen substituted C 1 ⁇ C 4 alkyl group, and a C 1 ⁇ C 4 alkoxyl group.
  • a compound as claimed in claim 12 being used as an effective component together with an excipient to provide a pharmaceutic composition for inhibiting one selected from a group consisting of a growth of a cancer cell, a disease of cell proliferation, and a growth of cell telomere.
  • a method for manufacturing a compound having the formula (I) includes steps of a) dissolving a diaminoanthraquinone in a dimethylformamide solution for forming a solution A, b)adding and dissolving a chloroacetyl chloride in the solution A for forming a solution B, c) mixing and reacting the solution B by a reverse flow method, and then transferring the solution B into an icy water for forming a solution C, d) filtering the solution C for obtaining a precipitate, and e) washing the precipitate by using an ethanol for obtaining the compound of the formula (I).
  • a method for manufacturing a compound having the formula (I) includes steps of a) dissolving a diaminoanthraquinone in a dimethylformamide solution for forming a solution A, b) adding and dissolving a reagent in the solution A for forming a solution B, wherein the reagent is one of a benzaldehyde and a carbon disulfide, c) catalyzing a reaction of the solution B by adding a concentrated sulfuric acid thereinto, and then transferring the solution B into an ice water for forming a solution C, d) filtering the solution C for obtaining a precipitate, and e) washing the precipitate by using an ethanol for obtaining the compound of the formula (I), wherein when the reagent is the carbon disulfide, a triethylamine is further added into the solution B before the step c).
  • a method for manufacturing a compound having the formula (III) includes steps of a) dissolving a diaminoanthraquinone in an acetone for forming a solution A, b) adding a concentrated sulfuric acid into the solution A for forming a solution B, c) transferring the solution B into a potassium carbonate column for obtaining a solution C, and d) using a methanol to crystallize the compound of the formula (III) in the solution C.
  • the step b) is performed in a room temperature.
  • a method for manufacturing a compound having the formula (IV) includes steps of a) dissolving a diaminoanthraquinone in a dimethylformamide solution for forming a solution A, b) adding a glyoxal ethanol solution into the solution A for forming a solution B, c) reacting the solution B by a reverse flow reaction, d) filtering the solution B for obtaining a precipitate, and e) washing the precipitate by using a hot alcohol and a dichloromethane for separating out the compound of the formula (IV).
  • the production rate will increase if the solvents used for dissolving the diaminoanthraquinone contain less water.
  • alcohol could be used for crystallization; alternatively, hot alcohol could be used for washing the products.
  • the products with high solubility could be dissolved in alcohol before crystallization.
  • the products with low solubility need to be washed by hot alcohol to wash out initial material or impurities and by-products generated in the reaction. Compared with recrystallization, although parts of products would be lost in the washing steps, it would be easier to obtain the purified products.
  • the compound provided in the present invention could be supplied with excipients, carriers or diluent, such starch or binder like carboxymethyl cellulose (CMC), so as to prepare granulated pill, tablet, or capsule.
  • the compound could be dissolved in phosphate buffer for adjusting the pH thereof, so as to prepare injection.
  • the compound could be supplied with penetration enhancer, so as to prepare absorbate by skin.
  • the method for manufacturing the heteroannelated anthraquinone derivative includes cyclization and condensation reactions.
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in 30 mL of N,N-dimethylformamide, and chloroacetyl chloride (0.5 mL, 6 mmol) is added thereinto. After ten hours of mixing and reacting by a reverse flow, the mixture is transferred into 200 mL of icy water. After filtering, the precipitate is collected and washed by hot alcohol, so as to obtain the black compound No. 2.
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) was dissolved in dimethylformamide (30 mL), and propionaldehyde (0.29 g, 5 mmol) is added thereinto. Concentrated sulfuric acid (0.1 mL) is added thereinto for catalyzation. After mixing and reacting at room temperature for one hour, the reacted mixture is transferred into 200 mL of icy water and is extracted by using dichloromethane. The extract is dried, and crystallized by using alcholo, so as to obtain the brown compound No. 4.
  • Embodiment 10 (2-Mercapto-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 23)
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in N,N-dimethylformamide (30 mL), and triethylamine (3 mL) is further added thereinto after carbon disulfide (0.4 g, 5 mmol) is added thereinto. After mixing in room temperature and performing reverse flow for ten hours, the reacted mixture is transferred into 200 mL of icy water. After filtering, the precipitate is collected and washed by hot alcolhol, so as to obtain reddle compound No. 23 with melting point of 407-409° C., and the production rate is 80%.
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in dimethylformamide (30 mL), and concentrated sulfuric acid (0.1 mL) is further added thereinto for catalyzation after benzaldehyde (0.6 mL, 5 mmol) is added thereinto. After mixing and reacting in room temperature for one hour, the reacted mixture is transferred into 200 mL of icy water. After filtering, the precipitate is collected and washed by hot alcolhol, so as to obtain yellowish brown compound No. 11.
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in dimethylformamide (30 mL), and concentrated sulfuric acid (0.1 mL) is further added thereinto for catalyzation after vanillin (0.77 g, 5 mmol) is added thereinto. After mixing and reacting in room temperature for one hour, the reacted mixture is transferred into 200 mL of icy water. After filtering, the precipitate is collected and washed by hot alcolhol, so as to obtain brown compound No. 14.
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in THF (30 mL), and triethylamine (3 mL) is further added thereinto for catalyzation after thionyl chloride (0.15 g, 20 mmol) is dripped thereinto. After mixing and reacting in room temperature for one hour, the reacted mixture is transferred into 200 mL of icy water. After filtering, the precipitate is collected and recrystallized by hot alcolhol, so as to obtain yellow compound No. 22 with melting point of 227-228° C., and the production rate is 74%.
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in dry acetone (100 mL), and concentrated sulfuric acid (0.1 mL) is further added thereinto. After mixing and reacting in room temperature for 48 hours, the reacted mixture is transferred into a potassium carbonate column. The product is collected and recrystallized by methanol, so as to obtain the purple compound 20, and the production rate is 31%. In the purification steps of the Embodiment 21, regular extraction method will reduce the production rate, and thus the basic column is used to remove the acid in the rough extract, so as to increase the production rate.
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in N,N-dimethylformamide (30 mL), and concentrated sulfuric acid (0.1 mL) is further added thereinto after acetophenone (0.5 ml, 6 mmol) is added thereinto. After mixing and reacting in room temperature for 72 hours, the reacted mixture is transferred into icy water (200 mL) for precipitation. The precipitate is collected and recrystallized by hot alcohol, so as to obtain the black compound 21, and the production rate is 28%.
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in N,N-dimethylformamide (30 mL), and concentrated sulfuric acid (0.1 mL) is further added thereinto after methyl vinyl ketone (0.36 g, 5 mmol) is added thereinto. After mixing and reacting in room temperature for 72 hours, the reacted mixture is transferred into icy water (200 mL) for precipitation. The precipitate is collected and recrystallized by hot alcohol, so as to obtain the black compound 24, and the production rate is 25%.
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in N,N-dimethylformamide (30 mL), and 40% glyoxal (0.8 g, 5 mml) in EtOH (50 mL) is added thereinto. After reverse flow for 16 hours, the water is evaperated out, and the reacted mixture is transferred into icy water (200 mL) for precipitation. The precipitate is collected and washed by hot alcohol and dichloromethane repeatedly, so as to obtain the black compound 25, and the production rate is 23%.
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in N,N-dimethylformamide (30 mL), and oxalic acid (0.46 g, 5 mmol) and concentrated sulfuric acid (0.1 mL) is added thereinto. After reverse flow for 16 hours, the reacted mixture is transferred into icy water (200 mL) for precipitation. The precipitate is collected and washed by hot alcohol and, so as to obtain the black compound 26, and the production rate is 30%.
  • Telomeric repeat amplification protocol (TRAP) is employed to detect the effect of the heteroannelated anthraquinone derivatives synthesized in the present invention for inhibinting the telomerase activity.
  • the telemerase is used to prolong the oligonucleotide with telomere sequence in the conditions of 90° C. for 10 minutes, 72° C. for 3 minutes, 50° C. for 60 seconds and 94° C.
  • telomere reacted product for 30 seconds
  • CX primer 5′-CCCTTA CCCTTA CCCTTA CCCTAA-3′
  • the PCR conditions includes 39 cycles of PCR reaction in 50° C. for 30 seconds, 72° C. for 60 seconds for 39 PCR cycles, followed by one cycle of reaction in 94° C. for 30 seconds, 50° C. for 30 seconds, 72° C. for 30 seconds and 72° C. for 1 minute, and the reaction is ended in 4° C.
  • the PCR product is analyzed by electrophoresis using 10% acrylamide gel.
  • the positive control (P) is sterile water (dddH 2 O)
  • the negative control (N) is 5 ⁇ l 0.1 mg/mL RNase A (CLONTECH).
  • the positive control (P) produces lots of telomere fragment, while the negative control (N) does not.
  • the compounds provided by the present invention inhibit the telomerase activity by stabilizing G-quadruplex structures and blocking the interaction between telomerase and telomere, or directly inhibit the telomerase activity, so as to inhibit the prologation of telomere. It is found in the present experiments that the Embodiments A4 and A5 have better inhibition effects.
  • the heteroannelated anthraquinone derivatives synthesized in the present invention have various inhibition effects on different cancer cell lines at 1.0 ⁇ 10 ⁇ 5 molal concentration (M) as shown in Table 2.
  • M 1.0 ⁇ 10 ⁇ 5 molal concentration
  • the Embodiment A2 of the present invention inhibits the growth of breast cancer cell HS578T
  • the Embodiment B1 has overall and the most obvious inhibition on different cancer cells. Therefore, the heteroannelated anthraquinone derivatives synthesized in the present invention are potential drugs for inhibiting cancer cells.

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Abstract

A heteroannelated anthraquinone derivative compound is provided. The heteroannelated anthraquinone derivative compound is represented by a formula (I):
Figure US20090253707A1-20091008-C00001
wherein R1 is a substituent being one selected from a group consisting of i) a first substituent being one selected from a group consisting of a hydryl group, an amino group, a nitro group, a hydroxyl group and a cyan group, ii) a second substituent being one selected from a group consisting of (CH2)nX, a straight (CH2)n alkyl group, a (CH2)n alkoxyl group, a branched (CH2)n alkyl group, a C3˜C12nephthenic group, and a C3˜C12 cyclic alkoxyl group, wherein 1=n=12, and X is a halogen, iii) a third substituent being one selected from a group consisting of a straight C1˜C8 alkyl group with a double-bond, a C1˜C8 alkoxyl group with a double-bond, a branched C1˜C8 alkyl group with a double-bond and a C3˜C8 nephthenic group with a double-bond, and iv) a fourth substituent of a C5˜C12 heterocyclic group.

Description

    FIELD OF THE INVENTION
  • The present invention relates to heteroannelated anthraquinone derivatives for inhibiting a proliferation activity of a cancer cell, and more particularly to a series of heteroannelated anthraquinone derivatives and the synthesis method thereof.
    • BACKGROUND OF THE INVENTION
  • In normal somatic cells, the telomere, which is located at the end of a chromosome, gets shortened at each time of cell mitosis. When the telomere is shortened to some level, the cell will lose the ability of replication and go into apoptosis stage. Telomerase, which is a ribonucleoprotein, acts on the telomere in a eukaryocyte, so as to prolong or maintain the length of the telomere. A telomerase mainly includes two portions; one is a protein sub-unit with activity of reverse transcription, i.e. the human telomerase reverse transcriptase (hTERT), and the other one is an RNA template for synthesizing repeated sequences of the telomerase, i.e. the human telomerase RNA component (hTR), wherein the RNA template includes the single RNA sequence, -AAUCCC, which is complementary to the telomerase sequence. Telomerase activity is rarely detected in normal human somatic cells, but is usually detected in the cells that keep proliferating, such as hematopoietic cells, embryogenic cells, stem cells, etc. It is estimated that about 85-90% of human tumor cells have telomerase activity, and that is the reason why tumor cells do not go into apoptosis like a normal cell and can keep proliferating (Urquidi et al., Annu. Rev. Med. 2000, 51, 65-79). Reductions in hTERT mRNA expression level and telomerase activity are observed during the processes of cell going aged or immortalized (Bestilny et al., Cancer Res. 1996, 56, 3796-802). Furthermore, the telomerase activity of a somatic cell that should not express the telomerase activity could be reproduced by introduction of the hTERT cDNA thereinto for a high level expression of telomerase activity (Bodnar et al., Science. 1998, 279, 349-52).
  • The telomere at chromosome ends of eukaryotic cells is guanine-rich. In normal physiological conditions, the single strand DNA of the telomere spontaneously forms a G-quadruplex structure. The G-quadruplex structure includes two portions, wherein one is a small loop composed of TTA, and the other one is a guanine-tetrad composed of four guanines formed by cyclic hydrogen bonds. In order to inhibit the differentiation of tumor cells, an alternative besides the direct inhibition to telomerase activity is to stabilize the G-quadruplex structure for inhibiting its reaction with the complementary single strand RNA (AAUCCC), so as to prevent the telomerase from extending the telomere. Chromosome replications of tumor cells may be inhibited by the mentioned method, so as to achieve the anti-caner effect directly or indirectly (Smogorzewska et al., Annu. Rev. Biochem. 2004, 73, 177-208).
  • It is observed in current studies that anthraquinone can stabilize the G-quadruplex structure for its formula with plane tri-cyclic structure. According to the researches to the quindoline derivatives (10H-indolo[3,2-b]quinoline) with tetra-cyclic structure, berberin with non-plane polycyclic structure and the analogs synthesized therefrom, it is known that the aromatic groups of the mentioned compounds play an important role in the bonding to the G-quardruplex structure. Over-expressions of known oncogenes usually induce cancers and are associated with many cell proliferation disorders, such as chronic lymphocytic leukemia, esophagus cancer, myeloma, etc. In additions, those genes also participate in many pathological and physiological processes. Many experiments have proved that over-expressions of tumor suppressor genes play important role in the prevention and treatment of tumors. Therefore, the research and development of the drugs for curing cell proliferation disorders can be applied in the cure of human cancers, just like the disclosures of Canadian Patent No. 2,428,206.
