MX2008006333A - N-oxides of cytotoxic anthraquinones as hypoxia-targeting prodrugs in cancer treatment. - Google Patents

Abstract

The present invention generally relates to chemotherapeutic treatment of cancer. The invention more specifically provides novel DNA-directed N-oxide derivatives of chloroethylaminoanthraquinones and their precursor hydroxylated compounds, which display cytotoxic activity despite an absence of alkylating capability. The compounds of the invention further are inactive until reduced in a hypoxic environment.

Description

N-OXIDES OF CYTOTOXIC TRAQUINONES AS PRO-DRUGS DIRECTED TO HYPOXIA Field of the Invention The present invention relates generally to cancer chemotherapeutic treatment. The invention relates more specifically to novel N-oxides derived from anthraquinones, directed to DNA, which are inactive until reduced in a hypoxic environment. Background of the Invention Resistance to anti-tumor drugs is the main cause for cancer chemotherapy failure and a number of mechanisms for resistance are known. However, it may be possible to exploit differences in resistant and non-resistant tumor cells, thereby developing anti-tumor agents and treatments that are more effective against resistant tumors than against non-resistant tumors. Solid tumors comprise more than 90% of all human cancers and can be considerably less oxygenated compared to normal tissues, a phenomenon that is associated with radiation resistance and chemotherapy in the clinic. Chemotherapy and conventional radiation therapy will preferentially kill tumor tissue that is well spread with oxygenated blood. Tissues of hypoxic tumors are poorly disseminated and they have low oxygen. Therefore, solid tumors are frequently refractory to conventional therapy. However, cell death in regions of tumors with low oxygen tension (hypoxia) is crucial if the cancer is to be treated effectively. Nitrogen mustards used in the clinic make an important contribution to cancer chemotherapy, but they are problematic for two reasons: (1) they have considerable systemic toxicity and (2) they are recognized as DNA alkylating agents, but they have no intrinsic affinity for their objective. Thus there is a need for chemotherapeutic agents that are effective under low oxygen tension and can target DNA. SUMMARY OF THE INVENTION The present invention provides a method for targeting a DNA-related cytotoxic anthraquinone to DNA within a cell mass, comprising contacting a DNA-related cytotoxic anthraquinone N-oxide with the cell mass, in which the interior of the cell mass is hypoxic and where the N-oxide is reduced under hypoxic conditions, thereby pointing a cytotoxic anthraquinone afin DNA to the interior of the cell mass. In one embodiment, the cell mass is a cellular spheroid. In another embodiment, the cell mass is a tumor. The tumor can be a carcinoma or a sarcoma. In certain embodiments, the tumor is a lung tumor, of chest, ovary, stomach, pancreas, larynx, esophagus, testes, liver, parotid, biliary tract, colon, rectum, cervix, uterus, endometrium, kidney, bladder , prostate, or thyroid gland. In certain embodiments, the tumor is squamous cell carcinoma, adenocarcinoma, small cell carcinoma, melanoma, glioma, neuroblastoma, Wilms tumor, Ewing's sarcoma, neuroblastoma, rhabdomyosarcoma, or osteosarcoma. In one aspect of the invention, the N-oxide localizes to the interior of the cell mass. In one embodiment of the invention, the DNA-related cytotoxic anthraquinone is a chloroethylaminoanthraquinone. In another embodiment, the DNA-related cytotoxic anthraquinone is a compound of the formula I: (i) wherein R1 to R4 are each selected from the group consisting of H, C ^ alkyl, X1, -NHR ° N (R5) 2 wherein R ° is a C1-12 alkanediyl and each R5 is H or optionally alkyl C1-4 substituted, and a group of formula II: wherein at least one of R6, R7 and R8 is selected from X2, and C1-4alkyl substituted with X2 and any other are H or C1-4alkyl; R9 is selected from H, C1-4 alkyl, X2 and alkyl substituted with X2; m is 0 or 1; n is 1 or 2; X1 is a halogen atom, a hydroxyl group, a C1.6 alkoxyl group, an aryloxy group or an acyloxy group; and X2 is a halogen atom, a hydroxyl group, a C1-6 alkoxy group, an aryloxy group or an acyloxy group; provided that at least one of R1 to R4 is a group of formula II. The present invention also provides a method for treating a solid tumor in a subject comprising: administering to the subject an N-oxide of a DNA-related cytotoxic anthraquinone, where the incorporation of N-oxidation of the cytotoxic anthraquinone prevents DNA affinity, where the reduction of N-oxide generates a therapeutically effective cytotoxin; thereby treating a solid tumor in a subject. The present invention also provides hypoxia-targeting drugs containing DNA-related cytotoxic anthraquinone N-oxides. Also provided are devices for Molecular delivery for directing a deactivated therapeutic agent to a cell comprising a cytotoxic agent directed to DNA of claim 9 having an N-oxide component. In accordance with the present invention a method for treating a solid tumor in a subject is also provided, comprising the steps of administering to the patient a therapeutically effective amount of an N-oxide derivative of an alkylating or non-alkylating anthraquinone, wherein the N-oxide derivative of the alkylating or non-alkylating anthraquinone does not display DNA affinity and is inactive until reduced in a hypoxic environment, thereby treating a solid tumor in a subjection. The invention also provides a method for directing a cytotoxic agent to the DNA of a cell comprising preparing a complex of an N-oxide and an alkylating chloroethylaminoanthraquinone or a non-alkylating hydroxyethylaminoanthraquinone, wherein the N-oxide of the alkylating or nonalkylating anthraquinone does not display DNA affinity; and contacting a cell with the complex, thereby directing the cytotoxic agent to the cell's DNA. The N-oxide of the alkylating anthraquinone or non-alkylating anthraquinone typically does not include substantial DNA cross-linking. In certain embodiments, the N-oxide of the alkylating anthraquinone or non-alkylating anthraquinone does not display cytotoxicity in the presence of normal oxygen tension. Brief Description of the Drawings Figure 1 is an illustration of Synthetic Methods A and B. Figure 2 shows the formulas for Monosubstituted Structure A, Structure B non-symmetric and Structure C symmetric. Figure 3 is an illustration of the synthetic scheme 2. Figure 4 is an illustration of the synthetic scheme 3. Figure 5 is an illustration of the synthetic scheme 4. Figure 6 is an illustration of the synthetic scheme 5. Detailed Description of the Invention present invention provides methods for directing a DNA-related cytotoxic anthraquinone to DNA within a cell mass by contacting a DNA-related cytotoxic anthraquinone N-oxide with the cell mass. The anthraquinone fraction is prevented from interacting with DNA from the outer cells of the mass, but it can penetrate into the cell mass. Under hypoxic conditions at the center of the cell mass, the N-oxide is reduced to a cytotoxic form. The cell masses of the invention can be naturally occurring masses such as tumors or can be produced in a laboratory, e.g., as a three-dimensional mass, such as a cellular spheroid. In one embodiment of the invention, the three-dimensional cell mass or spheroid is formed from cultured tumor cells, such as HT29 cells. Tumors of the invention can be benign or malignant.

In certain embodiments, the tumor is a solid tumor, which may, for example, be a sarcoma, carcinoma, or lymphoma. Solid tumors encompassed by the methods of the invention include tumors of the lung, breast, ovaries, stomach, pancreas, larynx, esophagus, testes, liver, parotid, biliary tract, colon, rectum , cervix, uterus, endometrium, kidney, bladder, prostate, or thyroid gland. In certain embodiments, the tumor is squamous cell carcinoma, adenocarcinoma, small cell carcinoma, melanoma, glioma, neuroblastoma, Wilms tumor, Ewing's sarcoma, neuroblastoma, rhabdomyosarcoma, or osteosarcoma, and the like. The DNA-related cytotoxic anthraquinone of the methods of the invention can be a chloroethylaminoanthraquinone. In certain embodiments, the DNA-related cytotoxic anthraquinone is a compound of the formula I: () where R1 to R4 are each selected from the group consisting of H, C ^ alkyl, X1, -NHR ° N (R5) 2 wherein R ° is a C 1-12 alkanediyl and each R 5 is H or optionally substituted C 1-4 alkyl, and a group of the formula II: wherein at least one of R6, R7 and R8 is selected from X2, and Cx_4 alkyl substituted with X2 and any other are H or C- ^ alkyl; R 9 is selected from H, C 1 alkyl, X 2 and C 1-4 alkyl substituted with X 2; m is 0 or 1; n is 1 or 2; X1 is a halogen atom, a hydroxyl group, a C1_6 alkoxy group, an aryloxy group or an acyloxy group; and X2 is a halogen atom, a hydroxyl group, a C1-6 alkoxy group, an aryloxy group or an acyloxy group; provided that at least one of R1 to R4 is a group of formula II. Suitable compounds for use in the methods of the invention are described in PCT International Publication WO 2005/061453 and are described in the examples set forth below.

The present invention provides methods for preparing N-oxides of chloroethylamino functionalities (known as the reactive component of nitrogen mustards) and their hydroxylated precursor compounds as part of sterically restricted alicyclic (pyrrolidinyl and piperidinyl) ring systems. Specifically, the invention provides methods for preparing N-oxides of alkylating chloroethylaminoanthraquinones directed to DNA and its precursor hydroxylated compounds, which display cytotoxic activity despite an absence of alkylating capacity. These chlorinated and hydroxylated compounds can be deactivated by oxidation with dimethyldioxirane (DMD), to produce N-oxide derivatives. This synthesis results in acetone as the sole by-product and produces an excellent yield (> 95%) of target compounds. In one embodiment, compounds of the invention are useful hypoxia-targeted pro-drugs. As further illustrated in the following examples, N-oxide compounds of the invention have substantially reduced or eliminated activity in DNA intercalating ability assays. Moreover, the N-oxide compounds of the invention show significantly reduced cytotoxicity. In one embodiment, the compounds of the invention display the ability to access the interior of cell masses, such as solid tumors, without inducing cytotoxicity. In another embodiment, the compounds of the invention are inactive until they are reduced in a hypoxic environment. As such, they are particularly suitable for delivering a cytotoxic DNA ligation agent to hypoxic regions of cell growth, such as the interior of solid tumors. The present invention also provides pharmaceutical compositions comprising N-oxides of anthraquinones and a pharmaceutically acceptable excipient, carrier or diluent. The compounds of the invention can be used to prepare molecular delivery devices to direct to a hypoxic environment. In one embodiment of the invention, the compounds of the invention are alkylation agents directed to DNA under low oxygen tension, and thus direct their alkylating ability to hypoxic environments. In another embodiment, the N-oxide component can be attached to a non-covalent DNA ligation cytotoxic agent to produce molecular delivery devices to direct the cytotoxic agent to DNA in hypoxic regions. In one embodiment of the invention, methods are provided for treating solid tumors in a subject or a cell mass comprising administering to a patient a therapeutically effective amount of an N-oxide of an alkylating anthraquinone, wherein the N-oxide of the chloroethylaminoanthraquinone or the hydroxylated precursor compound does not display affinity to DNA and is inactive until reduced in a hypoxic environment, thereby treating a solid tumor in a subject.

Also provided are methods for treating a solid tumor in a subject or a cell mass by administering to the subject a therapeutically effective amount of an N-oxide prodrug of an alkylating anthraquinone or non-alkylating anthraquinone. N-oxidation of cytotoxic anthraquinones will prevent DNA binding capacity, and potent cytotoxicity of such anthraquinones can only be generated by metabolism of key N-oxide components. The compounds, compositions and methods of the invention may be particularly useful for treating conditions exhibiting low oxygen tension because the N-oxides of the alkylating anthraquinone do not display cytotoxicity in the presence of normal (physiological) oxygen tension. Thus, the compounds have the ability to penetrate normally oxygenated cells and tissues without killing the normal cells and tissue surrounding them, but they become effective cytotoxic agents by themselves when accessing a pathologically hypoxic environment. Thus, the compounds of the invention may be useful as prodrugs for hypoxic conditions, such as the interior of solid tumors or cell masses. Moreover, the compounds of the invention can be used to direct an agent, such as a cytotoxic agent, to the DNA of the cell. According to this method of the invention, a complex of an N-oxide component of an alkylating chloroethylaminoanthraquinone or a hydroxyethylaminoanthraquinone does not Alkylator is prepared. A cell then comes into contact with the N-oxide pro-drug, which subsequent to metabolism will generate bioreduction products that target DNA. Having generally described the invention, it will be more easily understood by reference to the following examples (see also Annex A appended thereto, which is incorporated by reference in its entirety) which are provided by way of illustration, and are not intended to be limiting of the present invention, unless specified. EXAMPLES Example 1: General Method for Synthesis of Anthraquinones Hydroxyethylamino-anthraquinones (HAQs) 1 -monosubstituted were prepared by displacing chlorine from 1-chloroanthraquinone with an aminoalkylamino side chain in a polar solvent such as 2-methoxyethanol. The 1,4-disubstituted HAQs were synthesized as described in Pors et al. (J. Med. Chem., 47: 1856-1859 (2004)) using previously described methods (Johnson et al., Cancer Treat. Rep., 63, 425-439 (1979), Murdock et al., J. Med. Chem. 1979, 22, 51-60) by the condensation of either leucoquinizarin or 5,8-dihydroxyleucoqui-nizarin (5, 8, 9, 10-tetrahydroxyanthracene). 1,4-dione) with an excess amount of N-alkyl-N-droxyalkylaminoalkylamine, which was synthesized as described in Aspinall (J. Am. Chem. Soc. 63: 852-853 (1948)) and Preston and collaborators (J. Med. Chem. 7: 471-482 (1964)). The 1, 4 -displaced HAQs are typically isolated at a yield between 20 and 50%, depending on the purity of the secondary chains used. Chlorination was subsequently achieved under mild conditions using triphenylphosphine-carbon tetrachloride complex (PPh3-CCl4). This method was highly efficient for the conversion of HAQs to chloroethyl derivatives, with approximately 80% yields. The general synthetic methods A and B of the invention follow the general schemes expressed in Figure 1. Method A: (i) N-alkyl-N-hydroxyalkylaminoalkylamine, reflux in 2-methoxyethanol for 6 hours; (ii) Ph3P-CCl4 in CH2C12 / CH3CN (4: 1) at room temperature for 48 hours, hydrochloride salt made by the addition of ethereal hydrogen chloride. Method B: (i) leucoquinizarin (X = H) or 5,8-dihydroxy-leucoquinizarin (X = OH) heated with appropriate N-alkyl-N-hydroxyalkylaminoalkylamine for 5 hours, R1 # R2, R3, R4 = CH3 or CH2CH2OH, n = lo 2; (ii) Ph3P-CCl4 in CH2C12 / CH3CN (4: 1) at room temperature for 48 hours, hydrochloride salt made by the addition of ethereal hydrogen chloride, Rlf R2, R3, R4 = CH3 or CH2CH2OH, n = 2 The compounds have the general formulas shown in Structures A, B, and C (Figure 2) and are prepared as described in more detail below. The constituents of certain specific compounds are given in Table 1, below.

Table 1 Structure Ri R2 n X Hydroxyethylaminoanthraquinone 1 C CH2CH2OH OH 1 H 2 C CH2CH2OH OH 2 H 3 C CH 3 OH 1 H 4 C CH2CH2OH OH 2 OH B CH3 OH - OH 6 C CH3 OH 1 OH 7 B CH2CH2OH OH - OH 8 C CH2CH2OH OH 1 OH 9 A CH3 OH 1 - 10 A CH3 OH 2 - Chlorine ilaminoanthraquinone 11 C CH2CH2C1 Cl 1 OH CH2CH2C1 12 B CH2CH2C1 Cl - OH 13 C CH2CH2C1 Cl 2 OH 14 A CH2CH2C1 Cl 2 - 15 C CH3 Cl 1 OH 16 C CH3 Cl 1 H 17 A CH3 Cl 2 - 18 C CH2CH2C1 Cl 2 H 19 C CH2CH2C1 Cl 1 H A CH3 Cl 1 - Example 2: Synthesis of 1 [. { 2 - [Dimethylamino] ethyl} amino] -4- [. { 2 - [bis (2-hydroxyethyl) amino] ethyl} amino] -5,8-dihydroxyanthracene-9,10-dione (7) 5,8-Dihydroxyleucoquinizarin (0.2 g, 0.75 mmol) is added to a mixture of N, N-bis (2-hydroxyethyl) -ethylenediamine (0.67 g) , 3.6 mmol) and N, N-dimethylethylenediamine (0.194 g, 2.2 mmol) at 60 ° C under N2 and heated for 5 hours. The reaction was cooled to room temperature, and aqueous NaOH (2M, 0.2 cm3) was added and stirred overnight exposed to air. The reaction was diluted with CH2C12 (80 cm3), washed with water (3 x 80 cm3), dried with MgSO4, and concentrated. The crude solid was purified by chromatography (CH30H: CH2C12: NH3, 4.5: 94: 0.5 increasing to 19.5: 80: 0.5). The resulting solid was further purified by redissolving in CH3OH and precipitation with dry diethyl ether to obtain the product as a dark blue solid (60.03 mg, 20% yield), melting point 204.2-205 ° C. NMR Example 3: Dihydrochloride 1- [. { 2- [Bis (2-chloroethyl) amino] ethyl} amino - 4 - [. { 2 - [dime t i 1 amino] ethyl} amino] -5,8-dihydroxyanthracene-9,10-dione Triphenylphosphine (0.11 g, 0.32 mmol) and then CC14 (0.19 g, 1.25 mmol) were added to a stirred solution of 7 (0.05 g, 0.10 mmol) in CH2C12 ( 5.0 cm3) under N2. The resulting solution was allowed to stir at room temperature for 24 hours. The residue was precipitated by the addition of dry etheral HCl, isolated by filtration, and dried under vacuum. The raw product is dissolved in a minimum amount of CH2Cl2 / EtOH (1: 1) at 60 ° C and was isolated from the byproduct of triphenylphosphine oxide and excess triphenylphosphine by precipitation with EtOH / EtOAc (1: 1). The product was isolated as a dark blue solid (51.5 mg, 83%), melting point 190.0-192.1 ° C; NMR? (CDCl3 / CD3OD) d: 3.0 (s, 6H, 2 x NCH3), 3.4 (t, 4H, 2 x CH2N), 3.6 (t, 4H, 2 x CH2N), 3.85 (t, 4H, 2 x CH2NHAr) 3.9 (t, 4H, 4 x CH2C1), 7.1 (s, 2H, ArH), 7.3 (s, 2H, ArH), 10.6 (t, 2H, 2 x NHAr); IR vmax (KBr) cm "1: 3,600-3,300 (OH, 1,580 (C = 0), 1,230 (NH); (CH 3 OH / DMSO) = 14, 162 cm" 1; vmax (620 nm); MS, m / z (M + H) + 509; Anal. (C 24 H 30 N 4 O 4 Cl 2-2HCl 2 H 2 O) C, H, N. Example 4: 1,4-Bis- [. {2- [bis (2-hydroxyethyl) amino] ethyl.}. amino] anthra-ceno- 9, 10 -dione (1) The procedure and the reaction conditions follow those for the synthesis of 3, using N, N-bis (2-hydroxyethyl) ethylenediamine (3.7 g , 20.0 mmol) and leucoquinizarin (0.3 g, 1.26 mmol) Purification by flash column chromatography (CH3OH: CH2C12, 1: 1) produced the product as dark blue crystals (132.3 mg, 22% yield), melting point 177.5-178.9 ° C; NMR ¾ (CDC13 / CD30D) peaks: d 3.4 (t, 8H, 4 x CH2N), 3.5 (t, 4H, 2 x CH2N), 3.85 (q, 4H, 2 x CH2NHAr), 4.0 (t, 8H, 4 x CH2OH), 7.7 (s, 2H, ArH), 7.85 (m, 2H, ArH), 8.3 (m, 2H, ArH), 10.4 (t, 2H, 2 x NHAr), IR vmax (KBr) cm "1: 3,600-3,300 (OH), 1,590 (C = 0), 1,230 (NH); (dH 2 O) = 8.060 cm" 1; Amax (624 nm); FAB-MS, m / z (M + H ) + 501; Anal. (C26H36N406) C, H, N.