  • Although it has been published that a heteroannelated anthraquinone derivative can be synthesized by an acylation reaction of 1,2-diaminoanthraquinone to obtain a bis-substituent derivative, followed by a consensation reaction. However, this method only discloses the substituent of aromatic groups, and has a poor production rate (Peng et al., J. Org. Chem. 2005, 70, 10524-31).
  • Based on the above, the present invention provides heteroannelated anthraquinone derivatives and the synthesis method thereof, which is accomplished by preserving the chromophore group with plane tri-cyclic structure and the carbonyl groups at 9 and 10, which have better binding ability, then changing the tri-cyclic structure into tetra-cyclic structure and adding various side chains derived from different modified substituents, so as to synthesize a series of heteroannelated anthraquinone derivatives.
    • SUMMARY OF THE INVENTION
  • The present invention provides a series of heteroannelated anthraquinone derivatives for inhibiting the proliferation activity of cancer cells, which facilitate the study and application regarding cancer cells.
  • In accordance with the first aspect of the present invention, a heteroannelated anthraquinone derivative compound is provided. The compound is represented by a formula (I):
  • Figure US20090253707A1-20091008-C00002
  • wherein R1 is a substituent being one selected from a group consisting of i) a first substituent being one selected from a group consisting of a hydryl group, an amino group, a nitro group, a hydroxyl group and a cyan group, ii) a second substituent being one selected from a group consisting of (CH2)nX, a straight (CH2)n alkyl group, a (CH2)n alkoxyl group, a branched (CH2)n alkyl group, a C3˜C12nephthenic group, and a C3˜C12 cyclic alkoxyl group, wherein 1=n=12, and X is a halogen, iii) a third substituent being one selected from a group consisting of a straight C1˜C8 alkyl group with a double-bond, a C1˜C8 alkoxyl group with a double-bond, a branched C1˜C8 alkyl group with a double-bond and a C3˜C8 nephthenic group with a double-bond, and iv) a fourth substituent of a C5˜C12 heterocyclic group, wherein one of the nephthenic group and the heterocyclic group further has at least one of an ortho-substitution, a meta-substitution and a para-substitution, and comprises at least a fifth substituent for any of the substitutions being one selected from a group consisting of an alkyl group with a C1˜-C3 substituent branch, an amino group, a nitro group, a hydroxyl group and a cyan group, a C1˜C5 alkyl group, a halogen substituted C1˜C5 alkyl group, a C1˜C5 alkoxyl group, a halogen substituted C1˜C5 alkoxyl group, a C1˜C5 cyclic alkoxyl group, and a halogen substituted C1˜C5 cyclic alkoxyl group.
  • Preferably, the halogen is one selected from a group consisting of a fluorine, a chlorine, a bromine and an iodine.
  • Preferably, the second substituent is one selected from a group consisting of a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a pentyl group, an isopentyl group, a cyclopentyl group, a heptyl group, an isoheptyl group, a cycloheptyl group, an octyl group, an isooctyl group, a cyclooctyl group, a straight alkyl group with a branch substituted by a straight C1˜C5 alkyl group, a nephthenic group with a branch substituted by a straight C1˜C5 alkyl group, alkoxyl derivatives of the mentioned alkyl groups, and halogenated derivatives of the mentioned alkyl groups.
  • Preferably, the third substituent is one selected from a group consisting of a vinyl group, a propenyl group, a butenyl group, an isobutenyl group, a pentenyl group, an isopentenyl group, a cyclopentenyl group, a hexenyl group, a cyclohexenyl group, a heptenyl group, an cycloheptenyl group, a straight alkyl group with a branch substituted by a straight C1˜C3 alkyl group, a nephthenic group with a branch substituted by a straight C1˜C3 alkyl group, alkoxyl derivatives of the mentioned groups, and halogenated derivatives of the mentioned groups.
  • Preferably, the heteroannelated anthraquinone derivative compound is used as an effective component together with an excipient to provide a pharmaceutic composition for inhibiting one selected from a group consisting of a growth of a cancer cell, a disease of cell proliferation, and a growth of cell telomere.
  • In accordance with the second aspect of the present invention, a heteroannelated anthraquinone derivative compound is provided. The compound is represented by a formula (II):
  • Figure US20090253707A1-20091008-C00003
  • Preferably, the heteroannelated anthraquinone derivative compound is used as an effective component together with an excipient to provide a pharmaceutic composition for inhibiting one selected from a group consisting of a growth of a cancer cell, a disease of cell proliferation, and a growth of cell telomere.
  • In accordance with the third aspect of the present invention, a heteroannelated anthraquinone derivative compound is provided. The compound is represented by a formula (III):
  • Figure US20090253707A1-20091008-C00004
  • wherein either one of R2 and R3 is one of i) a first substituent being one of a hydryl group and a sulfuryl-group, and ii) a second substituent being one selected from a group consisting of a C1˜C8 alkyl group, a C1˜C8 alkoxyl group, a C3˜C8 nephthenic group, and a C3˜C8 cyclic alkoxyl group, a straight alkyl group with a branch substitutent, a nephthenic group with a branch substitutent by a straight C1˜C5 alkyl group and halogenated derivatives of the mentioned substitent groups.
  • Preferably, the second substituent is one selected from a group consisting of a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a pentyl group, an isopentyl group, a cyclopentyl group, a heptyl group, an isoheptyl group, a cycloheptyl group, an octyl group, an isooctyl group, a cyclooctyl group, a phenyl group, a benzyl group, a phenethyl group, a straight alkyl group with a branch substituted by a straight C1˜C3 alkyl group, a nephthenic group with a branch substituted by a straight C1˜C3 alkyl group, alkoxyl derivatives of the mentioned substituent groups, and halogenated derivatives of the mentioned substituent groups.
  • Preferably, the heteroannelated anthraquinone derivative is used as an effective component together with an excipient to provide a pharmaceutic composition for inhibiting one selected from a group consisting of a growth of a cancer cell, a disease of cell proliferation, and a growth of cell telomere.
  • In accordance with the fourth aspect of the present invention, a heteroannelated anthraquinone derivative compound is provided. The compound is represented by a formula (IV):
  • Figure US20090253707A1-20091008-C00005
  • wherein R4 is one selected from a group consisting of a hydryl group, a C1˜C4 alkyl group, a C1˜C4 alkoxyl group, a C1˜C4 ketone group, a straight alkyl group with a branch substituted by a straight C1˜C3 alkyl group, a halogen substituted C1˜C4 alkyl group, and a C1˜C4 alkoxyl group.
  • Preferably, A compound as claimed in claim 12, being used as an effective component together with an excipient to provide a pharmaceutic composition for inhibiting one selected from a group consisting of a growth of a cancer cell, a disease of cell proliferation, and a growth of cell telomere.
  • In accordance with the fifth aspect of the present invention, a method for manufacturing a compound having the formula (I) is provided. The method includes steps of a) dissolving a diaminoanthraquinone in a dimethylformamide solution for forming a solution A, b)adding and dissolving a chloroacetyl chloride in the solution A for forming a solution B, c) mixing and reacting the solution B by a reverse flow method, and then transferring the solution B into an icy water for forming a solution C, d) filtering the solution C for obtaining a precipitate, and e) washing the precipitate by using an ethanol for obtaining the compound of the formula (I).
  • In accordance with the sixth aspect of the present invention, a method for manufacturing a compound having the formula (I) is provided. The method includes steps of a) dissolving a diaminoanthraquinone in a dimethylformamide solution for forming a solution A, b) adding and dissolving a reagent in the solution A for forming a solution B, wherein the reagent is one of a benzaldehyde and a carbon disulfide, c) catalyzing a reaction of the solution B by adding a concentrated sulfuric acid thereinto, and then transferring the solution B into an ice water for forming a solution C, d) filtering the solution C for obtaining a precipitate, and e) washing the precipitate by using an ethanol for obtaining the compound of the formula (I), wherein when the reagent is the carbon disulfide, a triethylamine is further added into the solution B before the step c).
  • In accordance with the seventh aspect of the present invention, a method for manufacturing a compound having the formula (III) is provided. The method includes steps of a) dissolving a diaminoanthraquinone in an acetone for forming a solution A, b) adding a concentrated sulfuric acid into the solution A for forming a solution B, c) transferring the solution B into a potassium carbonate column for obtaining a solution C, and d) using a methanol to crystallize the compound of the formula (III) in the solution C.
  • Preferably, the step b) is performed in a room temperature.
  • In accordance with the eighth aspect of the present invention, a method for manufacturing a compound having the formula (IV) is provided. The method includes steps of a) dissolving a diaminoanthraquinone in a dimethylformamide solution for forming a solution A, b) adding a glyoxal ethanol solution into the solution A for forming a solution B, c) reacting the solution B by a reverse flow reaction, d) filtering the solution B for obtaining a precipitate, and e) washing the precipitate by using a hot alcohol and a dichloromethane for separating out the compound of the formula (IV).
  • Alternatively, in some steps of the above-mentioned methods, the production rate will increase if the solvents used for dissolving the diaminoanthraquinone contain less water. In the purification steps for the products, alcohol could be used for crystallization; alternatively, hot alcohol could be used for washing the products. The products with high solubility could be dissolved in alcohol before crystallization. The products with low solubility need to be washed by hot alcohol to wash out initial material or impurities and by-products generated in the reaction. Compared with recrystallization, although parts of products would be lost in the washing steps, it would be easier to obtain the purified products.
  • The compound provided in the present invention could be supplied with excipients, carriers or diluent, such starch or binder like carboxymethyl cellulose (CMC), so as to prepare granulated pill, tablet, or capsule. Alternatively, the compound could be dissolved in phosphate buffer for adjusting the pH thereof, so as to prepare injection. The compound could be supplied with penetration enhancer, so as to prepare absorbate by skin.
  • Additional objects and advantages of the invention will be set forth in the following descriptions.
    • DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
  • The present invention will now be described more specifically with the experiment results of the following embodiments. It is to be noted that the following descriptions of preferred embodiments of this invention are presented herein for the purposes of illustration and description only; it is not intended to be exhaustive or to be limited to the precise form disclosed.
  • Concretely speaking, the method for manufacturing the heteroannelated anthraquinone derivative includes cyclization and condensation reactions.
    • Embodiment 1 (2-Methyl-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 2)
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in 30 mL of N,N-dimethylformamide, and chloroacetyl chloride (0.5 mL, 6 mmol) is added thereinto. After ten hours of mixing and reacting by a reverse flow, the mixture is transferred into 200 mL of icy water. After filtering, the precipitate is collected and washed by hot alcohol, so as to obtain the black compound No. 2.
  • The compound No. 2 has the following characterstics: MW 262.0724 (C16H9N2O2); Rf: 0.79 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 1667 (CO); EI-MS m/z: 262 (M+, 100%); 1H-NMR (300 MHz, DMSO-d6) d (ppm): 2.72 (3H, s,—CH3), 7.75-7.82 (2H, m, Ar—H7,10), 7.93 (1H, d, J=8.4 Hz, Ar—H5), 8.13 (1H, d, J=8.4 Hz, Ar—H4), 8.19-8.23 (1H, m, Ar—H8,9), 11.01 (1H, br, —NH); and 13C-NMR (75 MHz, DMSO-d6) d (ppm): 23.89, 120.23, 121.22, 125.29, 126.19, 126.75, 127.19, 128.17, 128.87, 132.98, 134.18, 134.42, 148.22, 158.09, 182.43 (CO), 185.13 (CO).
    • Embodiment 2 (2-Chloroacetyl-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 3)
  • Figure US20090253707A1-20091008-C00006
  • Except controlling the reacting temperature in 50-60° C., all steps are identical with the steps for manufacturing the compound No. 2, and the yellowish brown compound No. 3 can be obtained.
  • The compound No. 3 has the following characterstics: MW 296.0353 (C16H9N2O2Cl); Rf: 0.5 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 3359(NH), 1660 (CO); HRMS (ESI-TOF) m/z: calcd for C16H10N2O2Cl+ [M+H]+: 297.0425, found: 297.0426; 1H-NMR (300 MHz, CDCl3) d (ppm): 4.92 (2H, s, —CH2Cl), 7.80-7.83 (2H, m, Ar—H7,10), 8.08 (1H, d, J=8.4 Hz, Ar—H5), 8.24(1H, d, J=8.4 Hz, Ar—H4), d8.26-8.35(2H, m, Ar—H8,9), d11.21(1H, br, —NH); and 13C-NMR (75 MHz, DMSO) d (ppm): 37.80, 119.35, 121.27, 125.95, 126.83, 127.40, 129.06, 132.35, 133.47, 133.64, 134.88, 135.10, 148.89, 156.93, 183.04 (CO), 183.83 (CO).
    • Embodiment 3 (2-Ethyl-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 4)
  • Figure US20090253707A1-20091008-C00007
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) was dissolved in dimethylformamide (30 mL), and propionaldehyde (0.29 g, 5 mmol) is added thereinto. Concentrated sulfuric acid (0.1 mL) is added thereinto for catalyzation. After mixing and reacting at room temperature for one hour, the reacted mixture is transferred into 200 mL of icy water and is extracted by using dichloromethane. The extract is dried, and crystallized by using alcholo, so as to obtain the brown compound No. 4.
  • The compound No. 4 has the following characterstics: MW 276.0899 (C17H12N2O2); Rf: 0.75 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 1669 (CO); HRMS (ESI-TOF) m/z: calcd for C17H13N2O2 + [M+H]+: 277.0971, found: 277.0975 calcd for C17H12N2O2Na+ [M+Na]+: 299.0971, found: 299.0794; 1H-NMR (300 MHz, CDCl3) d (ppm): 1.51 (3H, t, J=7.5 Hz, —CH3), 3.05 (2H, q, J=7.5 Hz, —CH2—), 7.73-7.81 (2H, m, Ar—H7,10), 7.99 (1H, d, J=8.4 Hz, Ar—H5), d8.16(1H, d, J=8.4 Hz, Ar—H4), d8.21-8.23(1H, m, Ar—H9), d8.27-8.31(1H, m, Ar—H8), d10.85(1H, br, —NH); and 13C-NMR (75 MHz, CDCl3) d (ppm): 11.87, 22.89, 117.74, 121.50, 125.21, 126.47, 127.55, 128.21, 132.72, 133.24, 133.72, 133.99, 134.37, 148.90, 161.64, 182.81 (CO), 185.15 (CO).
    • Embodiment 4 (2-Isopropyl-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 5)
  • Figure US20090253707A1-20091008-C00008
  • All steps for manufacturing the yellow compound No. 5 are identical with the steps of Embodiment 3, except that propionaldehyde is substituted by isobutyraldehyde (0.41 g, 5 mmol).
  • The compound No. 5 has the following characterstics: MW 290.1055 (C18H14N2O2); Rf: 0.7 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 3445 (NH), 1662 (CO); HRMS (ESI-TOF) m/z: calcd for C18H15N2O2 + [M+H]+: 291.1120, found: 291.1123; 1H-NMR (300 MHz, CDCl3) d (ppm): d1.56(6H, d, J=6.6 Hz, —CH3), d3.40(1H, sp, J=6.6 Hz, —CH—), d7.78-7.85(2H, m, Ar—H7,10), d8.11(1H, d, J=8.4 Hz, Ar—H5), d8.23(1H, d, J=8.4 Hz, Ar—H4), d8.25-8.36(2H, m, Ar—H8,9), d10.88(1H, s, —NH); and 13C-NMR (75 MHz, CDCl3) d (ppm): 21.15, 29.21, 117.66, 121.36, 125.21, 126.32, 127.42, 128.05, 132.49, 133.10, 133.61, 133.86, 134.24, 148.71, 165.35, 181.05(CO), 182.73(CO).
    • Embodiment 5 (2-Butyl-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 6)
  • Figure US20090253707A1-20091008-C00009
  • All steps for manufacturing the brown compound No. 6 are identical with the steps of Embodiment 3, except that propionaldehyde is substituted by pentanal (0.45 g, 5 mmol).
  • The compound No. 6 has the following characterstics: MW 304.1212 (C19H16N2O2); Rf: 0.65 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 1669 (CO); HRMS (ESI-TOF) m/z: calcd for C19H17N2O2 + [M+H]+: 305.1276, found: 305.1282 calcd for C19H15N2O2 − [M-H]−: 303.1131, found: 303.1135; 1H-NMR (300 MHz, CDCl3) d (ppm): d1.00(3H, t, J=7.2 Hz, —CH3), d1.50(2H, sx, J=7.5 Hz, —CH2—), d1.93(2H, qt, J=7.8 Hz —CH2—), d3.04(2H, t, J=7.5 Hz, —CH2—), d7.62-7.83(2H, m, Ar—H7,10), d8.03(1H, d, J=8.4 Hz, Ar—H5), d8.20, 1H, d, J=8.1 Hz, Ar—H4), d8.24-8.35(2H, m, Ar—H8,9) d10.83(1H, s, —NH); and 13C-NMR (75 MHz, CDCl3) d (ppm): 12.98, 21.78, 28.60, 29.27, 117.32, 121.07, 124.64, 125.98, 127.08, 127.83, 132.17, 132.84, 133.20, 133.61, 133.86, 148.25, 160.29, 182.31(CO), 184.78(CO).
    • Embodiment 6 (2-sec-Butyl-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 7)
  • Figure US20090253707A1-20091008-C00010
  • All steps for manufacturing the yellow compound No. 7 are identical with the steps of Embodiment 3, except that propionaldehyde is substituted by methylbutyraldehyde (0.46 g, 5 mmol).
  • The compound No. 7 has the following characterstics: MW 304.1212 (C19H16N2O2); Rf: 0.57 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 1665 (CO); HRMS (ESI-TOF) m/z: calcd for C19H17N2O2 + [M+H]+: 305.1276, found: 305.1280 calcd for C19H15N2O2 − [M−H]−: 303.1131, found: 303.1137; 1H-NMR (300 MHz, CDCl3) d (ppm): d1.00(3H, t, J=7.2 Hz, —CH3), d1.52(3H, d, J=6.9 Hz , —CH3), d1.82-2.02(2H, m, —CH2—), d3.04(1H, sx, J=7.2 Hz, —CH—), d7.62-7.83(2H, m, Ar—H7,10), d8.03(1H, d, J=8.4 Hz, Ar—H5), d8.20(1H, d, J=8.1 Hz, Ar—H4), d8.24-8.35(2H, m, Ar—H8,9), d10.83(1H, s, —NH); and 13C-NMR (75 MHz, CDCl3) d (ppm): 11.09, 18.09, 28.40, 35.71, 117.39, 121.07, 124.75, 125.95, 127.09, 127.84, 131.92, 132.83, 133.22, 133.59, 133.87, 148.06, 164.30, 182.31(CO), 184.82(CO).
    • Embodiment 7 (2-tert-Butyl-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 8)
  • Figure US20090253707A1-20091008-C00011
  • All steps for manufacturing the yellow compound No. 8 are identical with the steps of Embodiment 3, except that propionaldehyde is substituted by trimethylacetaldehyde (0.46 g, 5 mmol).
  • The compound No. 8 has the following characterstics: MW 304.1212 (C19H16N2O2); Rf: 0.8 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 3568(NH), 1664 (CO); HRMS (ESI-TOF) m/z: calcd for C19H17N2O2 + [M+H]+: 305.1276, found: 305.1283 calcd for C19H15N2O2 − [M−H]−: 303.1131, found: 303.1136; 1H-NMR (300 MHz, CDCl3) d (ppm): d1.58 (9H, s, —C(CH3)3), d7.77-7.84 (2H, m, Ar—H7,10), d8.08 (1H, d, J=8.4 Hz, Ar—H5), d8.21 (1H, d, J=8.4 Hz, Ar—H4), d8.25-8.28 (1H, m, Ar—H8), d8.33-8.36 (1H, m, Ar—H9), d10.83 (1H, s, —NH); and 13C-NMR (75 MHz, CDCl3) d (ppm): 29.24, 117.79, 121.47, 125.41, 126.39, 127.56, 128.17, 132.70, 133.23, 133.74, 133.96, 134.37, 148.73, 168.00, 182.77(CO), 185.26(CO).
    • Embodiment 8 (2-Heptyl-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 9)
  • Figure US20090253707A1-20091008-C00012
  • All steps for manufacturing the brown compound No. 9 are identical with the steps of Embodiment 3, except that propionaldehyde is substituted by octanal (0.29 g, 5 mmol).
  • The compound No. 9 has the following characterstics: MW 346.1681 (C22H22N2O2); Rf: 0.85 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 3447(NH), 1664 (CO); HRMS (ESI-TOF) m/z: calcd for C22H23N2O2 + [M+H]+: 347.1754, found: 347.1752; 1H-NMR (300 MHz, CDCl3)d (ppm): d0.87-0.91 (3H, m, —CH3), d1.26-1.35(6H, m, —CH2—), d1.56(2H, sx, J=7.0 Hz, —CH2—), d2.36(2H, q, J=7.0 Hz, —CH2—), d2.71(2H, t, J=7.0 Hz, —CH2—),d7.75-7.81 (2H, m, Ar—H7,10), d8.04 (1H, d, J=8.0 Hz, Ar—H5), d8.17 (1H, d, J=8.0 Hz, Ar—H4), d8.23-8.25 (1H, m, Ar—H8), d8.31-8.33 (1H, m, Ar—H9), d10.93 (1H, s, —NH); and 13C-NMR (75 MHz, CDCl3) d (ppm): 14.08, 22.63, 27.99, 28.79, 29.24, 29.46, 31.79, 117.49, 121.66, 125.28, 126.37, 127.54, 130.56, 133.27, 133.67, 134.06, 134.31, 137.37, 149.40, 158.89, 182.69(CO), 185.25(CO).
    • Embodiment 9 ((E)-2-(But-1-enyl)-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 10)
  • Figure US20090253707A1-20091008-C00013
  • All steps for manufacturing the brown compound No. 10 are identical with the steps of Embodiment 3, except that propionaldehyde is substituted by trans-2-pentenal (0.46 g, 5 mmol).
  • The compound No. 10 has the following characterstics: MW 302.1055 (C19H15N2O2); Rf: 0.57 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 1664 (CO); EI-MS m/z: 302 (M+, 100%); 1H-NMR (300 MHz, CDCl3) d (ppm): d0.98(3H, t, J=6.9 Hz, —CH3), d1.94-1.98(2H, m, —CH2—), d6.16-6.29(1H, m, —CH—), d6.51(1H, d, J=18 Hz, —CH—), d7.68(1H, d, J=8.4 Hz, Ar—H5), d7.82-7.89(2H, m, Ar—H7,10), d8.14(1H, d, J=8.1 Hz, Ar—H4), d8.27-8.35(2H, m, Ar—H8,9), d10.74(1H, s, —NH); and 13C-NMR (75 MHz, CDCl3) d(ppm): 14.39, 27.40, 117.37, 120.03, 121.07, 124.75, 125.95, 127.09, 127.84, 131.92, 132.83, 133.22, 133.59, 133.87, 134.90, 135.37, 149.06, 182.73(CO), 185.18(CO).
  • Embodiment 10 (2-Mercapto-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 23)
  • Figure US20090253707A1-20091008-C00014
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in N,N-dimethylformamide (30 mL), and triethylamine (3 mL) is further added thereinto after carbon disulfide (0.4 g, 5 mmol) is added thereinto. After mixing in room temperature and performing reverse flow for ten hours, the reacted mixture is transferred into 200 mL of icy water. After filtering, the precipitate is collected and washed by hot alcolhol, so as to obtain reddle compound No. 23 with melting point of 407-409° C., and the production rate is 80%.
  • The compound No. 23 has the following characterstics: MW 280.0306 (C15H8N2O2S); Rf: 0.80 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 3221(NH), 3192(NH), 1665(CO); HRMS (ESI-TOF) m/z: calcd for C15H9N2O2S+ [M+H]+: 281.0379, found: 281.0389; 1H-NMR (300 MHz, DMSO-d6) d (ppm): d7.54(1H, d, J=8.1 Hz, Ar—H5), d8.02 (1H, d, J=8.1 Hz, Ar—H4), d7.91-7.94 (2H, m, Ar—H7,10), d8.18-8.22 (2H, m, Ar—H8,9), d12.73 (1H, s, —NH), d13.29 (1H, s, —NH); and 13C-NMR (75 MHz, DMSO-d6) d (ppm): 113.89, 115.27, 122.41, 126.26, 126.76, 126.88, 130.95, 132.89, 133.06, 134.25, 134.47, 138.19, 172.89, 181.79(CO), 182.46(CO).
    • Embodiment 11 (2-Phenyl-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 11)
  • Figure US20090253707A1-20091008-C00015
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in dimethylformamide (30 mL), and concentrated sulfuric acid (0.1 mL) is further added thereinto for catalyzation after benzaldehyde (0.6 mL, 5 mmol) is added thereinto. After mixing and reacting in room temperature for one hour, the reacted mixture is transferred into 200 mL of icy water. After filtering, the precipitate is collected and washed by hot alcolhol, so as to obtain yellowish brown compound No. 11.
  • The compound No. 11 has the following characterstics: MW 324.0899 (C21H12N2O2); Rf: 0.55 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 3296(NH), 1660 (CO); EI-MS m/z: 324(M+, 100.00%), 325(19%); HRMS (ESI-TOF) m/z: calcd for C21H13N2O2 + [M+H]+: 325.0971, found: 325.0973; 1H-NMR (300 MHz, DMSO-d6) d (ppm): d7.57(3H, t, J=3 Hz, Ar′—H3,4,5), d7.89(2H, m, Ar—H7,10), d8.03(1H, d, J=8.4 Hz, Ar—H5), d8.08(1H, d, J=8.4 Hz, Ar—H4), d8.16(2H, m, Ar—H8,9), d8.40(2H, dd, J=6,3 Hz, Ar′—H2,6); and 13C-NMR (75 MHz, DMSO-d6) d (ppm): 119.62, 121.72, 125.06, 126.85, 127.42, 128,79, 128.86, 129.41, 129.50, 131.72, 133.72, 133.77, 134.92, 135.07, 149.26, 158.25, 183.06(CO), 183.79(CO).
    • Embodiment 12 (2-(4-N,N-Dimethylamino)phenyl-(3)H-anthra [1,2-d]imidazole-6,11-dione, No. 12)
  • Figure US20090253707A1-20091008-C00016
  • All steps for manufacturing the deep brown compound No. 12 are identical with the steps of Embodiment 11, except that benzaldehyde is substituted by 4-dimethylaminobenzaldehyde (0.77 g, 5 mmol).
  • The compound No. 12 has the following characterstics: MW 367.1321 (C23H17N3O2); Rf: 0.6 (ethyl acetate: dichloromethane=1:4); IR(KBr)cm−1: 3404(NH), 1659(CO); EI-MS m/z: 366(27%), 367(M+, 100.00%), 368(20%); HRMS (ESI-TOF) m/z: calcd for C23H18N3O2 + [M+H]+: 368.1393, found: 368.1393; 1H-NMR (300 MHz, CDCl3) d (ppm): d3.09 (6H, s, —N(CH3)2), d6.81 (2H, d, Ar—H), d7.79˜7.82 (3H, m, Ar—H), d8.03-8.22 (3H, m, Ar—H), d8.27˜8.36 (2H, m, Ar—H), d11.10 (1H, br, —NH); and 13C-NMR (75 MHz, CDCl3) d (ppm): 39.95, 111.65, 115.23, 117.13, 121.83, 124.24, 126.33, 127.37, 127.44, 128.27, 133.27, 133.45, 133.54, 134.12, 150.11, 152.10, 157.59, 182.47(CO), 185.09(CO).