Example 5: 1, 4 -Bis [. { 3 - [bis (2-hydroxyethyl) amino] propyl} amino] an-traceno- 9, 10 -dione (2) The procedure and the reaction conditions follow those for the synthesis of 3, using N, N-bis (2-hydroxyethyl) ethylenediamine (3.64 g, 20.0 mmol) and leucoquinizarin (0.3 g, 1.26 mmol). Purification by flash column chromatography (CH30H: CH2C12, 3: 7 increasing to 1: 1) afforded the product as dark blue crystals (113.0 mg, 18% yield), mp 137.6-138.6 ° C; XH NMR (CDC13 / CD30D) peaks: 1.8 (m, 4H, 2 x CH2CH2CH2), 2.3 (t, 8H, 4 X CH2N), 2.4 (t, 4H, 2 x CH2N), 3.4 (q, 4H, 2 x CH2NHAr), 3.7 (t, 8H, 4 x CH2OH), 7.7 (x, 2H, ArH), 7.85 (m, 2H, ArH), 8.3 (m, 2H, ArH), 10.7 (t, 2H, 2 x NHAr ); IR vmx (KBr) cm "1: 3,600-3,300 (OH), 1,590 (C = 0), 1,230 (N-H); (dH20) = 9.964 cm" 1; Xraax (630 nm); FAB-MS, m / z. { M + E) + 529; Anal. (C28H40N4Os) C, H, N. Example 6: 1, 4-Bis- [. { 2- [(2-Hydroxyethyl) (methyl) amino] ethyl} amino] anthracene- 9, 10 -dione (3) Leucoquinizarin (0.3 g, 1.26 mmol) was added to N-2-hydroxyethyl-N-methylethylenediamine (2.44 g, 20.0 mmol) at 60 ° C under nitrogen and heated to 4 ° C. hours. The reaction mixture was cooled to room temperature, aqueous NaOH (15%, 0.2 cm3) was added and the reaction was allowed to stir overnight exposed to air. The reaction mixture was diluted with CH2C12 (80 cm3) and washed with water (3 x 80 cm3). The organic layer was dried with MgSO4 and the solvent was concentrated in vacuo to yield a waxy solid.

This crude solid was purified by flash column chromatography (CH3OH: CHCH2C12, 1: 1 then CH3OH) and then redissolved in CH3OH followed by precipitation with dry diethyl ether to obtain dark blue crystals (105.7 mg, 19% yield), melting point 181.2 -182.3 ° C; NMR? (CDCl3 / CD3OD) peaks: d 2.5 (br s, 6H, 2 x CH3N), 2.8 (t, 2H, CH2CH2CH2N), 3.0 (t, 2H, CH2CH2N), 3.4 (q, 2H, CH2NHAr), 3.7 (t , 2H, CH2OH), 7.5 (s, 2H, Ar-H), 7.7 (m, 2H, Ar-H), 8.2 (m, 2H, Ar-NH), 10.7 (t, 2H, 2 x NHAr); IR vmax (KBr) cnT1: 3,600-3,300 (OH), 1,590 (C = 0), 1,230 (N-H); ?? (dH20) = 7,128 cnT1; Amax (626 nm); FAB-MS, m / z. { M + H) + 441; Anal. (C 24 H 32 N 404) C, H, N. Example 7: 1, 4-Bis [. { 3- [bis (2-hydroxyethyl) amino] propyl} amino] -5,8-dihydroxyanthracene- 9.10-dione (4) The procedure and the reaction conditions follow those for the synthesis of 6, using N, N-bis (2-hydroxyethyl) -1,3-propanediamine (2.16 g , 10.0 mmol) and 5, 8-dihydroxyleucoquinizarin (0.2 g, 0.75 mmol). Purification by flash column chromatography (CH30H: CH2C12: NH3, 4.5: 95: 0.5) afforded the product as a dark blue solid (128.1 mg, 31% yield), melting point 243.4-245.2 ° C; XH NMR (CDC13 / CD30D) d: 1.75 (t, 4H, 2 x CH2CH2CH2), 2.5 (t, 8H, 4 x CH2N), 2.6 (t, 4H, 2 x CH2N), 3.45 (q, 4H, 2 x CH2NAr), 3.6 (t, 8H, 4 x CH2OH), 7.2 (s, 2H, ArH), 7.6 (s, 2H, ArH), 10.6 (t, 2H, 2 x NHAr); IR vmax (KBr) was "1: 3,600-3,300 (OH), 1,580 (C = 0), 1,230 (NH); (dH20) = 9.844 cnT1; Xmax (612 nm); FAB-MS, m / z (M + U) + 561; Anal. (C28H40N4O8) C, H, N. Example 8: 1- [. { 2- [Dimethylamino] ethyl} 4- [. { 2- [2- (hydroxyethyl) (methyl) to ino] ethyl} amino] 5, 8-dihydroxyanthracene-9,10-dione (5) 5, 8 -Dihydroxyleucoquinizarin (0.2 g, 0.75 mmol) was added to N-2-hydroxyethyl-N-melethylenediamine (0.71 g, 6.0 mmol) at 60 ° C under nitrogen and heated for 30 minutes. N, N-dimethylethylenediamine (0.194 g, 2.2 mmol) was added and the reaction mixture was stirred at 80 ° C for an additional 5 hours. After cooling to room temperature, aqueous NaOH (15%, 0.2 cm3) was added and the reaction mixture was exposed to air and stirred overnight. The reaction mixture was diluted with CH2C12 (80 cm3) and washed with water (3 x 80 cm3). The organic layer was dried with MgSO4 and the solvent was concentrated in vacuo to yield a waxy solid. This crude solid was purified by flash column chromatography (CH3OH: CH2C12: NH3, 4.5: 94: 0.5) The resulting solid was further purified by re-dissolving in CH30H and precipitation with diethyl ether to obtain the product as dark blue crystals ( 34.8 mg, 11% yield), mp 207.5-209.5 ° C; RM NMR (CDC13 / CD30D) d: 2.7 (s, 9H, 3 x NCH3), 3.1 (t, 4H, 2 x CH2N), 3.3 (t, 2H, CH2N), 3.9 (q, 4H, 2 x CH2NHAr), 4.1 (t, 2H, CH2OH), 7.1 (s, 2H, ArH), 7.3 (s, 2H, ArH), 10.8 (t, 2H, NHAr), IR Amax (KBr) cm'1: 3,600-3,300 (OH), 1,580 (C = 0), 1,230 (NH); (dH20) = 7,128 cm "1; Amax (608 nm); FAB-MS, m / z (M + H) + 443; Anal. (C23H30N4O5) C, H, N. Example 9: 1, 4-Bis [ { 2- [2- (hydroxyethyl) (methyl) amino] ] ethyl.}. amino] - ,8-dihydroxyanthracene-9,10-dione (6) 5,8-Dihydroxy-bilokyquinizarine (0.2 g, 0.75 mmol) was added to N-2-hydroxyethyl-N-methylethylenediamine (1.3 g, 12.0 mmol) at 60 ° C under nitrogen and heated for 5 hours. The reaction mixture was cooled to room temperature, aqueous NaOH (2, 0.2 cm3) was added and the reaction was exposed to air and stirred overnight. The reaction mixture was diluted with CH2C12 (80 cm3) and washed with water (3 x 80 cm3). The organic layer was dried with MgSO4 and the solvent was concentrated in vacuo to yield a waxy solid. This crude solid was purified by flash column chromatography (CH3OH: CH2C12: NH3, 5: 94: 1). The resulting solid was further purified by re-dissolving in CH3OH and precipitation with dry diethyl ether to obtain the product as dark blue crystals (87.1 mg, 25% yield), mp 211.3-213.5 ° C; XH NMR (CDC13 / CD30D) d: 2.3 (s, 6H, 2 x CH3N), 2.7 (t, 4H, 2 x CH2N), 2.8 (t, 4H, 2 x CH2N), 3.6 (q, 4H, 2 x CHjNAr), 3.7 (t, 4H, 2 x CH2OH), 7.2 (s, 2H, ArH), 7.4 (s, 2H, ArH), 10.6 (t, 2H, 2 x NHArH); IR vmax (KBr) cm'1: 3,600-3,300 (OH), 1,580 (C = 0), 1,230 (N-H); ?? (dH20) = 14, 604 cm "1; Xmax (608 nm); FAB-MS, m / z (M + K) + 473; Anal. (C24H32N406) C, H, N. Example 10: 1,4- Bis [ { 2- [bis (2-hydroxyethyl) amino] ethyl] amino] -5,8-dihydroxyanthracene-9,10-dione (8) The procedure and the reaction conditions followed those for the synthesis of 6, using N, N-bis (2-hydroxyethyl) ethylenediamine (2.0 g, 10 mmol) and 5, 8-dihydroxyleuco- quinizarin (0.2 ^ g, 0.75 mmol). Purification by flash column chromatography (CH3OH: NH3, 99.5: 0.5) afforded the product as a dark blue solid (94.2 mg, 24% yield); melting point 218.5-219.5 ° C; R N? (CDCl3 / CD3OD) d: 2.7 (t, 8H, 4 x CH2N), 2.9 (t, 4H, 2 x CH2N), 3.5 (q, 4H, 2 x CH2NAr), 3.7 (t, 8H, 4 x CH2OH) , 7.1 (s, 2H, ArH), 7.3 (s, 2H, ArH), 10.6 (t, 2H, 2 x NHAr); IR vmax (KBr) cm "1: 3,600-3,300 (OH), 1,580 (C = 0), 1,230 (N-H); (dH20) = 8.876 cm" 1; Xmax (606 nm); FAB-MS, m / z (M + U) + 533; Anal. (C26H36N408) C, H, N. Example 11: 1- [. { 2 - [2 - (Hydroxyethyl) (methyl) amino] ethyl} amino] anthra-ceno- 9, 10 -dione (9) A N-2-hydroxyethyl-N-methylethylenediamine (2.4 g, 0.02 mol) in 2-methoxyethanol (10 cm3) was added 1-chloroanthraquinone (0.5 g, 2.05 mmol) and the mixture was refluxed for 6 hours. After evaporation, the resulting waxy solid was diluted with CH2C12 (20 cm3) and washed with water (3 x 20 cm3) to remove any unreacted amine. After evaporation, the crude product was lyophilized and subsequently purified by flash column chromatography (CH2Cl: EtOH, 9: 1). The product was further purified by re-dissolving the product in EtOH and precipitation with dry diethyl ether to obtain the objective compound as a red / orange solid (100 mg, 15% yield), melting point 105.9-106.8 ° C; RMN ¾ (CDC13 / CD30D) d: 2.3 (s, 3H, CH3N), 2.7 (t, 2H, CH2CH2N), 2.8 (t, 2H, CH2CH2N), 3.4 (q, 2H, CH2NHAr), 3.7 (t, 2H, CH2OH ), 7.0 (d, 1H, Ar-H), 7.5 (m, 2H, Ar-H), 7.7 (m, 2H, Ar-H), 