    • Embodiment 13 (2-(4-Nitrophenyl)-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 13)
  • Figure US20090253707A1-20091008-C00017
  • All steps for manufacturing the deep brown compound No. 13 are identical with the steps of Embodiment 11, except that benzaldehyde is substituted by 4-nitrobenzaldehyde (0.78 g, 5 mmol).
  • The compound No. 13 has the following characterstics: MW 369.0750 (C21H11N3O4); Rf: 0.6 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 3460(NH), 1657(CO), 1517, 1345(NO2); EI-MS m/z: 249(100%), 369(M+, 35%); HRMS (ESI-TOF) m/z: calcd for C21H12N3O4 + [M+H]+: 370.0822, found: 370.0823; 1H-NMR (300 MHz, DMSO-d6) d (ppm): d7.79-7.82 (3H, m, Ar—H7,10), d7.14 (1H, d, J=8.1 Hz, Ar—H4), d8.23 (1H, d, J=8.1 Hz, Ar—H5), d8.23-8.32 (2H, m, Ar—H8,9), d8.39 (2H, d, J=8.1 Hz, Ar′—H2,6), d8.58 (2H, d, J=8.1 Hz, Ar′—H3,5), d10.15 (1H, br, —NH); and 13C-NMR (75 MHz, DMSO-d6) d (ppm): 117.81, 122.43, 123.62, 125.24, 125.88, 126.10, 127.92, 133.22, 133.36, 134.53, 143.08, 146.39, 146.77, 155.89, 172.18, 178.35, 179.40, 183.20(CO), 185.56(CO).
    • Embodiment 14 (2-(4-Hydroxy-3-methoxyphenyl)-1H-anthra[1,2-d]imidazole-6,11-dione, No. 14)
  • Figure US20090253707A1-20091008-C00018
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in dimethylformamide (30 mL), and concentrated sulfuric acid (0.1 mL) is further added thereinto for catalyzation after vanillin (0.77 g, 5 mmol) is added thereinto. After mixing and reacting in room temperature for one hour, the reacted mixture is transferred into 200 mL of icy water. After filtering, the precipitate is collected and washed by hot alcolhol, so as to obtain brown compound No. 14.
  • The compound No. 14 has the following characterstics: MW 370.0954 (C22H14N2O4); Rf: 0.2 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 3411(OH), 3411(NH), 1664(CO); EI-MS m/z: 369(57%), 370(M+, 100%) HRMS (ESI-TOF) m/z: calcd for C22H15N2O4 + [M+H]+: 370.1026, found: 370.1025; 1H-NMR (300 MHz, DMSO-d6) d (ppm): d3.91(3H, s, —OCH3), d6.90(1H, d, J=8.4 Hz, Ar′—H5), d7.81-7.88(3H, m, Ar—H7,10, Ar′—H2), d7.92-7.96(3H, m, Ar—H4,5, Ar′—H6), d7.99(1H, s, —NH), d8.11(2H, td, J=Hz, Ar—H8,9), d9.78(1H, br, —OH); and 13C-NMR (75 MHz, DMSO-d6) d (ppm): 56.57, 112.72, 116.37, 119.21, 119.65, 122.05, 122.95, 123.88, 126.81, 127.41, 128.42, 133.50, 133.64, 134.87, 135.09, 148.48, 150.87, 158.33, 182.85(CO), 183.79(CO).
    • Embodiment 15 (2-p-Tolyl-1H-anthra[1,2-d]imidazole-6,11-dione, No. 15)
  • Figure US20090253707A1-20091008-C00019
  • All steps for manufacturing the twany compound No. 15 are identical with the steps of Embodiment 14, except that vanillin is substituted by p-tolualdehyde (0.7 ml, 5 mmol).
  • The compound No. 15 has the following characterstics: MW 338.1055 (C22H14N2O4); Rf: 0.65 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 3397(NH), 1659(CO); EI-MS m/z: 338(M+, 100%), 339(24%) HRMS (ESI-TOF) m/z: calcd for C22H15N2O4 + [M+H]+: 339.1128, found: 339.1128; 1H-NMR (300 MHz, CDCl3) d (ppm): d2.46(3H, s, Ar′—CH3), d7.37(2H, d, J=8.1 Hz, Ar′—H3,5), d7.79(2H, t, J=3.6 Hz, Ar—H7,10), d8.03(2H, d, J=7.8 Hz, Ar′—H2,6), d8.08(1H, d, J=8.4 Hz, Ar—H5), d8.21(1H, d, J=8.4 Hz, Ar—H4), d8.24-8.34(2H, m, Ar—H8,9), d11.21(1H, s, —NH); and 13C-NMR (75 MHz, CDCl3) d (ppm): 21.58, 117.89, 121.96, 125.44, 125.75, 126.46, 127.00, 127.58, 128.43, 130.00, 133.20, 133.26, 133.72, 133.99, 134.38, 142.05, 149.50, 156.86, 182.60(CO), 185.16(CO).
    • Embodiment 16 (2-(4-Bromophenyl)-1H-anthra[1,2-d]imidazole-6,11-dione, No. 16)
  • Figure US20090253707A1-20091008-C00020
  • All steps for manufacturing the red brown compound No. 16 are identical with the steps of Embodiment 14, except that vanillin is substituted by 4-bromobenzaldehyde (0.93 g, 5 mmol).
  • The compound No. 16 has the following characterstics: MW 402.0004 (C21H11N2O2Br); Rf: 0.4 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 3391(NH), 1658(CO); EI-MS m/z: 402(M+, 100%), 404(97%), HRMS (ESI-TOF) m/z: calcd for C21H12N2O2Br+ [M+H]+: 403.0085, found: 403.0073 calcd for C21H10N2O2Br− [M−H]−: 400.9939, found: 400.9923; 1H-NMR (300 MHz, CDCl3) d (ppm): d7.72(2H, d, J=8.7 Hz, Ar′—H3,5), d7.80-7.83(2H, m, Ar—H7,10), d8.06(2H, d, J=8.7 Hz, Ar′—H2,6), d8.13(1H, d, J=8.4 Hz, Ar—H4), d8.25(1H, d, J=8.4 Hz, Ar—H5), d8.27-8.36(2H, m, Ar—H8,9), d11.29(1H, s, —NH); and 13C-NMR (75 MHz, CDCl3) d (ppm): 122.18, 125.86, 126.11, 126.57, 127.64, 127.69, 128.50, 128.89, 132.61, 133.20, 133.35, 133.87, 134.01, 134.57, 149.40, 155.62, 182.63(CO), 185.25(CO).
    • Embodiment 17 (2-(4-Cyanophenyl)-1H-anthra[1,2-d]imidazole-6,11-dione, No. 17)
  • Figure US20090253707A1-20091008-C00021
  • All steps for manufacturing the yellowish brown compound No. 17 are identical with the steps of Embodiment 14, except that vanillin is substituted by 4-cyanobenzaldehyde (0.67 g, 5 mmol).
  • The compound No. 17 has the following characterstics: MW 349.0851 (C22H11N3O2); Rf: 0.65 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 3341(NH), 2229(CN), 1667(CO); HRMS (ESI-TOF) m/z: calcd for C22H12N3O2 + [M+H]+: 350.0924, found: 350.0925; 1H-NMR (300 MHz, CDCl3)d(ppm): d7.80-7.85(2H, m, Ar—H7,10), d8.06(2H, d, J=8.1 Hz, Ar—H3′,5′), d8.18(1H, d, J=8.4 Hz, Ar—H5), d8.27-8.32(4H, m, Ar—H4,8,2′,6′), d8.35-8.38(1H), m, Ar—H9), d11.46(1H, s, —NH); and 13C-NMR (75 MHz, DMSO-d6) d (ppm): 114.71, 118.04, 118.52, 122.39, 126.39, 126.63, 127.57, 127.75, 129.45, 132.76, 133.04, 133.11, 133.34, 133.93, 133.99, 134.70, 149.17, 154.25, 182.56(CO), 185.21(CO).
    • Embodiment 18 (2-(2,5-Dimethoxyphenyl)-1H-anthra[1,2-d]imidazole-6,11-dione, No. 18)
  • Figure US20090253707A1-20091008-C00022
  • All steps for manufacturing the red brown compound No. 18 are identical with the steps of Embodiment 14, except that vanillin is substituted by 2,5-dimethoxybenzaldehyde (0.89 g, 5 mmol).
  • The compound No. 18 has the following characterstics: MW 384.1110 (C23H16N2O4); Rf: 0.4 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 3417(NH), 1660(C═O), 1226(C—O); HRMS (ESI-TOF) m/z: calcd for C23H17N2O4 + [M+H]+: 385.1183, found: 385.1181; 1H-NMR (300 MHz, CDCl3) d (ppm): d3.93(3H, s, Ar5′-OCH3), d4.21(H, s, Ar2′—OCH3), d7.09(2H, d, J=1.2 Hz, Ar—H3′,4′), d7.79-7.82(2H, m, Ar—H7,10), d8.13(1H, d, J=8.1 Hz, Ar—H5 ), d8.13(1H, s, Ar—H6′), d8.25(1H, d, J=8.1 Hz, Ar—H4), d8.29-8.36(2H, m, Ar—H8,9), d12.37(1H, s, —NH); and 13C-NMR (75 MHz, CDCl3) d (ppm): 56.08, 56.69, 113.13, 113.36, 116.86, 118.14, 119.98, 121.92, 124.92, 126.46, 127.54, 129.92, 132.57, 133.43, 133.70, 134.06, 134.24, 135.39, 152.20, 154.23, 155.18, 182.82(CO), 184.88(CO).
    • Embodiment 19 (2-(Benzo[d][1,3]dioxol-5-yl)-1H-anthra[1,2-d]imidazole-6,11-dione, No. 19)
  • Figure US20090253707A1-20091008-C00023
  • All steps for manufacturing the red brown compound No. 19 are identical with the steps of Embodiment 14, except that vanillin is substituted by piperonal (0.77 g, 5 mmol).
  • The compound No. 19 has the following characterstics: MW 368.0797 (C22H12N2O4); Rf: 0.45 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 3444(NH), 1670(C═O), 1257(C—O), 1210(C—O); HRMS (ESI-TOF) m/z: calcd for C22H13N2O4 + [M+H]+: 369.0867, found: 369.0887; 1H-NMR (300 MHz, CDCl3) d (ppm): d6.11(2H, s, —OCH2O—), d7.00(1H, d, J=7.8 Hz, Ar—H5′), d7.67(1H, s, Ar—H2′), d7.79-7.82(2H, m, Ar—H7,10), d8.13(1H, d, J=8.1 Hz, Ar—H5), d8.24(1H, d, J=7.8 Hz, Ar—H6′), d8.25(1H, d, J=8.1 Hz, Ar—H4), d8.29-8.36(2H, m, Ar—H8,9), d11.18(1H, s, —NH); and 13C-NMR (75 MHz, CDCl3) d (ppm): 101.93, 107.37, 108.96, 117.86, 121.83, 122.05, 122.78, 125.35, 126.52, 127.62, 128.40, 133.27, 133.43, 133.76, 134.08, 134.44, 148.71, 149.62, 150.56, 156.55, 182.66(CO), 185.27(CO).
    • Embodiment 20 (Anthra[2,1-c][1,2,5]thiadiazole-6,11-dione, No. 22)
  • Figure US20090253707A1-20091008-C00024
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in THF (30 mL), and triethylamine (3 mL) is further added thereinto for catalyzation after thionyl chloride (0.15 g, 20 mmol) is dripped thereinto. After mixing and reacting in room temperature for one hour, the reacted mixture is transferred into 200 mL of icy water. After filtering, the precipitate is collected and recrystallized by hot alcolhol, so as to obtain yellow compound No. 22 with melting point of 227-228° C., and the production rate is 74%.
  • The compound No. 22 has the following characterstics: MW 266.0150 (C14H6N2O2S); Rf: 0.8 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 1671(CO); EI-MS m/z: 210(57%), 238(64%), 266(M+, 100%), HRMS (ESI-TOF) m/z: calcd for C14H7N2O2S+ [M+H]+: 267.0223, found: 267.0226; 1H-NMR (300 MHz, CDCl3) d (ppm): d7.84(1H, dd, J=12.15,6.9 Hz, Ar—H7), d7.85(1H, dd,J=13.2,7.5 Hz, Ar—H10), d8.33(1H, dd, J=22.5, 7.2 Hz, Ar—H8), d8.33(1H, dd, J=22.5, 7.2 Hz, Ar—H9), d8.41(1H, d, J=9.3 Hz, Ar—H5), d8.56(1H, d, J=9.3 Hz, Ar—H4); and 13C-NMR (75 MHz, CDCl3) d (ppm): 125.07, 126.35, 126.99, 127.34, 127.61, 132.08, 133.47, 134.15, 134.75, 135.16, 150.93, 157.99, 181.97(CO), 183.31(CO).
    • Embodiment 21 (2,2-Dimethyl-2,3-dihydro-1H-anthra[1,2-d]imidazole-6,11-dione, No. 20)
  • Figure US20090253707A1-20091008-C00025
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in dry acetone (100 mL), and concentrated sulfuric acid (0.1 mL) is further added thereinto. After mixing and reacting in room temperature for 48 hours, the reacted mixture is transferred into a potassium carbonate column. The product is collected and recrystallized by methanol, so as to obtain the purple compound 20, and the production rate is 31%. In the purification steps of the Embodiment 21, regular extraction method will reduce the production rate, and thus the basic column is used to remove the acid in the rough extract, so as to increase the production rate.
  • The compound No. 20 has the following characterstics: Melting point: 235-237° C., MW 278.1055 (C17H14N2O2); Rf: 0.5 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 3419(NH), 3239(NH), 1639 (CO); EI-MS m/z: 263(100%), 278(M+, 8.6%), HRMS (ESI-TOF) m/z: calcd for C17H15N2O2 + [M+H]+: 279.1128, found: 279.1133; 1H-NMR (300 MHz, DMSO-d6) d (ppm): d1.48(6H, s, —CH3), d6.26(1H, d, J=7.8 Hz, Ar—H4), d7.37(1H, d, J=7.8 Hz, Ar—H5), d7.73-7.76(m, 2H, Ar—H7,10), d8.05(s, 1H, —NHC—), d8.08-8.12(m, 2H, Ar—H8,9), d8.79(s, 1H, —CNH—); and 13C-NMR (75 MHz, DMSO-d6) d (ppm): 30.18, 81.70, 104.02, 108.04, 120.99, 123.54, 126.32, 127.07, 133.41, 133.54, 134.79, 135.46, 143.05, 148.12, 179.89(CO), 182.47(CO).
    • Embodiment 22 (2-Methyl-2-phenyl-2,3-dihydro-1H-anthra[1,2-d]imidazole-6,11-dione, No. 21)
  • Figure US20090253707A1-20091008-C00026
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in N,N-dimethylformamide (30 mL), and concentrated sulfuric acid (0.1 mL) is further added thereinto after acetophenone (0.5 ml, 6 mmol) is added thereinto. After mixing and reacting in room temperature for 72 hours, the reacted mixture is transferred into icy water (200 mL) for precipitation. The precipitate is collected and recrystallized by hot alcohol, so as to obtain the black compound 21, and the production rate is 28%.
  • The compound No. 21 has the following characterstics: Melting point: 368-371° C., MW 340.1212 (C22H16N2O2); Rf: 0.8 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 3348(NH), 1671 (CO); HRMS (ESI-TOF) m/z: calcd for C22H17N2O2 + [M+H]+: 341.1284, found: 341.1033; 1H-NMR (300 MHz, DMSO-d6) d (ppm): d1.22(3H, s, —CH3), d7.56-7.62(3H, m, Ar′—H2,4,6), d7.90-7.94(2H, m, Ar—H7,10), d8.08(1H, d, J=8.1 Hz, Ar—H5), d8.22(1H, d, J=8.1 Hz, Ar—H4), d8.18-8.22(2H, m, Ar′—H3,5), d8.40-8.42(2H, m, Ar—H8,9); and 13C-NMR (75 MHz, DMSO) d (ppm): 28.79, 83.56, 103.62, 109.74, 119.13, 121.35, 124.03, 126.20, 1267.76, 128.32, 128.77, 131.31, 132.99, 134.30, 134.45, 143.05, 157.25, 182.60(CO), 182.89(CO).
    • Embodiment 23 (2,3-dimethylnaphtho[2,3-f]quinoxaline-7,12-dione, No. 24)
  • Figure US20090253707A1-20091008-C00027
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in N,N-dimethylformamide (30 mL), and concentrated sulfuric acid (0.1 mL) is further added thereinto after methyl vinyl ketone (0.36 g, 5 mmol) is added thereinto. After mixing and reacting in room temperature for 72 hours, the reacted mixture is transferred into icy water (200 mL) for precipitation. The precipitate is collected and recrystallized by hot alcohol, so as to obtain the black compound 24, and the production rate is 25%.
  • The compound No. 24 has the following characterstics: Melting point >400° C., MW 288.0899 (C18H12N2O2); Rf: 0.6 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 1671 (CO); HRMS (ESI-TOF) m/z: calcd for C18H13N2O2 + [M+H]+: 289.0988, found: 289.0970; 1H-NMR (300 MHz, DMSO-d6) d (ppm): d2.72(3H, s, —CH3), d2.88(3H, s, —CH3), d7.91-7.94(2H, m, Ar—H8,11), d8.07(1H, d, J=8.4 Hz, Ar—H5), d8.16(1H, d, J=8.4 Hz, Ar—H4), d8.19-8.21(2H, m, Ar—H9,10); and 13C-NMR (75 MHz, DMSO-d6) d (ppm): 14.91, 30.74, 120.19, 125.46, 126.21, 126.26, 127.16, 128.18, 128.87, 133.01, 133.10, 134.19, 134.27, 134.42, 158.87, 162.28, 182.49(CO), 183.37(CO).
    • Embodiment 24 (Naphtho[2,3-f]quinoxaline-7,12-dione, No. 25)
  • Figure US20090253707A1-20091008-C00028
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in N,N-dimethylformamide (30 mL), and 40% glyoxal (0.8 g, 5 mml) in EtOH (50 mL) is added thereinto. After reverse flow for 16 hours, the water is evaperated out, and the reacted mixture is transferred into icy water (200 mL) for precipitation. The precipitate is collected and washed by hot alcohol and dichloromethane repeatedly, so as to obtain the black compound 25, and the production rate is 23%.
  • The compound No. 25 has the following characterstics: Melting point: 270-272° C., MW 260.0586 (C16H8N2O2); Rf: 0.45 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 3413(NH), 3365(NH), 1626 (CO); EI-MS m/z: 150(54%), 238(73%), 260(M+, 100%); HRMS (ESI-TOF) m/z: calcd for C16H9N2O2 + [M+H]+: 261.0659, found: 261.0663; 1H-NMR (300 MHz, CDCl3) d (ppm): d7.82-7.87 (2H, m, Ar—H8,11), d8.29-8.36 (2H, m, Ar—H9,10), d8.48 (1H, d, J=8.7 Hz, Ar—H5), d8.72 (1H, d, J=8.7 Hz, Ar—H6), d8.99 (1H, d, J=1.5 Hz, —N═CH—), d9.25 (1H, d, J=1.5 Hz, —CH═N—); and 13C-NMR (75 MHz, CDCl3) d (ppm): 126.72, 127.05, 127.46, 130.05, 131.98, 133.77, 134.76, 135.18, 135.88, 135.93, 136.03, 145.42, 146.40, 147.77, 183.21(CO), 183.61(CO).
    • Embodiment 25 (Naphtho[2,3-f]quinoxaline-2,3,7,12(1H,4H)-tetraone, No. 26)
  • Figure US20090253707A1-20091008-C00029
  • 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in N,N-dimethylformamide (30 mL), and oxalic acid (0.46 g, 5 mmol) and concentrated sulfuric acid (0.1 mL) is added thereinto. After reverse flow for 16 hours, the reacted mixture is transferred into icy water (200 mL) for precipitation. The precipitate is collected and washed by hot alcohol and, so as to obtain the black compound 26, and the production rate is 30%.
  • The compound No. 25 has the following characterstics: Melting point: 245-246° C., MW 292.0484 (C16H8N2O4); Rf: 0.25 (ethyl acetate: dichloromethane=1:4); IR (KBr) cm−1: 1710 (CO), 1671 (CONH) ; EI-MS m/z: 248(100%), 292(M+) HRMS (ESI-TOF) m/z: calcd for C16H9N2O4 + [M+H]+: 293.0557, found: 293.0568; 1H-NMR (300 MHz, DMSO-d6) d (ppm): d7.71 (1H, d, J=8.0 Hz, Ar—H5), d7.93-7.98 (2H, m, Ar—H8,11), d8.04 (1H, d, J=8.0 Hz, Ar—H6), d8.17-8.24 (2H, m, Ar—H9,10), d8.99 (1H, d, J=1.5 Hz, —NH—), d9.25 (1H, d, J=1.5 Hz, —NH—); and 13C-NMR (75 MHz, DMSO-d6) d (ppm); 118.08, 120.52, 122.87, 126.26, 126.34, 126.78, 127.71, 128.17, 129.58, 134.48, 134.55, 135.07, 154.64(NHCO), 154.73(NHCO), 180.08(CO), 181.07(CO).
  • The chemical formula, production rates and melting points of the above-mentioned heteroannelated anthraquinone derivatives of series A are illustrated in Table 1, and the chemical formula, production rates and melting points of the above-mentioned heteroannelated anthraquinone derivatives of serieses B, C and D are described in the embodiments, respectively.
  • TABLE 1
    Figure US20090253707A1-20091008-C00030
    Melting point Production
    Compound No. R1 (° C.) Rate (%)
    2 —CH3 >400 67
    3 —CH2Cl 272-273 86
    4 —CH2CH3 193-194 39
    5 —CH(CH3)2 199-200 41
    6 —(CH2)3CH3 192-193 36
    7 —CH(CH3)CH2CH3 118-119 40
    8 —CH(CH3)3 209-210 37
    9 —(CH2)6CH3 85-87 38
    10 —CH═CHCH2CH3 117-119 33
    11 —C6H5 232-233 74
    12 —C6H4-p-N(CH3)2 239-241 79
    13 —C6H4-p-NO2 342-343 89
    14 —C6H3-p-OH-m-OCH3 230-231 47
    15 —C6H4-p-CH3 256-257 76
    16 —C6H4-p-Br 302-303 75
    17 —C6H4-p-CN 353-354 77
    18 —C6H3-o,m-(OCH3)2 251-252 74
    19 3,4-benzdioxole 300-301 81
  • Telomeric repeat amplification protocol (TRAP) is employed to detect the effect of the heteroannelated anthraquinone derivatives synthesized in the present invention for inhibinting the telomerase activity. In the first stage of this method, the telemerase is used to prolong the oligonucleotide with telomere sequence in the conditions of 90° C. for 10 minutes, 72° C. for 3 minutes, 50° C. for 60 seconds and 94° C. for 30 seconds (TSG4 primer: 5′-GGG ATT GGG ATT GGG ATT GGG TT-3′) In the second stage, different compounds are added into the telomerase reacted product to further replicate the telomere product by PCR (CX primer: 5′-CCCTTA CCCTTA CCCTTA CCCTAA-3′). When the compound inhibits the telomerase activity, the replication reaction can not be resumed. The PCR conditions includes 39 cycles of PCR reaction in 50° C. for 30 seconds, 72° C. for 60 seconds for 39 PCR cycles, followed by one cycle of reaction in 94° C. for 30 seconds, 50° C. for 30 seconds, 72° C. for 30 seconds and 72° C. for 1 minute, and the reaction is ended in 4° C. The PCR product is analyzed by electrophoresis using 10% acrylamide gel. In the electrophoresis results, the positive control (P) is sterile water (dddH2O), and the negative control (N) is 5 μl 0.1 mg/mL RNase A (CLONTECH). The positive control (P) produces lots of telomere fragment, while the negative control (N) does not. The compounds provided by the present invention inhibit the telomerase activity by stabilizing G-quadruplex structures and blocking the interaction between telomerase and telomere, or directly inhibit the telomerase activity, so as to inhibit the prologation of telomere. It is found in the present experiments that the Embodiments A4 and A5 have better inhibition effects.
  • In addition, it is found in the in vitro experiments performed by the development therapeutics program of US cancer research center that the heteroannelated anthraquinone derivatives synthesized in the present invention have various inhibition effects on different cancer cell lines at 1.0×10−5 molal concentration (M) as shown in Table 2. For example, the Embodiment A2 of the present invention inhibits the growth of breast cancer cell HS578T, and the Embodiment B1 has overall and the most obvious inhibition on different cancer cells. Therefore, the heteroannelated anthraquinone derivatives synthesized in the present invention are potential drugs for inhibiting cancer cells.
  • TABLE 2
    No. 22 No. 4 No. 20 No. 25 No. 26
    Non-small cell lung
    cancer cell
    HOP-62 −100.00 97.73 XXX XXX XXX
    HOP-92 XXX 41.43 5.10 XXX −15.08
    Colorectal cancer cell
    HCC-2998 −50.00 67.67 136.96 −7.15 77.59
    Breast cancer cell
    HS 578T −7.40 −18.58 XXX XXX XXX
    MCF7 −50.74 69.82 83.58 39.68 85.17
    MDA-MB-435 −87.88 84.39 124.56 102.03 144.42
    MDA-MB-468 −73.17 XXX 77.25 75.28 38.35
    T-47D −45.52 63.05 82.96 85.19 87.10
    Ovary cancer cell
    IGROV1 −88.34 XXX −2.80 3.44 13.36
    OVCAR-4 −94.43 48.81 80.14 94.22 103.31
    Blood cancer cell
    MOLT-4 −40.09 64.17 116.41 22.91 121.52
    Kidney cancer cell
    ACHN −94.31 24.97 50.17 46.52 81.33
    SN12C −73.27 68.53 91.98 64.65 94.07
    UO-31 −79.30 23.94 30.65 51.45 61.43
    Skin cancer cell
    LOX IMV1 −50.6 39.98 61.88 44.18 96.94
    MALME-3M −71.54 56.94 155.47 180.88 149.83
    SK-MEL-2 −73.16 40.07 8.04 6.66 21.96
    UACC-257 −83.07 39.69 118.22 91.06 118.21
    UACC-62 −82.32 51.35 67.58 90.47 95.25
    CNS cancer cell
    SF-539 −47.11 83.16 93.56 40.72 101.16
    U251 −89.26 60.13 87.84 63.47 95.92
    Mean 2.68 58.42 80.41 69.36 100.83
    Delta 102.68 77.00 83.21 76.51 115.91
    Range 230.09 120.88 158.27 188.03 289.23
    XXX: not detected
  • The detailed in-vitro testing results of dose response of the Compound No. 22 obtained from National Cancer Institute Developmental Therapeutics Program are shown in Tables 3-1 to 3-9.
  • Figure US20090253707A1-20091008-C00031
  • The detailed in-vitro testing results of dose response of the Compound No. 4 obtained from National Cancer Institute Developmental Therapeutics Program are shown in Tables 4-1 to 4-9.
  • Figure US20090253707A1-20091008-C00032
  • The detailed in-vitro testing results of dose response of the Compound No. 25 obtained from National Cancer Institute Developmental Therapeutics Program are shown in Tables 5-1 to 5-9.