8.2 (d, 1H, Ar-H), 8.3 (d, 1H, Ar-H), 10.1 (t, 1H, NHAr); IR vmax (KBr) ctn "1: 3,600-3,300 (OH), 1,650 (C = 0), 1040 (N-H); (CH 3 OH / DMSO) = 4,761 cm" 1; Amax (521 nm); FAB-MS, m / z. { M + H) + 325; Anal. (C19H20N2O3) C, H, N. Example 12: 1- [. { 3 - [2 - (Hydroxyethyl) (methyl) amino] propyl} amino] an-traceno- 9, 10 -dione (10) The procedure and the reaction conditions follow the method for the synthesis of 9, using 1-chloroanthraquinone (0.2 g, 0.82 mmol) and N-2-hydroxyethyl-N- methyl-1,3-propanediamine (1.1 g, 8.2 mmol). Purification by flash column chromatography (CH2C12: EtOH, 9: 1) afforded the product as a red solid (47.2 mg, 18% yield), mp 98.5-99.2 ° C; X H NMR (CDCl 3 / CD 3 OD) d: 1.8 (m, 2 H, CH 2 CH 2 CH 2), 2.3 (s, 3 H, CH 3 N), 2.7 (t, 2 H, CH 2 N), 2.8 (t, 2 H, HNCH 2 CH 2 N), 3.4 (q, 2 H , CH2NHAr), 3.7 (t, 2H, CH20H), 7.0 (d, 1H, Ar-H), 7.5 (m, 2H, Ar-H), 7.7 (m, 2H, Ar-H), 8.2 (d, 1H, Ar-H), 8.3 (d, 1H, Ar-H), 10.1 (t, 1H, NHAr); IR vmax (KBr) cm "1: 3,600-3,300 (OH), 1,650 (C = 0), · 1,040 (NH); (CH 3 OH / DMSO) = 3, 514 cm 1; Amax (504 nm); FAB-MS, m / z (M + H) + 339; Anal. (C20H22N2O3) C, H, N. Example 13: 1,4-bis [1 (2-bis (2-chloroethyl) amino dihydrochloride] ] ethyl.} amino] -5,8-dihydroxyanthracene-9,10-dione (11) The procedure and the reaction conditions follow the method for the synthesis of 16, using 8 (0.05 g, 0.09 mmol), triphenylphosphine ( 0.147 g, 0.56 mmol) and carbon tetrachloride (0.34 g, 2.25 mmol) The product was isolated as a blue solid dark (45.6 mg, 75% yield), melting point 191.6-192 ° C; XH NMR (CDCl3 / CD3OD) d: 3.0 (m, 12H, 6 x CH2N), 3.5 (q, 4H, 2 x CH2NHAr), 3.7 (t, 8H, 2 x CH2C1), 7.1 (s, 2H, ArH) , 7.3 (s, 2H, ArH), 10.4 (t, 2H, 2 x NHAr); IR max (KBr) cm "1: 3,600-3,300 (OH), 1,580 (C = 0), 1,230 (N-H); (CH 3 OH / DMSO) = 8,950 cm" 1; Amax (673 nm); FAB-MS, m / z (M + U) + 601; Anal. (C26H32N404C14 · 2HC1) C, H, N. Example 14: Di 1, 4-bis idrochloride. { 3 - [bis (2-chloroethyl) amino] propyl} amino] -5, 8-dihydroxyanthracene-9, 10-dione (13) The procedure and the reaction conditions follow the method for the synthesis of 16, using 4 (0.05 g, 0.79 mmol), triphenylphosphine (0.124 g, 0.47 mmol ) and carbon tetrachloride (0.288 g, 1.89 mmol). The product was isolated as a dark blue solid (44.7 mg, 81% yield), mp 205.1-206.5 ° C; XR NMR (CDCl3 / CD3OD) d: 2.2 (t, 4H, 2 X CH2CH2CH2), 3.5 (t, 8H, 4 x CH2N), 3.6 (t, 4H, 2 x CH2N), 3.7 (q, 4H, 2 x CH2NHAr), 3.9 (t, 8H, 4 x CH2Cl), 7.1 (s, 2H, ArH), 7.3 (s, 2H, ArH), 10.6 (t, 2H, 2 x NHAr); IR vmax (KBr) cm "1: 3,600-3,300 (OH), 1,580 (C = 0), 1,230 (N-H); (CH 3 OH / DMSO) = 9, 125 cm" 1; Xmax (675 nm); FAB-MS, m / z (M + H) + 635; Anal. (C28H36N404C14 · 2HC1 · 2H20) C, H, N. Example 15: 1- [. Hydrochloride. { 3 - [bis (2-chloroethyl) amino] propyl} amino] anthracene- 9, 10 -dione (14) The procedure and the reaction conditions follow the method for the synthesis of 12, using 14a (0.05 g, 0.136 mtnol), triphenylphosphine (0.071 g, 0.27 mmol) and carbon tetrachloride (0.246 g, 1.62 mmol). The product was isolated as a red solid (48.0 mg, 80% yield), mp 194.5-196.5 ° C; X H NMR (CDCl 3 / CD 3 OD) d: 2.2 (m, 2 H, CH 2 CH 2 CH 2), 3.5 (t, 2 H, CH 2 CH 2 N), 3.54 (t, 2 H, CH 2 CH 2 N), 3.65 (t, 2 H, CH 2 CH 2 N), 3.7 (q, 2 H , CH2NHAr), 4.0 (t, 4H, 2 x CH2Cl), 7.3 (d, 1H, Ar-H), 7.7 (m, 2H, Ar-H), 7.8 (m, 2H, Ar-H), 8.2 ( d, 1H, Ar-H), 8.3 (d, 1H, Ar-H); IR vmax (KBr) crn "1: 3,550-3,310 (OH), 1,600 (C = 0), 1,230 (NH); (CH 3 OH / DMSO) = 7,948 cm -1; Xmax (503 nm); FAB -MS, m / z (M + H) + 405; Anal. (C21H22N202C12 | 2HC1) C, H, N. Example 16: 1- [ { 3 - [Bis (2-hydroxyethyl) amino] propyl. amino] anthrace-no-9, 10-dione (14a) To NN-bis (2-hydroxyethyl) propanediamine (3.3 g, 20.0 mmol) in 2-methoxyethanol (10 cm3) was added 1-chloroanthraquinone(0.5 g, 2.05 mmol) and the mixture was refluxed for 6 hours. Upon cooling, the reaction mixture was diluted with CH2C12 (20 cm3) and washed with water (3 x 20 cm3) to remove any unreacted amine. After evaporation, the crude product was further purified by precipitation in CH3OH with dry diethyl ether to obtain the objective compound as a red powder (75.3 mg, 10.2% yield), melting point 91.2-92.2 ° C. NMR * H (CDC13 / CD30D) peaks: d 1.8 (m, 2H, CH2CH2CH2), 2.3 (t, 6H, 3 x CH2N), 3.4 (q, 2H, CH2NHAr), 3.7 (t, 4H, 2 x CH2OH) , 7.0 (d, 1H, ArH), 7.5 (m, 2H, ArH), 1.1 (m, 2H, ArH), 8.2 (d, 1H, ArH), 8.3 (d, 1H, ArH), 10.1 (t, 2H, NHAr); FAB-MS, m / z. { M + U) + 369; IR vmax (KBr) was "1: 3,600-3,300 (OH), 1,650 (C = 0), 1,040 (NH); (MeOH / DMSO) = 1.961 ern'1; Xmax (510 nm) .Example 17: 1,4-Bis [. {2 - [2 - (Chloroethyl) (methyl) amino] ethyl] amino] -5,8-dihydroxyanthracene-9,10-dione dihydrochloride (15) The procedure and conditions of reaction followed the method for the synthesis of 16, using 6 (0.05 g, 0.11 mmol), triphenylphosphine (0.08 g, 0.32 mmol) and carbon tetrachloride (0.19 g, 1.2 mmol) .The product was isolated as a dark blue solid (52.5 mg, 85% yield), melting point 201.2-203.1 ° C; XH NMR (CDC13 / CD30D) 5: 3.0 (s, 6H, 2 X CH3N), 3.5 (t, 4H, 2 x CH2NCH2), 3.6 (t, 4H, 2 x CH2NCH2), 3.9 (q, 4H, 2 x CH2NRAr), 7.2 (s, 2H, ArH), 7.4 (s, 2H, ArH), 10.6 (t, 2H, 2 x NHAr); IR vraax (KBr) cm "1: 3,600-3,300 (OH), 1,580 (C = 0), 1,230 (NH); ?? (CH3OH / DMSO) = 27.026 cm "1; Amax (666 nm); FAB-MS, m / z (M + H) + 509; Anal. (C24H30N4O4Cl2 | 2HC1 · 2H20) C, H, N. Example 18: 1,4-bis Dihydrochloride [ { 2 - [2 - (chloroethyl) (methyl) amino] ethyl} amino] anthracene-9,10-dione (16) Triphenylphosphine (0.086 g, 0.33 mmol) , then carbon tetrachloride (0.15 g, 1.32 mmol) were added to a stirred solution of 3 (0.05 g, 0.11 mmol) in a mixture of CH2C12 (4.0 cm3) and CH3CN (1.0 cm3) under nitrogen. allowed to stir at room temperature for 48 hours.The crude product was precipitated by the addition of dry ethereal hydrogen chloride, isolated by filtration and dried under vacuum.The solid residue was dissolved in a minimum amount of CH2Cl2 / EtOH (1: 1) at 60 ° C and was isolated from the by-product of triphenylphosphine oxide and excess triphenylphosphine by precipitation with EtOH / EtOAc (1: 1). The product was isolated as a dark blue solid (47.4 mg, 79% yield), melting point 185.4-186 ° C; RN ¾ (CD30D / CDC13) 5: 3.1 (s, 6H, 2 x CH3N), 3.6 (t, 4H, 2 X CH2CH2N), 3.7 (t, 4H, 2 x CH2CH2N), 3.9 (q, 4H, 2 x CH2NRAr), 3.95 (t, 4H, 2 x CH2CH2N), 7.6 (s, 2H, ArH), 7.8 (m, 2H, Ar-H), 8.3 (m, 2H, Ar-H), 10.1 (t, 1H , NHAr); IR vmax (KBr) crrf1: 3,550-3,310 (NRH), 1,600 (C = 0), 1,230 (N-H); ?? (CH30H / DMS0) = 12.027 cm "1; Amax (638 nm); FAB-MS, m / z (M + H) + 477; Anal. (C24H30N4O2Cl2 · 2HC1 · 2H20) C, H, N. Example 19: 1- [. {3 - [2 - (Chloroethyl) (methyl) amino] propyl} amino] anthracene-9,10-dione hydrochloride (17) The procedure and the reaction conditions follow the method for the synthesis of 12, using 10 (0.05 g, 0.15 mmol), triphenylphosphine (0.078 g, 0.3 mmol) and carbon tetrachloride (0.137 g, 0.9 mmol) The product was isolated as a red solid (35.5 mg, 60%) , melting point 205-207 ° C; XH NMR (CD30D) d: 2.25 (m, 2H, CH2CH2CH2), 3.1 (s, 3H, CH3N), 3.4 (t, 2H, CH2CH2N), 3.54 (t, 2H, CH2CH2N), 3.7 (q, 2H, CH2NArH), 4.0 (t, 2H, CH2Cl), 7.3 (d, 1H, Ar-H), 7.7 (m, 2H, Ar-H), 7.8 (m, 2H, Ar -H), 8.2 (d, 1H, Ar-H), 8.3 (d, 1H, Ar-H), 10.1 (t, 1H, NHAr), IR vmax (KBr) cm "1: 3,550-3,310 (NRH) , 1,600 (C = 0), 1,230 (NH); ?? (CH3OH / DMSO) = 1.297.5 cm "1; Amax (498 nm); FAB-MS, m / z (M + H) + 357; Anal. (C20H19N2O2Cl-HCl) C, H, N.