  • Figure US20090253707A1-20091008-C00033
  • TABLE 3-1
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Leukemia
    CCRF-CEM 0.445 1.624 1.589 1.503 1.323 0.472 0.470 97 90 74 2 2 2.18E−6 >1.00E−4 >1.00E−4
    HL-60 (TB) 0.744 2.175 2.214 2.209 2.079 0.461 0.421 103 102 93 −38 −43 2.14E−6 5.13E−6 >1.00E−4
    K-562 0.180 1.220 1.232 1.174 1.038 0.375 0.165 101 96 83 19 −8 3.23E−6 4.92E−5 >1.00E−4
    MOLT-4 0.455 1.447 1.444 1.462 1.199 0.274 0.280 97 99 73 −40 −38 1.59E−6 4.43E−6 >1.00E−4
    RPMI-8226 0.654 1.899 1.899 1.820 1.418 0.653 0.523 100 94 61 — −20 1.53E−6 9.91E−6 >1.00E−4
    SR 0.167 0.676 0.718 0.738 0.669 0.374 0.278 108 112 99 41 −22 6.89E−6 >1.00E−4 >1.00E−4
  • TABLE 3-2
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Non-Small Cell Lung Cancer
    A549/ATCC 0.110 0.550 0.566 0.518 0.513 0.081 0.091 104 93 92 −27 −18 2.25E−6 5.94E−6 >1.00E−4
    EKVX 0.652 1.960 1.914 1.813 1.745 0.554 0.251 96 89 84 −15 −62 2.19E−6 7.03E−6 5.65E−5
    HOP-62 0.342 1.187 1.242 1.242 1.243 0.380 0.175 107 107 107 4 −49 3.59E−6 1.21E−5 >1.00E−4
    HOP-92 0.770 1.201 1.179 1.150 1.174 0.765 0.560 95 88 94 −1 −27 2.91E−6 9.84E−6 >1.00E−4
    NCI-H226 1.003 1.740 1.718 1.701 1.556 1.467 0.956 97 95 75 63 −5 1.56E−5 8.53E−5 >1.00E−4
    NCI-H23 0.418 1.199 1.209 1.125 0.775 0.265 0.271 101 91 46 −37 −35 8.02E−7 3.59E−6 >1.00E−4
    NCI-H322M 0.347 0.840 0.856 0.922 0.940 0.890 0.555 103 116 120 110 42 7.64E−5 >1.00E−4 >1.00E−4
    NCI-H460 0.245 1.818 1.818 1.767 1.614 0.116 0.104 100 97 87 −53 −58 1.84E−6 4.19E−6 9.54E−6
    NCI-H522 0.541 2.032 2.079 2.073 1.887 0.634 0.441 103 103 90 6 −18 3.01E−6 1.78E−5 >1.00E−4
  • TABLE 3-3
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Colon Cancer
    COLO 205 0.199 0.969 0.927 0.872 0.957 0.069 0.057 95 87 98 −66 −71 1.97E−6 3.98E−6 8.04E−6
    HCC-2998 0.268 0.572 0.599 0.581 0.588 0.098 0.081 109 103 105 −63 −70 2.12E−6 4.20E−6 8.32E−6
    HCT-116 0.138 0.938 0.927 0.912 0.863 0.145 0.095 99 97 91 1 −31 2.84E−6 1.06E−5 >1.00E−4
    HCT-15 0.285 1.440 1.554 1.485 1.323 0.254 0.138 110 104 90 −11 −52 2.49E−6 7.80E−6 9.06E−5
    HT29 0.231 1.387 1.432 1.444 1.403 0.195 0.108 104 105 101 −16 −53 2.75E−6 7.36E−6 8.10E−5
    KM12 0.217 0.841 0.884 0.889 0.861 0.567 0.103 107 108 103 56 −53 1.14E−5 3.28E−5 9.48E−5
    SW-620 0.175 1.174 1.231 1.201 1.240 0.633 0.056 106 103 107 46 −68 8.55E−6 2.52E−5 6.92E−5
  • TABLE 3-4
    Log10 Concentration
    Panel/ Time Mean Optical Densities Percent Growth
    Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    CNS Cancer
    SF-268 0.357 0.951 0.959 0.938 0.893 0.459 0.193 101 98 90 17 −46 3.55E−6 1.87E−5 >1.00E−4
    SF-295 0.415 1.524 1.550 1.579 1.527 0.404 0.202 102 105 100 −3 −51 3.08E−6 9.40E−6 9.39E−5
    SF-539 0.574 1.690 1.578 1.517 1.499 0.006 0.012 90 84 83 −99 −98 1.52E−6 2.86E−6 5.38E−6
    SNB-19 0.464 1.328 1.349 1.339 1.330 0.067 0.008 102 101 100 −86 −98 1.86E−6 3.46E−6 6.43E−6
    SNB-75 0.640 1.050 0.950 0.911 0.957 −0.004 −0.009 76 66 77 −100 −100 1.42E−6 2.73E−6 5.22E−6
    U251 0.220 1.137 1.194 1.177 0.939 0.086 0.082 106 104 78 −61 −63 1.60E−6 3.65E−6 8.32E−6
  • TABLE 3-5
    Log10 Concentration
    Panel/ Time Mean Optical Densities Percent Growth
    Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Melanoma
    LOX 0.363 2.033 2.046 2.006 1.219 0.212 0.244 101 98 51 −42 −33 1.03E−6 3.56E−6 >1.00E−4
    IMVI
    MALME- 0.229 0.481 0.487 0.520 0.512 0.107 0.065 102 115 112 −53 −72 2.37E−6 4.76E−6 9.55E−6
    3M
    M14 0.339 1.395 1.398 1.394 1.411 0.232 0.199 100 100 102 −32 −41 2.44E−6 5.78E−6 >1.00E−4
    SK- 0.284 0.761 0.810 0.806 0.731 0.221 0.194 110 109 94 −22 −32 2.38E−6 6.42E−6 >1.00E−4
    MEL-2
    SK-MEL- 0.300 1.110 1.135 1.161 1.165 0.703 0.023 103 106 107 50 −93 9.88E−6 2.24E−5 5.03E−5
    28
    SK- 0.540 2.145 2.107 1.896 1.477 −0.009 −0.002 98 85 58 −100 −100 1.13E−6 2.34E−6 4.83E−6
    MEL-5
    UACC- 0.493 0.980 0.962 0.986 0.870 0.083 0.047 96 101 77 −83 −91 1.48E−6 3.03E−6 6.21E−6
    257
    UACC-62 0.431 1.918 1.751 1.787 1.798 0.331 0.214 89 91 92 −23 −50 2.31E−6 6.29E−6 9.62E−6
  • TABLE 3-6
    Log10 Concentration
    Panel/ Time Mean Optical Densities Percent Growth
    Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Ovarian Cancer
    OVCAR-3 0.305 0.775 0.852 0.821 0.710 0.216 0.075 116 110 86 −29 −75 2.06E−6 5.59E−6 2.82E−5
    OVCAR-4 0.363 0.880 0.916 0.850 0.531 −0.015 −0.014 107 94 32 −100 −100 5.20E−7 1.76E−6 4.19E−6
    OVCAR-5 0.446 0.930 0.924 0.903 0.953 0.192 0.187 99 94 105 −57 −58 2.18E−6 4.44E−6 9.06E−6
    OVCAR-8 0.299 1.154 1.200 1.171 0.695 0.169 0.185 105 102 46 −43 −38 8.59E−7 3.28E−6 >1.00E−4
    SK-OV-3 0.530 1.224 1.239 1.154 1.150 0.414 0.015 102 90 89 −22 −97 2.26E−6 6.35E−6 2.36E−5
  • TABLE 3-7
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Renal Cancer
    786-0 0.450 1.828 1.894 1.916 2.049 0.517 0.130 105 106 116 5 −71 3.93E−6 1.16E−5 5.27E−5
    A498 0.605 1.481 1.527 1.518 1.449 1.479 1.340 105 104 96 100 84 >1.00E−4 >1.00E−4 >1.00E−4
    ACHN 0.355 1.317 1.389 1.452 1.220 0.063 0.218 107 114 90 −82 −39 1.71E−6 3.33E−6 —
    CAKI-1 0.294 0.870 0.813 0.844 0.798 0.226 0.099 90 95 88 −23 −66 2.18E−6 6.16E−6 4.15E−5
    SN12C 0.304 1.076 1.007 1.097 0.948 0.284 0.199 91 103 83 −7 −35 2.35E−6 8.42E−6 >1.00E−4
    TK-10 0.362 0.792 0.865 0.935 0.983 0.868 0.337 117 133 144 118 −7 3.49E−5 8.80E−5 >1.00E−4
    UO-31 0.147 0.498 0.539 0.562 0.499 0.041 0.050 111 118 100 −72 −66 1.95E−6 3.81E−6 7.41E−6
  • TABLE 3-8
    Log10 Concentration
    Panel/ Time Mean Optical Densities Percent Growth
    Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Prostate Cancer
    PC-3 0.372 1.158 1.128 1.096 1.050 0.459 0.402 96 92 86 11 4 3.03E−6 >1.00E−4 >1.00E−4
    DU-145 0.230 0.704 0.750 0.772 0.752 0.425 −0.002 110 114 110 41 −100 7.41E−6 1.95E−5 4.42E−5
  • TABLE 3-9
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Breast Cancer
    MCF7 0.282 1.325 1.202 1.081 0.929 0.101 0.104 88 77 62 −64 −63 1.24E−6 3.10E−6 7.72E−6
    NCI/ADR-RES 0.436 1.282 1.343 1.296 0.608 0.395 0.363 107 102 20 −10 −17 4.32E−7 4.80E−6 >1.00E−4
    MDA-MB-231/ 0.478 1.197 1.226 1.100 1.063 0.510 0.525 104 87 81 4 6 2.56E−6 >1.00E−4 >1.00E−4
    ATCC
    HS 578T 0.413 1.287 1.362 1.410 1.289 0.663 0.595 109 114 100 29 21 5.03E−6 >1.00E−4 >1.00E−4
    MDA-MB-435 0.280 1.351 1.350 1.373 1.160 0.190 0.137 100 102 82 −32 −51 1.91E−6 5.23E−6 8.78E−5
    BT-549 0.254 0.524 0.503 0.529 0.594 0.426 0.122 92 102 126 64 −52 1.31E−5 3.55E−5 9.62E−5
    T-47D 0.377 0.816 0.775 0.763 0.473 0.156 0.150 91 88 22 −59 −60 3.75E−7 1.87E−6 7.79E−6
    MDA-MB-468 2.275 3.124 3.096 3.134 3.152 0.022 0.031 97 101 103 −99 −99 1.83E−6 3.24E−6 5.72E−6
  • TABLE 4-1
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Leukemia
    CCRF-CEM 0.321 1.468 1.505 1.400 1.407 0.910 0.488 103 94 95 51 15 1.09E−5 >1.00E−4 >1.00E−4
    HL-60(TB) 0.691 1.628 1.626 1.630 1.639 1.092 0.873 100 100 101 43 19 7.53E−6 >1.00E−4 >1.00E−4
    K-562 0.269 1.578 1.498 1.469 1.412 1.097 0.903 94 92 87 63 48 7.83E−5 >1.00E−4 >1.00E−4
    MOLT-4 0.734 2.108 2.076 2.057 2.015 1.402 0.726 98 96 93 49 −1 9.31E−6 9.51E−5 >1.00E−4
    RPMI-8226 0.443 1.284 1.259 1.121 1.060 0.547 0.390 97 81 73 12 −12 2.42E−6 3.21E−5 >1.00E−4
  • TABLE 4-2
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Non-Small Cell Lung Cancer
    A549/ATCC 0.193 0.895 0.832 0.892 0.876 0.614 0.315 91 100 97 60 17 1.71E−5 >1.00E−4 >1.00E−4
    EKVX 0.897 1.986 1.856 1.792 1.540 1.059 0.894 88 82 59 15 — 1.60E−6 9.43E−5 >1.00E−4
    HOP-62 0.474 1.375 1.283 1.318 1.254 1.127 0.814 90 94 87 72 38 4.42E−5 >1.00E−4 >1.00E−4
    HOP-92 0.892 1.397 1.360 1.297 1.214 1.134 1.010 93 80 64 48 23 7.38E−6 >1.00E−4 >1.00E−4
    NCI-H226 0.817 1.747 1.612 1.642 1.608 1.404 1.022 85 89 85 63 22 2.08E−5 >1.00E−4 >1.00E−4
    NCI-H23 0.485 1.638 1.547 1.500 1.333 1.051 0.732 92 88 74 49 21 9.17E−6 >1.00E−4 >1.00E−4
    NCI-H322M 0.721 1.844 1.757 1.746 1.643 1.177 0.976 92 91 82 41 23 5.94E−6 >1.00E−4 >1.00E−4
    NCI-H460 0.233 1.933 1.666 1.630 1.494 0.651 0.266 84 82 74 25 2 3.07E−6 >1.00E−4 >1.00E−4
    NCI-H522 0.713 2.605 2.403 2.370 2.360 1.735 1.328 89 88 87 54 32 1.54E−5 >1.00E−4 >1.00E−4
  • TABLE 4-3
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Colon Cancer
    COLO 205 0.213 1.012 0.960 0.958 0.891 0.544 0.284 93 93 85 41 9 6.36E−6 >1.00E−4 >1.00E−4
    HCC-2998 0.660 2.134 1.963 2.044 1.983 1.527 0.988 88 94 90 59 22 1.74E−5 >1.00E−4 >1.00E−4
    HCT-116 0.248 2.129 1.969 2.043 1.716 1.044 0.450 92 95 78 42 11 6.10E−6 >1.00E−4 >1.00E−4
    HCT-15 0.248 1.514 1.391 1.422 1.121 0.588 0.348 90 93 69 27 8 2.82E−6 >1.00E−4 >1.00E−4
    HT29 0.151 0.999 0.951 0.998 0.893 0.557 0.241 94 100 88 48 11 8.84E−6 >1.00E−4 >1.00E−4
    KM12 0.268 1.092 1.072 1.040 1.003 0.625 0.373 98 94 89 43 13 7.15E−6 >1.00E−4 >1.00E−4
    SW-620 0.150 0.998 0.991 0.968 0.902 0.480 0.202 99 96 89 39 6 5.97E−6 >1.00E−4 >1.00E−4
  • TABLE 4-4
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    CNS Cancer
    SF-268 0.319 1.084 0.986 1.053 0.990 0.758 0.530 87 96 88 57 28 1.77E−5 >1.00E−4 >1.00E−4
    SF-295 0.695 1.929 1.785 1.806 1.549 1.127 0.812 88 90 69 35 9 3.65E−6 >1.00E−4 >1.00E−4
    SF-539 0.639 1.878 1.642 1.666 1.631 1.204 0.798 81 83 80 46 13 7.46E−6 >1.00E−4 >1.00E−4
    SNB-19 0.656 1.341 1.229 1.299 1.289 1.073 0.921 84 94 92 61 39 3.09E−5 >1.00E−4 >1.00E−4
    SNB-75 0.661 1.282 1.068 1.070 0.965 0.916 0.770 66 66 49 41 17 8.72E−7 >1.00E−4 >1.00E−4
    U251 0.280 1.443 1.369 1.393 1.260 0.854 0.597 94 96 84 49 27 9.58E−6 >1.00E−4 >1.00E−4
  • TABLE 4-5
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Melanoma
    LOX IMVI 0.316 2.231 2.245 2.058 1.903 0.956 0.508 101 91 83 33 10 4.61E−6 >1.00E−4 >1.00E−4
    MALME-3M 0.694 1.247 1.174 1.161 1.153 0.835 0.683 87 84 83 26 −2 3.75E−6 8.69E−5 >1.00E−4
    M14 0.435 1.796 1.627 1.731 1.500 1.119 0.776 88 95 78 50 25 1.02E−5 >1.00E−4 >1.00E−4
    SK-MEL-28 0.239 0.861 0.794 0.762 0.730 0.537 0.211 89 84 79 48 −12 8.58E−6 6.36E−5 >1.00E−4
    SK-MEL-5 0.639 2.089 1.284 1.249 1.501 0.607 0.515 44 42 59 −5 −19 . 8.36E−6 >1.00E−4
    UACC-257 0.437 0.825 0.763 0.761 0.808 0.694 0.506 84 84 96 66 18 2.16E−5 >1.00E−4 >1.00E−4
    UACC-62 0.639 2.092 1.844 1.978 1.874 1.231 1.015 83 92 85 41 26 6.18E−6 >1.00E−4 >1.00E−4
  • TABLE 4-6
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Ovarian Cancer
    IGROV1 0.518 1.681 1.555 1.537 1.174 0.583 0.421 89 88 56 6 −19 1.34E−6 1.69E−5 >1.00E−4
    OVCAR-3 0.283 0.746 0.745 0.773 0.713 0.549 0.319 100 106 93 57 8 1.41E−5 >1.00E−4 >1.00E−4
    OVCAR-4 0.565 1.740 1.719 1.694 1.535 0.999 0.745 98 96 83 37 15 5.18E−6 >1.00E−4 >1.00E−4
    OVCAR-5 0.395 0.931 0.865 0.884 0.900 0.852 0.637 88 91 94 85 45 7.57E−5 >1.00E−4 >1.00E−4
    OVCAR-8 0.228 0.904 0.881 0.841 0.847 0.623 0.393 96 91 92 58 24 1.77E−5 >1.00E−4 >1.00E−4
    SK-OV-3 0.566 1.432 1.392 1.359 1.223 0.673 0.687 95 92 76 12 14 2.55E−6 >1.00E−4 >1.00E−4
  • TABLE 4-7
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Renal Cancer
    786-0 0.664 2.228 2.288 2.259 2.143 1.725 1.264 104 102 95 68 38 4.02E−5 >1.00E−4 >1.00E−4
    A498 0.564 1.224 1.202 1.221 1.065 0.793 0.453 94 97 74 34 −20 3.89E−6 4.27E−5 >1.00E−4
    ACHN 0.385 1.455 1.393 1.299 1.047 0.537 0.366 94 85 62 14 −5 1.77E−6 5.46E−5 >1.00E−4
    CAKI-1 0.547 1.711 1.680 1.610 1.430 0.780 0.654 97 91 76 20 9 2.90E−6 >1.00E−4 >1.00E−4
    SN12C 0.617 1.996 1.639 1.719 1.640 1.247 0.872 74 80 74 46 18 7.05E−6 >1.00E−4 >1.00E−4
    TK-10 0.612 1.245 1.212 1.327 1.088 0.856 0.633 95 113 75 39 3 4.88E−6 >1.00E−4 >1.00E−4
    UO-31 0.517 1.634 1.496 1.444 1.268 0.680 0.518 88 83 67 15 . 2.12E−6 >1.00E−4 >1.00E−4
  • TABLE 4-8
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Prostate Cancer
    PC-3 0.306 1.233 1.197 1.233 1.170 0.807 0.572 96 100 93 54 29 1.44E−5 >1.00E−4 >1.00E−4
    DU-145 0.226 0.724 0.713 0.713 0.666 0.411 0.344 98 98 88 37 24 5.62E−6 >1.00E−4 >1.00E−4
  • TABLE 4-9
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Breast Cancer
    MCF7 0.249 1.082 0.960 0.880 0.697 0.556 0.240 85 76 54 37 −4 1.68E−6 8.14E−5 >1.00E−4
    NCI/ADR-RES 0.461 1.540 1.483 1.524 1.421 1.010 0.530 95 99 89 51 6 1.05E−5 >1.00E−4 >1.00E−4
    MDA-MB-231/ATCC 0.453 1.133 1.121 1.097 1.063 0.820 0.700 98 95 90 54 36 1.66E−5 >1.00E−4 >1.00E−4
    HS 578T 0.296 0.704 0.734 0.736 0.526 0.393 0.202 107 108 56 24 −32 1.56E−6 2.67E−5 >1.00E−4
    MDA-MB-435 0.515 1.859 1.815 1.744 1.748 1.404 1.019 97 91 92 66 37 3.65E−5 >1.00E−4 >1.00E−4
    BT-549 1.015 2.001 2.009 2.006 1.951 1.606 1.166 101 100 95 60 15 1.67E−5 >1.00E−4 >1.00E−4
    T-47D 0.415 0.852 0.876 0.824 0.755 0.554 0.459 105 94 78 32 10 4.00E−6 >1.00E−4 >1.00E−4
    MDA-MB-468 0.494 1.038 0.944 0.977 0.923 0.654 0.458 83 89 79 29 −7 3.83E−6 6.33E−5 >1.00E−4
  • TABLE 5-1
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Leukemia
    CCRF-CEM 0.230 0.806 0.751 0.755 0.622 0.358 0.344 90 91 68 22 20 2.46E−6 >1.00E−4 >1.00E−4
    HL-60(TB) 0.336 0.640 0.587 0.540 0.478 0.347 0.153 83 67 47 3 −54 6.77E−7 1.15E−5 8.37E−5
    K-562 0.086 0.900 0.851 0.422 0.332 0.225 0.166 94 41 30 17 10 6.83E−8 >1.00E−4 >1.00E−4
    MOLT-4 0.273 1.048 0.959 0.900 0.830 0.529 0.302 89 81 72 33 4 3.65E−6 >1.00E−4 >1.00E−4
    RPMI-8226 0.429 1.331 1.245 1.161 0.926 0.702 0.535 90 81 55 30 12 1.61E−6 >1.00E−4 >1.00E−4
  • TABLE 5-2
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Non-Small Cell Lung Cancer
    A549/ATCC 0.551 1.857 1.771 1.792 1.552 1.022 0.594 93 95 77 36 3 4.53E−6 >1.00E−4 >1.00E−4
    EKVX 0.439 1.025 1.032 0.960 0.904 0.584 0.421 101 89 79 25 −4 3.45E−6 7.21E−5 >1.00E−4
    HOP-62 0.233 0.934 0.879 0.811 0.799 0.512 0.255 92 82 81 40 3 5.64E−6 >1.00E−4 >1.00E−4
    HOP-92 0.785 1.360 1.334 1.260 1.231 1.206 0.829 95 83 78 73 8 2.25E−5 >1.00E−4 >1.00E−4
    NCI-H226 0.780 1.765 1.631 1.577 1.497 1.415 0.769 86 81 73 64 −1 1.66E−5 9.52E−5 >1.00E−4
    NCI-H23 0.452 1.356 1.281 1.242 1.213 0.950 0.407 92 87 84 55 −10 1.20E−5 7.03E−5 >1.00E−4
    NCI-H322M 0.310 0.751 0.736 0.709 0.722 0.592 0.307 96 90 93 64 −1 1.63E−5 9.61E−5 >1.00E−4
    NCI-H460 0.229 1.901 1.869 1.815 1.309 0.507 0.179 98 95 65 17 −22 2.01E−6 2.69E−5 >1.00E−4
    NCI-H522 0.336 1.040 0.966 0.942 0.906 0.579 0.226 89 86 81 35 −33 4.64E−6 3.25E−5 >1.00E−4
  • TABLE 5-3
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Colon Cancer
    COLO 205 0.211 0.782 0.739 0.704 0.634 0.376 0.138 92 86 74 29 −35 3.40E−6 2.84E−5 >1.00E−4
    HCC-2998 0.326 1.161 1.135 1.113 0.759 0.658 0.315 97 94 52 40 −3 1.40E−6 8.35E−5 >1.00E−4
    HCT-116 0.142 1.101 1.060 1.089 1.018 0.666 0.175 96 99 91 55 3 1.23E−5 >1.00E−4 >1.00E−4
    HCT-15 0.274 1.667 1.502 1.449 1.343 0.784 0.266 88 84 77 37 −3 4.63E−6 8.43E−5 >1.00E−4
    HT29 0.174 1.186 1.176 1.131 0.925 0.636 0.184 99 95 74 46 1 7.01E−6 >1.00E−4 >1.00E−4
    KM12 0.224 0.967 0.884 0.896 0.786 0.522 0.185 89 90 76 40 −18 5.26E−6 4.95E−5 >1.00E−4
    SW-620 0.159 1.008 0.960 0.901 0.649 0.369 0.118 94 87 58 25 −26 1.71E−6 3.08E−5 >1.00E−4
  • TABLE 5-4
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    CNS Cancer
    SF-268 0.347 1.080 1.051 1.020 0.981 0.598 0.357 96 92 86 34 1 4.98E−6 >1.00E−4 >1.00E−4
    SF-295 0.598 1.530 1.440 1.375 1.481 0.828 0.456 90 83 95 25 −24 4.35E−6 3.23E−5 >1.00E−4
    SF-539 0.657 1.869 1.748 1.719 1.430 0.937 0.601 90 88 64 23 −9 2.18E−6 5.37E−5 >1.00E−4
    SNB-19 0.279 0.934 0.892 0.887 0.867 0.650 0.307 94 93 90 57 4 1.34E−5 >1.00E−4 >1.00E−4
    SNB-75 0.649 1.457 1.324 1.350 1.264 1.079 0.740 83 87 76 53 11 1.19E−5 >1.00E−4 >1.00E−4
    U251 0.231 1.283 1.242 1.205 1.172 0.604 0.184 96 93 89 35 −21 5.38E−6 4.29E−5 >1.00E−4
  • TABLE 5-5
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Melanoma
    LOX IMVI 0.311 2.100 1.927 1.830 1.766 0.867 0.244 90 85 81 31 −22 4.20E−6 3.89E−5 >1.00E−4
    MALME-3M 0.403 0.725 0.715 0.696 0.687 0.498 0.145 97 91 88 30 −64 4.48E−6 2.07E−5 7.08E−5
    M14 0.352 1.249 1.202 1.164 1.149 0.659 0.356 95 91 89 34 . 5.14E−6 >1.00E−4 >1.00E−4
    SK-MEL-2 0.212 0.515 0.505 0.471 0.521 0.388 0.171 97 85 102 58 −20 1.27E−5 5.59E−5 >1.00E−4
    SK-MEL-28 0.363 1.041 1.041 1.050 1.070 0.873 0.352 100 101 104 75 −3 2.10E−5 9.11E−5 >1.00E−4
    SK-MEL-5 0.644 2.455 2.270 2.280 2.136 1.150 0.049 90 90 82 28 −92 3.93E−6 1.71E−5 4.44E−5
    UACC-257 0.466 1.070 1.040 0.996 1.063 0.815 0.413 95 88 99 58 −11 1.30E−5 6.83E−5 >1.00E−4
    UACC-62 0.828 2.206 2.103 1.986 2.030 1.655 0.662 92 84 87 60 −20 1.33E−5 5.61E−5 >1.00E−4
  • TABLE 5-6
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Ovarian Cancer
    IGROV1 0.313 1.001 0.932 0.824 0.735 0.543 0.229 90 74 61 33 −27 2.55E−6 3.59E−5 >1.00E−4
    OVCAR-3 0.237 0.743 0.766 0.717 0.626 0.260 0.137 104 95 77 4 −42 2.34E−6 1.25E−5 >1.00E−4
    OVCAR-4 0.449 1.297 1.311 1.220 1.075 0.883 0.472 102 91 74 51 3 1.05E−5 >1.00E−4 >1.00E−4
    OVCAR-5 0.372 1.072 1.054 0.999 1.056 0.912 0.506 97 90 98 77 19 5.93E−5 >1.00E−4 >1.00E−4
    OVCAR-8 0.271 1.191 1.163 1.091 1.031 0.606 0.390 97 89 83 36 13 5.07E−6 >1.00E−4 >1.00E−4
    SK-OV-3 0.521 1.313 1.243 1.228 1.150 0.874 0.586 91 89 79 44 8 6.95E−6 >1.00E−4 >1.00E−4
  • TABLE 5-7
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Renal Cancer
    786-0 0.611 2.118 2.089 2.131 2.186 1.320 0.835 98 101 104 47 15 8.87E−6 >1.00E−4 >1.00E−4
    A498 0.575 1.116 1.079 1.034 1.058 0.839 0.456 93 85 89 49 −21 9.31E−6 5.03E−5 >1.00E−4
    ACHN 0.370 1.672 1.642 1.508 1.367 0.776 0.397 98 87 77 31 2 3.85E−6 >1.00E−4 >1.00E−4
    CAKI-1 0.369 1.388 1.325 1.271 1.260 0.762 0.409 94 89 87 39 4 5.83E−6 >1.00E−4 >1.00E−4
    RXF 393 0.826 2.065 2.024 1.973 1.829 1.355 0.919 97 93 81 43 7 6.43E−6 >1.00E−4 >1.00E−4
    SN12C 0.518 1.551 1.421 1.257 1.326 1.108 0.508 87 71 78 57 −2 1.32E−5 9.27E−5 >1.00E−4
    TK-10 0.190 0.513 0.518 0.464 0.457 0.306 0.196 102 85 83 36 2 5.00E−6 >1.00E−4 >1.00E−4
    UO-31 0.483 1.268 1.113 1.058 1.059 0.678 0.475 80 73 73 25 −2 3.02E−6 8.59E−5 >1.00E−4
  • TABLE 5-8
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Prostate Cancer
    PC-3 0.138 0.476 0.479 0.449 0.373 0.306 0.308 101 92 69 50 50 . >1.00E−4 >1.00E−4
    DU-145 0.200 0.762 0.775 0.735 0.739 0.515 0.103 102 95 96 56 −49 1.14E−5 3.43E−5 >1.00E−4
  • TABLE 5-9
    Log10 Concentration
    Time Mean Optical Densities Percent Growth
    Panel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0 −4.0 GI50 TGI LC50
    Breast Cancer
    MCF7 0.451 2.118 1.797 1.793 1.201 0.894 0.318 81 80 45 27 −29 7.22E−7 2.98E−5 >1.00E−4
    NCI/ADR-RES 0.476 1.685 1.621 1.586 1.530 0.934 0.567 95 92 87 38 8 5.68E−6 >1.00E−4 >1.00E−4
    MDA-MB-231/ATCC 0.444 1.084 1.085 1.008 0.987 0.854 0.535 100 88 85 64 14 1.91E−5 >1.00E−4 >1.00E−4
    HS 578T 0.415 0.913 0.854 0.861 0.819 0.710 0.405 88 90 81 59 −2 1.41E−5 9.14E−5 >1.00E−4
    MDA-MB-435 0.426 1.511 1.527 1.479 1.525 1.043 0.021 101 97 101 57 −95 1.11E−5 2.37E−5 5.04E−5
    BT-549 0.571 1.144 1.114 1.057 1.044 0.886 0.562 95 85 83 55 −2 1.22E−5 9.35E−5 >1.00E−4
    T-47D 0.393 0.891 0.819 0.794 0.747 0.674 0.362 85 80 71 56 −8 1.26E−5 7.51E−5 >1.00E−4
  • While the invention has been described in terms of what is presently considered to be the most practical and preferred embodiments, it is to be understood that the invention needs not be limited to the disclosed embodiments. On the contrary, it is intended to cover various modifications and similar arrangements included within the spirit and scope of the appended claims which are to be accorded with the broadest interpretation so as to encompass all such modifications and similar structures.