Example 20: 1,4-bis-Dihydrochloride. { 3- [bis (2-chloroethyl) amino] propyl} amino] anthracene-9, 10-dione (18) The procedure and the reaction conditions follow the method for the synthesis of 16, using 2 (0.05 g, 0.095 mmol), triphenylphosphine (0.15 g, 0.57 mmol) and tetrachloride of carbon (0.346 g, 2.28 mmol). The product was isolated as a dark blue solid (44.9 mg, 70% yield), melting point 187.2-188.9 ° C; NMR? (CDCl3 / CD3OD) d: 2.2 (m, 4H, 2 x CH2CH2CH2), 3.5 (t, 4H, 2 x CH2N), 3.6 (t, 8H, 4 X CH2N), 3.7 (q, 4H, CH2NAr), 3.9 (t, 8H, 4 x CH2C1), 7.4 (s, 2H, ArH); 7.7 (m, 2H, ArH); IR vmax (KBr) crn "1: 3,550-3,310 (NRH), 1,600 (C = 0), 1,230 (N-H); (CH30H / DMS0) = 2, 171 cm" 1; Amax (642 nm); FAB-MS, m / z. { M + K) + 603; Anal. (C28H36N402C14 · 2HC1 | 2H20) C, H, N; C, 47.23, H, 5.95, N, 7.87. Found: C, 47.89, 6.35, 7.39. Example 21: 1,4-bis Dihydrochloride. { 2 - [bis (2-chloroethyl) amino] ethyl} amino] anthracene-9, 10-dione (19) The procedure and the reaction conditions follow the method for the synthesis of 16, using 1 (0.05 g, 0.09 mmol), triphenylphosphine (0.144 g, 0.5 mmol) and carbon tetrachloride (0.32 g, 2.1 mmol). The product was isolated as a dark blue solid (35.4 mg, 64% yield), melting point 194-196 ° C; NMR? (CD30D / CDC13) d: 3.6 (t, 4H, 2 x CH2CH22N), 3.64 (t, 8H, 4 x CH2CH2N), 3.9 (q, 4H, 2 x CH2NHAr), 4.0 (t, 8H, 4 x CH2C1) 7.3 (d, 1H, Ar-H), 7.7 (m, 2H, Ar-H), 7.8 (m, 2H, Ar-H), 8.2 (d, 1H, Ar-H), 8.3 (d, 1H, Ar -H); IR vmax (KBr) cm "1: 3,550-3,310 (NRH), 1,600 (C = 0), 1,230 (N-H); ?? (CH3OH / DMSO) = 8, 570 cm "1; Amax (638 nm); FAB-MS, m / z (M + H) + 575; Anal. (C26H32N402C14 | 2HC1) C, H, N. Example 22: 1- [. {2 - [2 - (Chloroethyl) (methyl) amino] ethyl} amino] anthracene-9,10-dione hydrochloride (20) The procedure as 16 using triphenylphosphine (0.16 g, 0.6 mmol) , carbon tetrachloride (0.28 g, 1.8 mmol), 9 (0.1 g, 0.31 mmol) in CH2C12 (5.0 cm3) The product was isolated as a red solid (93.5 mg, 80% yield), mp 207.1- 209.2 ° C; XH NMR (CD30D / CDC13) d: 3.1 (s, 3H, CH3N), 3.5 (t, 2H, CH2CH2N), 3.7 (t, 2H, CH2CH2N), 3.9 (q, 2H, CH2NHAr), 3.95 (t, 2H, CH2C1), 7.3 (d, 1H, Ar-H), 7.7 (m, 2H, Ar-H), 7.8 (m, 2H, Ar-H), 8.2 (d, 1H, Ar-H ), 8.3 (d, 1H, Ar-H), 10.1 (t, 1H, NHAr), IR vraax (KBr) cm "1: 3,550-3,310 (NRH), 1,600 (C = 0), 1,230 (NH); ?? (CH3OH / DMSO) = 6,963 cm "1; Amax (488 run); FAB-MS, m / z (M + H) + 343; Anal. (C19H19N202C1 · HCl) C, H, N. Example 23: General Method for Synthesis of aminoalkylamino secondary chains Synthesis of the secondary chains of l- (2-aminoethyl) pyrrolidine and piperidine was a two-step procedure.The cyclic secondary amine was alkylated by bromoacetoni -tryl (dry Et3N, THF, 45- 50 ° C, 30 minutes, yield 63-92%) and the nitrile was converted to a primary amine by reduction with LiAlH4 (THF, reflux, 5 hours, yield 27-76%) This general method was used for 2-, 3- and 4-hydroxyl piperidines, 2- and 3-hydroxyl pyrrolidines and 2- and 6-bishydroxy-methyl-piperidines.

Example 24: General Methods for Synthesis of Aminoanthraquinones Treatment of 1,4-difluoro-5,8-dihydroxyanthraquinone with N, N-dimethylethylenediamine led to a mixture of the di- and mono-substituted anthrachonones from which it was isolated. intermediate HAQ107 by flash chromatography (N, N-dimethylethylenediamine, C5H5N, 22 ° C, 24 hours, 34%) (Scheme 2, Figure 3). Pure HAQ107 was then treated with the piperidine or pyrrolidine side chains to produce the target compounds (HAQ71, HAQ73, HAQ110, HAQ111 and HAQ121) and the non-hydroxylated analog HAQ148 in good yield after purification (Amine, C5H5N, 90 ° C, 30 minutes to 1 hour, 51-65%). HAQ70 and HAQ105, the anthraquinones configured symmetrically, were synthesized in a step by ipso substitution of both fluoro groups with C with secondary chains of l- (2-aminoethyl) -piperidine (C5H5N, 90 ° C, 1 hour, 34- 37%) (Scheme 3, Figure 4). The preparation of the chloropropylaminoanthraquinones CAQ74 and CAQ75 was carried out by treating the precursor alcohols (HAQ70 and HAQ71 respectively) with triphenylphosphine-carbon tetrachloride, a complex reagent, commonly used for the conversion of alcohols to corresponding halides (Ph3P, CC14, CH2C12 , reflux, N2, 5 hours, 68-81%). Synthesis of W-Acetonitrile-Piperidines and Hydroxylated Pyrrolidines Example 25: 3-Hydroxy-piperidin-1-yl-acetonitrile (SI) BrCH2CN (3.19 g, 25.82 mmol) was added dropwise to a solution of 3-hydroxypiperidine (6.53 g, 64.55 mmol) in dry THF (25 mL) under N2, maintaining the temperature between 45-50 ° C. After addition of BrCH2CN, the solution was refluxed for 30 minutes, before allowing the solution to cool to room temperature. The solvent was removed in vacuo and the residual oil was purified by flash chromatography using CH2Cl2: CH3OH (9: 1) as an extractor. The title compound was obtained as a straw colored oil (3.04 g, 83%). d? (250 MHz, CDC13): 1.9-2.15 (m, 3H, CH2CH2CH2, 1 x CH2CH2CHOH), 2.25 (m, 1H, 1 x CH2CH2CHOH), 2.55 (d, OH), 2.85-3 (m, 3H, NCH2CH2, 1 x NCH2CH), 3.1 (2xd, 1H, 1 x NCH2CH), 3.9 (s, 2H, NCH2CN) and 4.3 (m, 1H, CH2CHOH); FAB MS, m / z (+ H) + 141. Example 26: 3 -Hydroxymethyl -piperidin-1-yl-acetonitrile (S2) The method follows that of SI using 3-piperidinemethanol (4.79 g, 41.59 mmol), BrCH2CN ( 1.99 g, 16.64 mmol) and dry THF (25 mL). The title compound was produced as a straw colored oil (2.35 g, 92%) after flash chromatography using CH2C12 / CH30H (9: 1) as an extractor. d? (250 MHz; CDC13): 1.05 (m, 1H, CHCH2OH), 1.5-1.9 (m, 5H, OH, CH2CH2CH2 and CH2CH2CH), 2.15 (t, 1H, J = 10 Hz, 1 x NCH2CH), 2.35 (3xd , 1H, J = 4 Hz and J = 10 Hz, 1 x NCH2CH2), 2.7 (m, 1H, 1 x NCH2CH2), 2.85 (2xd, 1H, J = 4 Hz and J = 12 Hz, 1 x NCH2CH), 3.52 (s, 2H, NCH2CN) and 3.45-3.65 (m, 2H, CHCH2OH); 5C (62.9 MHz, CDCl3): 24.43, 26.14, 38.55, 46.75, 52.83, 55.73, 65.88 and 114.74 (CN); FAB MS, m / z (M + H) + 155.