  • Citations:
    • 1. Bestilny, L. J.; Brown, C. B.; Miura, Y.; Robertson, L. D.; Riabowol, K. T. Selective inhibition of telomerase activity during terminal differentiation of immortal cell lines. Cancer Res. 1996, 56, 3796-802.
    • 2. Bodnar, A. G.; Ouellette, M.; Frolkis, M.; Holt, S. E.; Chiu, C. P.; Morin, G. B.; Harley, C. B.; Shay, J. W.; Lichtsteiner, S.; Wright, W. E. Extension of life-span by introduction of telomerase into normal human cells. Science. 1998, 279, 349-52.
    • 3. Urquidi, V.; Tarin, D.; Goodison, S. Role of telomerase in cell senescence and oncogenesis. Annu. Rev. Med. 2000, 51, 65-79.
    • 4. Smogorzewska, A.; de Lange, T. Regulation of telomerase by telomeric proteins. Annu. Rev. Biochem. 2004, 73, 177-208.
    • 5. Peng, X.; Wu, Y.; Fan, J.; Tian, M.; Han, K. Colorimetric and ratiometric fluorescence sensing of fluoride: tuning selectivity in proton transfer. J. Org. Chem. 2005, 70, 10524-31.

Claims (20)

1. A heteroannelated anthraquinone derivative compound represented by a formula (I):
Figure US20090253707A1-20091008-C00034
wherein R1 is a substituent being one selected from a group consisting of:
i) a first substituent being one selected from a group consisting of a hydryl group, an amino group, a nitro group, a hydroxyl group and a cyan group;
ii) a second substituent being one selected from a group consisting of (CH2)nX, a straight (CH2)n alkyl group, a (CH2)n alkoxyl group, a branched (CH2)n alkyl group, a C3˜C12nephthenic group, and a C3˜C12 cyclic alkoxyl group, wherein 1=n=12, and X is a halogen;
iii) a third substituent being one selected from a group consisting of a straight C1˜C8 alkyl group with a double-bond, a C1˜C8 alkoxyl group with a double-bond, a branched C1˜C8 alkyl group with a double-bond and a C3˜C8 nephthenic group with a double-bond; and
iv) a fourth substituent of a C5˜C12 heterocyclic group.
2. A compound as claimed in claim 1, wherein R1 is an ethyl group.
3. A compound as claimed in claim 1, wherein one of the nephthenic group and the heterocyclic group further has at least one of an ortho-substitution, a meta-substitution and a para-substitution, and comprises at least a fifth substituent for any of the substitutions being one selected from a group consisting of an alkyl group with a C1˜C3 substituent branch, an amino group, a nitro group, a hydroxyl group and a cyan group, a C1˜C5 alkyl group, a halogen substituted C1˜C5 alkyl group, a C1˜C5 alkoxyl group, a halogen substituted C1˜C5 alkoxyl group, a C1˜C5 cyclic alkoxyl group, and a halogen substituted C1˜C5 cyclic alkoxyl group.
4. A compound as claimed in claim 1, wherein the halogen is one selected from a group consisting of a fluorine, a chlorine, a bromine and an iodine.
5. A compound as claimed in claim 1, wherein the second substituent is one selected from a group consisting of a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a pentyl group, an isopentyl group, a cyclopentyl group, a heptyl group, an isoheptyl group, a cycloheptyl group, an octyl group, an isooctyl group, a cyclooctyl group, a straight alkyl group with a branch substituted by a straight C1˜C5 alkyl group, a nephthenic group with a branch substituted by a straight C1˜C5 alkyl group, alkoxyl derivatives of the mentioned alkyl groups, and halogenated derivatives of the mentioned alkyl groups.
6. A compound as claimed in claim 1, wherein the third substituent is one selected from a group consisting of a vinyl group, a propenyl group, a butenyl group, an isobutenyl group, a pentenyl group, an isopentenyl group, a cyclopentenyl group, a hexenyl group, a cyclohexenyl group, a heptenyl group, an cycloheptenyl group, a straight alkyl group with a branch substituted by a straight C1˜C3 alkyl group, a nephthenic group with a branch substituted by a straight C1˜C3 alkyl group, alkoxyl derivatives of the mentioned groups, and halogenated derivatives of the mentioned groups.
7. A compound as claimed in claim 1, being used as an effective component together with an excipient to provide a pharmaceutic composition for inhibiting one selected from a group consisting of a growth of a cancer cell, a disease of cell proliferation, and a growth of cell telomere.
8. A heteroannelated anthraquinone derivative compound represented by a formula (II):
Figure US20090253707A1-20091008-C00035
9. A compound as claimed in claim 8, being used as an effective component together with an excipient to provide a pharmaceutic composition for inhibiting one selected from a group consisting of a growth of a cancer cell, a disease of cell proliferation, and a growth of cell telomere.
10. A heteroannelated anthraquinone derivative compound represented by a formula (III):
Figure US20090253707A1-20091008-C00036
wherein either one of R2 and R3 is one of:
i) a first substituent being one of a hydryl group and a sulfuryl-group; and
ii) a second substituent being one selected from a group consisting of a C1˜C8 alkyl group, a C1˜C8 alkoxyl group, a C3˜C8 nephthenic group, and a C3˜C8 cyclic alkoxyl group, a straight alkyl group with a branch substitutent, a nephthenic group with a branch substitutent by a straight C1˜C5 alkyl group and halogenated derivatives of the mentioned substitent groups.
11. A compound as claimed in claim 10, wherein the second substituent is one selected from a group consisting of a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a pentyl group, an isopentyl group, a cyclopentyl group, a heptyl group, an isoheptyl group, a cycloheptyl group, an octyl group, an isooctyl group, a cyclooctyl group, a phenyl group, a benzyl group, a phenethyl group, a straight alkyl group with a branch substituted by a straight C1˜C3 alkyl group, a nephthenic group with a branch substituted by a straight C1˜C3 alkyl group, alkoxyl derivatives of the mentioned substituent groups, and halogenated derivatives of the mentioned substituent groups.
12. A compound as claimed in claim 10, being used as an effective component together with an excipient to provide a pharmaceutic composition for inhibiting one selected from a group consisting of a growth of a cancer cell, a disease of cell proliferation, and a growth of cell telomere.
13. A heteroannelated anthraquinone derivative compound represented by a formula (IV):
Figure US20090253707A1-20091008-C00037
wherein R4 is one selected from a group consisting of a hydryl group, a C1˜C4 alkyl group, a C1˜C4 alkoxyl group, a C1˜C4 ketone group, a straight alkyl group with a branch substituted by a straight C1˜C3 alkyl group, a halogen substituted C1˜C4 alkyl group, and a C1˜C4 alkoxyl group.
14. A compound as claimed in claim 13, wherein R4 is a hydrogen.
15. A compound as claimed in claim 13, being used as an effective component together with an excipient to provide a pharmaceutic composition for inhibiting one selected from a group consisting of a growth of a cancer cell, a disease of cell proliferation, and a growth of cell telomere.
16. A method for manufacturing a compound having a formula (I) as claimed in claim 1, comprising steps of:
a) dissolving a diaminoanthraquinone in a dimethylformamide solution for forming a solution A;
b) adding and dissolving a chloroacetyl chloride in the solution A for forming a solution B;
c) mixing and reacting the solution B by a reverse flow method, and then transferring the solution B into an icy water for forming a solution C;
d) filtering the solution C for obtaining a precipitate; and
e) washing the precipitate by using an ethanol for obtaining the compound of the formula (I).
17. A method for manufacturing a compound having a formula (I) as claimed in claim 1, comprising steps of:
a) dissolving a diaminoanthraquinone in a dimethylformamide solution for forming a solution A;
b) adding and dissolving a reagent in the solution A for forming a solution B, wherein the reagent is one of a benzaldehyde and a carbon disulfide;
c) catalyzing a reaction of the solution B by adding a concentrated sulfuric acid thereinto, and then transferring the solution B into an ice water for forming a solution C;
d) filtering the solution C for obtaining a precipitate; and
e) washing the precipitate by using an ethanol for obtaining the compound of the formula (I),
wherein when the reagent is the carbon disulfide, a triethylamine is further added into the solution B before the step c).
18. A method for manufacturing a compound having a formula (III) as claimed in claim 10, comprising steps of:
a) dissolving a diaminoanthraquinone in an acetone for forming a solution A;
b) adding a concentrated sulfuric acid into the solution A for forming a solution B;
c) transferring the solution B into a potassium carbonate column for obtaining a solution C; and
d) using a methanol to crystallize the compound of the formula (III) in the solution C.
19. A method as claimed in claim 18, wherein the step b) is performed in a room temperature.
20. A method for manufacturing a compound having a formula (IV) as claimed in claim 13, comprising steps of:
a) dissolving a diaminoanthraquinone in a dimethylformamide solution for forming a solution A;
b) adding a glyoxal ethanol solution into the solution A for forming a solution B;
c) reacting the solution B by a reverse flow reaction;
d) filtering the solution B for obtaining a precipitate; and
e) washing the precipitate by using a hot alcohol and a dichloromethane for separating out the compound of the formula (IV).
US12/193,564 2008-04-02 2008-08-18 Heteroannelated anthraquinone derivatives and the synthesis method thereof Abandoned US20090253707A1 (en)

Priority Applications (4)

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US12/749,253 US8222287B2 (en) 2008-04-02 2010-03-29 Substituted anthra[1,2-D]imidazolediones and pharmaceutical utility thereof
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CN103319438A (en) * 2013-06-03 2013-09-25 中国人民解放军第二军医大学 4-substituted anthra[1,2-c][1,2,5]thiadiazole-6,11-dione derivative and its preparation method and application
US20130289028A1 (en) * 2012-04-27 2013-10-31 National Defense Medical Center Heterocyclic fused anthraquinone derivatives, manufacturing method and pharmaceutical composition using thereof
WO2013083611A3 (en) * 2011-12-07 2014-01-30 Henkel Ag & Co. Kgaa Ring-bridged anthraquinone dye for dyeing keratinous fibres
CN104250246A (en) * 2013-06-27 2014-12-31 中国科学院上海药物研究所 Anthraquinone and thiazole compound, preparation method and application thereof

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TWI533869B (en) 2014-03-11 2016-05-21 國立中央大學 Indication of anthra(2,1-c)(1,2,5)thiadiazole-6,11-dione compound in alleviating pain
TWI533871B (en) 2014-03-11 2016-05-21 國立中央大學 Indication of naphtho(2,3-f)quinoxaline-7,12-dione compound in alleviating pain

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WO2013083611A3 (en) * 2011-12-07 2014-01-30 Henkel Ag & Co. Kgaa Ring-bridged anthraquinone dye for dyeing keratinous fibres
US20130289028A1 (en) * 2012-04-27 2013-10-31 National Defense Medical Center Heterocyclic fused anthraquinone derivatives, manufacturing method and pharmaceutical composition using thereof
US8877748B2 (en) * 2012-04-27 2014-11-04 National Defense Medical Center Heterocyclic fused anthraquinone derivatives, manufacturing method and pharmaceutical composition using thereof
CN103319438A (en) * 2013-06-03 2013-09-25 中国人民解放军第二军医大学 4-substituted anthra[1,2-c][1,2,5]thiadiazole-6,11-dione derivative and its preparation method and application
CN103319438B (en) * 2013-06-03 2016-03-02 中国人民解放军第二军医大学 4-position replaces anthra [1,2-c] [1,2,5] thiadiazoles-6,11-derovatives and its preparation method and application
CN104250246A (en) * 2013-06-27 2014-12-31 中国科学院上海药物研究所 Anthraquinone and thiazole compound, preparation method and application thereof

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US8222287B2 (en) 2012-07-17
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