Example 27: 4-Hydroxy-piperdin-1-yl-acetonitrile (S3) BrCH2CN (28.55 g, 0.238 mmol) was added dropwise to a solution of 4-hydroxypiperidine (24.98 g, 0.216 mol) and Et3N (33.18 mL, 0.238 mmol) in dry THF (100 mL) under N2, maintaining the temperature between 45-50 ° C. After the addition of BrCH2CH, the solution was refluxed for 30 minutes, before allowing the solution to cool to room temperature. The title compound was produced as a straw-colored oil (18.97 g, 63%) after purification by flash chromatography using ether / CH30H (19: 1) as an extractor. d? (250 MHz, CDC13): 1.65 (m, 2H, 1 x CHCH2CH and 1 x CHCl2CH2), 1.75 (s, 1H, OH), 1.95 (m, 2H, 1 x CH2CH2CH, 1 x CHCH2CH2), 2.45 (m, 2H, 1 x NCH2CH2 and 1 x NCH2CH2), 2.78 (m, 2H, 1 x NCH2CH2 and 1 x NCH2CH2), 3.55 (s, 2H, NCH2CN) and 3.75 (m, 1H, CH2CHOH); £ c (62.9 MHz, CDCl3): 33.96, 46.09, 49.73, 66.58 and 114.71 (CN); IR v ^ / cm "1; 3.375 (broad), 2,230, 1,420, 1,330, 1,150 and 1,060; FAB MS, m / z (M + H) + 141. Example 28: 2-Hydroxymethyl-piperidin-1-yl- acetonitrile (S4) The method follows that of S3 using 2-piperidinemethanol (26.50 g, 0.230 mol), BrCH2CN (30.35 g, 0.253 mol), Et3N (35.27 mL, 0.253 mol) and dry THF (150 mL). The crude product was purified by flash chromatography using ether / CH30H (19: 1) as an extractor. The title compound was crystallized from ether to yield cream crystals (31.46 g, 89%). d? (250 MHz, CDC13): 1.2-1.85 (m, 6H, NCH2CH2CH2, CH2CH2CH2CH and CH2CH2CH), 2.05 (s (broad), 6H, OH), 2.4 (m, 1H, NCH2CH2), 2.55 (3xd, 1H, 1 x NCH2CH2), 2.95 (m, 1H, NCHCH2), 3.45 (d, 1H, J = 17 Hz, 1 x NC¾CH), 3.5 (2xd, 1H, J = 3 Hz and 12 Hz, 1 x CHCH2OH), 3.76 (2xd , 1H, J = 3 Hz and 12 Hz, CHCH2OH) and 4.05 (d, 1H, J = 17 Hz, 1 x NCH2CN); 5C (62.9 MHz; CDC13): 23.71, 25.25, 28.69, 43.43, 54.04, 60.73 and 115.05 (CN); FAB MS, m / z (M + H) + 155; IR vmax / cm ^; 3,400 (OH, broad m), 2,350 and 2,240 (CN) and 1,650. Example 29: 2-Hydroxymethyl-pyrrolidin-1-yl-acetonitrile (Sil) The method follows that of S3 using 2-pyrrolidinemethanol (24.27 g, 0.241 mol), BrCH2CN (31.81 g, 0.265 mol), Et3N (37 mL, 0.265) mol) and dry THF (150 mL). The product was obtained as a straw-colored oil (21.60 g, 64%) after purification by flash chromatography using ether / CH3OH (19: 1). d? (250 MHz, CDCl 3): 1.5-2.0 (m, 5H, CH2CH2CH2, CH2CH2CH, OH), 2.7 (m, 1H), 2.85 (m, 1H), 3.05 (m, 1H), 3.45 (2xd, 1H, J = 4 Hz and J = ll Hz, 1 x CHCH2OH), 3.65 (2xd, 1H, J = 4 Hz and 11 Hz, 1 x CHCH2OH) and 3.75 (d, 2H, NCH2CN); 5C (62.9 MHz; CDC13): 23.37, 27.45, 40.96, 53.95, 62.43, 63.06 and 115.48 (CN); IR v ^ / cm "1; 3,375 (NH2), 3,300 (NH2), 3,200 (OH), 2,970-2,800 (CH2, CH3), 1,600, 1,475, 1,375, 1,230 and 1,060; FAB MS, m / z (M + ) + 141. Example 30: 3-Hydroxy-pyrrolidin-1-yl-acetonitrile (S12) The method follows that of S3 using 3-hydroxypyrrolidine (15 g, 0.172 3 mol), BrCH2CN (22.67, 0.189 mmol) and dry THF (60 mL) The title compound was produced as a straw-colored oil (15.39 g, 71%) after flash chromatography using CH2C12 / CH30H (9: 1) as an extractor d (250 MHz, CDC13): 1.9 -2.25 (m, 2H, 2 x H-ring), 2.3 (m, 1H, H-ring), 2.65 (d, OH), 2.85-3.05 (m, 3H, 3 x H-ring), 3.95 (d, 2H , NCH2CN) and 4.2 (m, 1H, CH2CH0H); FAB MS, m / z. { M + U) + 127. Example 31: 2, 6-Bis-hydroxymethyl-piperidin-1-yl-acetonitrile (S5) Step 1: 2,6-Piperidinemethanol (S15). 2, 6-Pyridine-dimethanol (15 g, 107.9 mmol) was suspended in glacial acetic acid (250 mL) and hydrogenated at atmospheric pressure and room temperature for 48 hours using Pt02 (1.5 g) as a catalyst. The catalyst was then removed by filtration through celite and the acidic solution was concentrated in vacuo to obtain an oily residue. The oil was diluted with EtOAc (50 mL) and stirred at ice temperature. A saturated solution of brine and concentrated ammonia (pH-12) was added slowly until the pH was 11-12. The organic phase was then separated from the aqueous phase, which was extracted with EtOAc (3 x 50 mL). The combined organic phases were dried (MgSO 4) followed by filtration and evaporation of solvent under vacuum to yield a straw colored oil (5.21 g, 33%). FAB MS, m / z (M + H) + 146. Step 2. The method follows that of S5. 2,6-piperidinedi-methanol (3.80 g, 26.21 mmol), iodoacetonitrile (5.24 g, 31.45 mmol), Et 3 N (4.38 mL, 31.45 mmol) and dry DMF (20 mL). Purification by flash chromatography using CH2C12 / CH30H (9: 1) as an extractant afforded the title compound as a straw colored oil (2.5 g, 53%). FAB MS, m / z (M + H) + 185. Iodoacetonitrile was prepared by the use of Finkelstein reaction. BrCH2CN (3.77 g, 0.0314 mmol) was added dropwise to a stirred solution of Nal 25 (4.71 g, 0.031 mmol) in acetone. Precipitation of NaBr occurred within a few minutes and indicated that halide exchange had taken place. Sodium bromide was filtered, and the acetone was removed in vacuo.

Crude yield (5.24 g, 100%). Synthesis of W-2 -Aminoethyl Piperidines and Hydroxylated Pyrrolidines Example 32: 1- (2-Amino-ethyl) -piperidin-3 -ol (S6) LiAlH4 (2.44 g, 64.2 mmol) was added to dry THF (20 mL) at 0 ° C in a three neck round bottom flask under N2. The solution was stirred for 15 minutes before the 3-hydroxypiperidin-1-yl-acetonitrile (3 g, 21.4 mmol), diluted in dry THF (5 mL), was added slowly by syringe. The reaction mixture was then refluxed for 5 hours before allowing the solution to cool to room temperature. Excess LiAlH4 was destroyed by the addition of 2.4 mL of H20, 2.4 mL of NaOH (15%) and finally EtOAc was added dropwise until no effervescence was observed. The granular precipitate formed (lithium hydroxide and aluminum hydroxide) was filtered and washed several times with CH2C12 and EtOAc. The organic layer was dried (MgSO4) and the solvent was removed in vacuo to yield a thick yellowish oil. The title compound was purified by Kugelrohr disttion (172 ° C, 0.05 mbar) and obtained as a straw-colored oil (1.95 g, 63%). d? (250 MHz, CDC13): 1.45-1.7 (m, 3H, CH2CH2CH2, 1 x CH2CH2CHOH), 1.76 (m, 1H, 1 x CH2CH2CHOH), 1.95 (s, 3H, OH, NH2), 2.25-2.55 (m, 6H, H2NCH2CH2, NCH2CH2 (NCH2CH), 2.75 (t, 2H, H2NCH2H2), and 3.9 (m, 1H, CH2CHOH ); 5C (62.9 MHz; CDCl3): 21.93, 32.01, 38.88, 53.84, 60.80, 61.06 and 66.36; FAB MS, m / z (M + K) + 145. Example 33: [1- (2-Amino-ethyl ) -3-piperidin-2-yl] -methanol (S7) The method follows that of S6 using 3-hydroxymethyl-piperidin-1-yl-acetonitrile (2.95 g, 19.1 mmol), LiAlH4 (2.18 g, 57.3 mmol) and dry THF (15 mL) The title compound (2.30 g, 76%) was produced as a colorless oil by Kugelrohr disttion. (164 ° C, 0.01 mbar). d? (250 MHz, CDC13): 1.1 (m, 1H, CHCH2OH), 1.5-1.9 (m, 7H, OH, NH2, CH2CH2CH2 and CH2CH2CH), 1.95 (t, 1H, J = 10 Hz, 1 x NCH2CH), 2.1 (3xd, 1H, J = 3 Hz and 10 Hz, 1 x NCH2CH2), 2.4 (t, 2H, J = 6Hz, H2NCH2CH2N), 2.6 (m, 1H, 1 x NCH2CH2), 2.8 (t, 3H, J = 6 Hz, H2NCH2CH2N and 1 x NCH2CH), 3.45-3.65 (m, 2H, CHCH20H ); 5C (62.9 MHz, CDCl3): 24.66, 27.50, 38.19, 38.91, 54.54, 57.43, 61.61 and 66.55; IR v ^ / cm "1: 3.375 (broad), 1,675, 1,625, 1,450, 1,100 and 1,050; FAB MS, m / z { M + K) + 159. Example 34: 1- (2-Amino-ethyl ) -piperidin-4 -ol (S8) The method follows that of S6 using 4-hydroxy-piperidin-1-yl-acetonitrile (18.97 g, 0.136 mol), LiAlH4 (15.48 g, 0.408 mol) and dry THF (150 mL) The title compound (8.56 g, 44%) was produced as a straw colored oil after Kugelrohr disttion (178 ° C, 0.05 mbar) d (250 MHz, CDC13): 1.55 (m, 2H, 1 x CHCH2CH2 and 1 x CH2CH2CH), 1.85 (m, 2H, 1 x CHCH2CH2 and 1 x CH2CH2CH), 2-2.25 (m, 5H, NCH2CH2, NCH2CH2 and OH), 2.38 (t, 2H, H2NCH2CH2N), 2.72 (t, 4H, H2NCH2CH2N, NH2) and 3.65 (m, 1H, CH2CHOH); 5C (62.9 MHz; CDCl3): 34.56, 38.98, 51.35, 60.84 and 67.64; FAB MS, m / z (M + H) + 145; IR ^ / cm "1: 3.375 (broad), 1,600, 1,460, 1,370, 1,290 and 1,070. Example 35: [1- (2-amino-ethyl) -piperidin-2-yl] -methanol (S9) method follows that of S6 using 2-hydroxymethyl-1-piperdin-1-yl-acetonitrile (31.96 g, 0.208 mol), LiAlH4 (23.68 g, 0.624 mol) and dry THF (200 mL) The title compound (8.74 g) , 27%) was produced as a straw colored oil after Kugelrohr disttion (225 ° C, 0.13 mbar) d (250 MHz, CDC13): 1.2-1.75 (m, 6H, CH2CH2CH2, CH2CH2CH and CH2CH2CH), 2.2 ( m, 1H, 1 X NCH2CH2), 2.35 (m, 2H, H2NCH2CH2N), 2.58 (s (broad), 3H, OH and NH2), 2.75 (t, 2H, H2NCH2CH2N), 2.85 (3xd, 1H, 1 x NCH2CH2), 2.92 (m, 1H, NCHCH2) , 3.4 (2xd, 1H, J = 4 Hz and 12 Hz, 1 x CHOH2OH) and 3.76 (2xd, 1H, J = 4 Hz and 12 Hz, 1 x CHCH2OH); FAB MS, m / z (M + H) + 159. Example 36: [1- (2-amino-ethyl) -piperidin-bis-2,6,6-yl] -methanol (S10) The method follows that of S6 using 2,6-bis-hydroxymethyl-piperidin-1-yl-acetonitrile (2.40 g, 13.04 mmol), LiAlH 4 (1.49 g, 39.13 mmol) and dry THF (30 mL). The title compound was produced as a straw colored oil without purification (1.03 g, 42%). It was found necessary to stir the dried destroyed LiAlH4 complex in dry THF for 10 hours at 40 ° C to optimize the yield of the desired dihydroxylated diamine. FAB MS, n? / Z (M + H) + 189. Example 37: [1- (2-Amino-ethyl) -pyrrolidin-2-yl] -methanol (S13) The method follows that of S6 using 2-hydroxymethyl-pyrrolidin-1-yl-acetonitrile (19.5 g, 0.139 mol), LiAlH4 (15.84 g, 0.417 mol) and dry THF (150 mL). The title compound (12.5 g, 63%) was produced as a straw colored oil by Kugelrohr distillation (142 ° C, 0.3 mbar). d? (250 Hz; CDC13): 1.6-1.9 (m, 4H, CH2CH2CH2, CH2CH2CH), 1.98 (s (broad), 3H, NH2, OH), 2.3 (m, 1H), 2.45 (m, 1H), 2.55 ( m, 1H), 2.75-2.85 (m, 3H), 3.19 (m, 1H, NCHCH2), 3.4 (2xd, 1H, J = 3 Hz and J = ll Hz, 1 x CHCH2OH), 3.6 (2xd, 1H, J = 3 Hz and J = ll Hz, 1 x CHCH2OH); IR v ^ / cm "1: 3,375 (NH 2), 3,300 (NH 2), 3,200 (OH), 2,970-2,800 (CH 2, CH 3), 1,600, 1,475, 1,375, 1,230 and 1,060; FAB MS, m / z (M + H) + 145. Example 38: l-Amino-ethyl-pyrrolidin-3-ol (S14) The method follows that of S6 using 3-hydroxy-pyrrolidin-1-yl acetonitrile (15 g, 0.107 mol), LiAlH4 ( 10.17 g, 0.268 mol) and dry THF (150 mL) The title compound (9.55 g, 69%) was produced as a straw colored oil and used for the next step without further purification. D? (250 MHz; CDC13 ): 1.55-1.85 (m, 2H, 2 x H-ring), 2.05 (s, 3H, OH, NH2), 2.25-2.55 (m, 6H, 4 x H-ring and H2NCH2CH2N), 2.9 (t, 2H , H2NCH2CH2N) and 4.05 (m, 1H, CH2CHOH); FAB MS, m / z (M + H) + 131. Preparation of Chromophores Example 39: 1,5-Diamino-4,8-dihydroxyanthraquinone In a round-bottomed flask of 2 liters was placed 1,5-diaminoanthracene-9,10-dione (12 g, 50 mmol) Concentrated sulfuric acid (180 g) was added and the mixture was stirred for 15 minutes at 0 ° C before adding sodium chlorate (14.4 g, 134 mmol) in portions over 45 minutes. The reaction mixture was allowed to warm to room temperature where it was allowed to stir for 3 hours before it was poured into a 1% solution of cooled sodium hydrogenated sulfite (1 L). The precipitated solid was removed by filtration and washed successively with cold water and then hot water. After lyophilization overnight, the product (11.3 g, 83%) was obtained as a crude purple-blue solid. FAB MS, m / z (M + H) + 271. Example 40: 5-8-Dihydroxyleucoquinizarin (leuco-1,4,5,8-tetrahydroxy-tetraquinone) (B) A 1,5-diamino-4,8 crude dihydroxyanthraquinone (11 g, 0.041 mmol) was added NaOH (2.5 M, 200 mL) and the suspension was refluxed gently for 3 hours before it was allowed to cool to room temperature. Hydrogenated sodium sulphite (31.74 g, 0.182 mol) was added in portions and the reaction mixture was refluxed again for 3 hours. It was cooled to room temperature and acidified with concentrated hydrochloric acid to pH 3. The precipitate was isolated by filtration and washed successively with cold water and then hot water. After lyophilization overnight, the title compound was produced as a crude brown solid (8 g, 73%). FAB MS, m / z (M + H) + 251. Example 41: 1, 4-Difluoro-5,8-Dihydroxyanthraquinone (C) A mixture of ground AlCl 3 (2,955 g, 22.16 mmol), NaCl (432 mg, 7.39 mmol), 1,4-dihydroxybenzene (224 mg, 2.03 mmol) and dry 3,6-difluorophthalic acid (340 mg, 1.85 mmol) were vigorously stirred in a round bottom flask and heated to 220 ° C. in an oil bath for 3 hours. The oil bath was removed and the reaction was quenched by the addition of iron and concentrated hydrochloric acid (10 mL). The final aqueous solution was filtered under suction and the precipitated material was washed with water followed by freeze drying. No additional work was required, as the coffee title compound (470 mg, 92%) was pure as observed by TLC and confirmed by NMR and MS: d? (250 MHz, CDC13): 7.3 (s, 2H), 7.55 (m, 2H), 12.9 (s, 2H); FAB MS, m / z (M + H) + 277. Example 42: 1- [[2- (Dimethylamino) ethyl] amino] -4-fluoro-5,8-dihydroxyanthracene-9,10-dione (HAQ107) 1 , 4-Difluoro-5,8-dihydroxyanthraquinone (0.50 g, 1812 mmol), N, N-dimethylethylenediamine (0.16 g, 1812 mmol) and pyridine (3 mL) were stirred for 24 hours at room temperature. The mixture was quenched in cold brine (50 mL) and left for 3 hours before the crude product was isolated by filtration. The crude product was subjected to chromatography using an extraction gradient of 1 to 5% MeOH in CH2C12. The HAQ107 product was produced as a purple powder (0.24 g, 38%). d? (250 MHz, CDC13): 2.35 (s, 6H, 2 x NCH3), 2.7 (t, 2H, HNCH2CH2N), 3.5 (q, 2H, HNCH2CH2N), 7.1 (s, 1H), 7.1 (s, 1H), 7.4 (s, 2H, C (6) H and C (7) H), 10.75 (t, 2H, C (1) NH and C (4) NH) and 13.4 (s, 2H, C (5) OH and C (8) OH); 5C (62.9 MHz; D SO); FAB MS, m / z (M + H) + 344. Chromophore Substitution Reactions Examples 43 and 44: Animation of Leucoquinizarin and 5,8-Dihydroxy-leucoquinizarin l-. { [(2-Dimethylamino) ethyl] amino} -4-. { [2- (3-hydroxy-piperidin-1-yl) ethyl] amino} -anthracene- 9, 10-dione (HAQ22) and 1,4-Bis. { [2- (3-Hydroxy-piperidin-1-yl) ethyl] -amino} -anthracene- 9, 10-dione (HAQ24) N, -dimethylethylenediamine (0.92 g, 10.42 mmol) and l- (2-aminoethyl) -3-piperidin-3-ol (1.50 g, 10.42 mmol) in EtOH (5 mL ) were added simultaneously to a suspension of leucoquinizarin (0.63 g, 2.61 mmol) in EtOH (25 mL) under N2. After 8 hours of stirring at reflux temperature, the reaction mixture was stirred at room temperature another 14 hours. The EtOH was removed in vacuo and the remaining residue was added to ice-cold brine. The precipitated solid was isolated by filtration and lyophilized. The dark blue solid was subjected to flash chromatography on a short first column by using CH2C12 to remove non-polar by-products, then by increasing the polarity gradually by removing more by-products and finally by using CH2Cl2 / CH3OH (4: 1), obtaining the desired raw components. The crude solid was subjected to flash chromatography using CH2Cl2 / CH3OH / NH3 (94: 6: 0.75) as an extractor. To obtain pure components, a final purification was made by preparative TLC using CH2C12 / CH30H / NH3 (94: 6: 0.75) as an extractor. HAQ22 and HAQ24 were produced as dark blue solids (0.12 g, 10% and (0.16 g, 12%), respectively. HAQ22. d? (250 MHz, CDCl3): 1.5 (m, 2H, CH2CH2CH2), 1.8 (m (1H, 1 x CH2CH2CH), 2.0 (m, 1H, 1 x CH2CH2CH), 2.2 (t, 1H, 1 x NCH2CH2), 2.3 (s, 6H, 2 x NCH3), 2.5 (d, 1H, 1 x NCH2CH), 2.6-2.8 (m, 7H, 2 x NCH2CH2N, 1 x NCH2CH and OH), 3.4 (m, 4H, 2 x H2NCH2CH2N), 3.9 (m, 1H, CH2CH2OH), 7.1 (d, 2H, C (2) H, C (3) H), 7.62 (m, 2H, C (6) H, C (7) H), 8.32 (m, 2H, C (5) H, C (8) H), 10.75 (t, 2H, C (l) NH) and 11 (t, 1H, C (4) H); 5C (62.9 MHz; CDCl3): 21.18, 31.47, 10 39.72, 41.13, 45.72, 53.05, 56.05, 58.63, 60.06, 65.99, 110.15, 123.55, 126.16, 131.97, 134.48, 145.78 and 182.41; FAB MS, m / z (M + H) + 437; IR viax / cm: 3,450 (broad, OH), 3,220 (NH), 3,020 (Ar-CH), 2,960-2,800 (CH 2, CH 3), 1,650, 1,625, 1,575, 1,480, 1,380 and 1,220. HAQ24. d? (250 MHz, CDC13): 1.5-1.9 (m, 10H, 8 x H-ring and 2 x OH), 15 2.1 (m, 2H, 2 x H-ring), 2.25 (m, 2H, 2 x ring- H), 2.5 (d, 2H, 2 x H-ring), 2.75-2.95 (m, 6H, 4 x H-ring and 2 x HNCH2CH2N), 3.5 (q, 4H, 2 x HNCH2CH2N), 3.95 (m, 2H, 2 x CH2CHOH), 7.2 (s, 2H, C (2) H and C (3) H), 7.65 8m, 2H, C (6) H and C (7) H), 8.35 8m, 2H, C (5) H and C (8) H) and 11.0 (t, 2H, C (1) NH and C (4) NH); FAB MS, m / z (M + H) + 493. Example 45: Schemes 2 and 3 The reaction schemes are shown in schemes 2 (figure 3) and 3 (figure 4). In these schemes, step (I) is the addition of a secondary chain of amino alkyl amino carried out in pyridine at 90 ° C for 30 minutes at 1 hour; step (II) is chlorination carried out using (Ph) 3PCCly and CH2C12 and a reflux for 3 to 10 hours using ethereal HCl. In scheme 3, step (III) is an additional secondary chain link passage carried out under reflux in ethanol; and step IV is chlorination of the secondary chain hydroxyl groups carried out in pyridine at 30-60 ° C for 2 to 5 hours, using ethereal HCl. Example 46: 1, 4-Bis. { [2 - (3-Hydroxymethylpiperidin-1-yl) ethyl] amino} -5,8-dihydroxyanthracene-9,10 -dione (HAQ70) [1- (2-aminoethyl) -piperidin-3-yl] -methanol (1.9 g, 12 mmol) in EtOH (2.5 mL) was added to a suspension stirring of 5,8-dihydroxyleucoquinizarin (272 mg, 1 mmol) in EtOH (15 mL) under N2. After 7 hours of stirring at reflux temperature, the reaction mixture was cooled to room temperature and stirred for another 16 hours. The EtOH was removed in vacuo and the remaining residue was added to ice-cold brine. The precipitated solid was isolated by filtration and lyophilized. The dark blue solid was subjected to flash chromatography using CH2C12 followed by gradual increase in polarity to CH2Cl2 / CH3OH (4: 1). Subsequently, the crude product was subjected to flash chromatography using CH2Cl2 / CH3OH / NH3 (94: 6: 0.75) as an extractor. The title compound was produced as a dark blue solid (115.9 mg, 21%). Melting point 180-183 ° C. d? (250 MHz; CDC13): 1.1-1.95 (m, 12H, 2 x OH and 10 x H-ring), 2.25 (m, 4H, 4 x H-ring), 2.7 (t, 6H, 2 x HNCH2CH2N and 2 x H-ring ), 2.95 (2xd, 2H, 2 x H-ring), 3.5 (m, 4H, 2 x HNCH2CH2), 3.65 (m, 4H, 2 x CHCH2OH), 7.1 (s, 2H C (2) H and C (3) H), 7.2 (s, 2H, C (6) H and C (7) H), 10.5 (t, 2H, C (1) NH and C (4) NH) and 13.6 (s, 2H, C (5) OH and C (8) OH); 5C (62.9 MHz; CDC13); FAB MS, m / z. { M + U) + 553; IR v ^ / cm "1: 3,400 (OH), 3,225 (NH), 20 3,100 (Ar-CH), 2,960-2,800 (CH2, CH3), 1,650, 1,625, 1,575, 1,480, 1,370 and 1,225; Analytical calculation for C30H40N4O6: C, 65.20; H, 5.47; N, 10.14, Found: C, 65.16; H, 5.49; N, 9.93, Example 47: l, 4-Bis- { [2- (3-Hydroxymethylpiperdin-l- il) ethyl] amino.}. -antracene-9,10-dione (HAQ38) Although not shown in scheme 3 (figure 4), the method follows that of HAQ70 using leucoquinizarin (0.23 g, 0.95 mmol), [1 - (2-aminoethyl) -piperidin-3-yl] -methanol (0.06 g, 3.8 mmol) and ethanol (25 mL) The title compound was produced as a dark blue solid (0.15 g, 29%). fusion 112-114 ° C. (250 MHz, CDCl 3): 1.15 (m, 2H, 2 x CH 2 CHCH 2 OH), 1.5-1.75 (m, 6H, 2 x CH 2 CH 2 CH and 2 x CH 2 CH 2 CH 2), 1.85 (m, 2H, 2 x CH2CH2CH), 2.3 (m, 4H, 4 x H-ring), 2.5 (s) (broad), 4H, 2 x H-ring, 2 x OH), 2.65 (t, 4H, J = 5 Hz, 2 x HNCH2CH2N), 2.75 (2xd, 2H, J = 3 Hz and 12 Hz, 2 x H-ring), 3.42 (q, 4H, J = 5 Hz, 2 x HNCH2CH2N), 3.55 (2xd , 2H, J = 5 Hz and 12 Hz, 2 x CHCH2OH), 3.7 (2xd, 2H, J = 9 Hz and 12 Hz, 2 x CHCH2OH), 7.1 (s, 2H, C (2) H and C (3 ) H), 7.6 (m, 2H, C (6) H and C (7) H), 8.3 (m, 2H, C (5) H, C (8) H) and 10.75 (t, 2H, C ( 1) NH and C (4) NH); 5C (62.9 MHz; CDC13): 24.08, 26.92, 37.90, 40.52, 54.53, 56.95, 57.75, 65.70, 109.89, 123.87, 126.13, 132.09, 134.46, 146.6 and 182.36; FAB MS, m / z (M + H) + 521; IR v ^ cm'1: 3,400 (OH), 3,090 (Ar-CH), 2,960-2,800 (CH2, CH3), 1,650, 1,585, 1,550, 1,520, 1,265, 1,175 and 1,125. Analytical calculation for C30H40N4O4: C, 69.21; H, 7.74; N, 10.76. Found: C, 69.22; H, 7.88; N, 10.69. Ipso Substitution of 1,4-Difluoro-5,8-Dihydroxy-anthraquinone Fluorides by Diamine Example 48: 1- [(2-Dimethylamino) ethylamino] -4- [2- (3-hydroxymethyl-piperdin-1-yl) ethylamino] -5,8-dihydroxy-anthracene-9,10 -dione (HAQ71) The method follows that of HAQ105 using HAQ107 (200 mg, 0.581 mmol), [1- (2-amino-yl) -piperidin-3-yl) ] -methanol (350 mg, 2.215 mmol), pyridine (2 mL), 90 ° C, 30 minutes. The product was achieved as a dark blue powder (190 mg, 68%). Melting point 181-183 ° C. d? (250 MHz, CDCl3): 1.2 (m, 2H, 2 x H-ring), 1.6-1.9 (m, 5H, OH and 4 x H-ring), 2.18-2.3 (m, 2H, H-ring), 2.35 (s, 6H, 2 x NCH3), 2.6-2.75 (m, 4H, 2 x HNCH2CH2N), 2.9 (2xd, 1H, 2 x H-ring), 3.46 (m, 4H, 2 x HNCH2CH2N), 3.65 ( 2xd, 2H, CHCH2OH), 7.15 (s, 2H, C (2) H and C (3) H), 7.2 (s, 2H, C (6) H and C (7) H), 10.4 (t, 1H , C (l) H), 10.5 (t, 1H, C (4) H), 13.5 (s, 1H, C (8) H) and 13.6 (s, 1H, C (5) H); 5C (62.9 MHz; CDCl3): 24.33, 26.92, 38.29, 40.03, 40.87, 45.42, 54.23, 57.03, 58.20, 65.99, 108.97, 115.33, 123.43, 123.65, 124.51, 145.99, 146.09, 155.32, and 184.98; FAB MS, m / z (M + H) + 483; IR v ^ / cra'1: 3,425 (OH), 3,225 (H), 3,100 (Ar-CH), 2,975-2,800 (CH 2, CH 3), 1,650, 1,625, 1,575, 1,490, 1,360 and 1,225; Analytical calculation for C26H34N405: C, 64.71; H, 7.10; N, 11.61. Found: C, 64.81; H, 7.14; N, 11.56. Example 49: 1 - [(2-Dimethylamino) ethylamino] -4 - [2 - (3-hydroxy- piperidin-1-yl) ethylamino] -5,8-dihydroxy-anthracene-9,10 -dione (HAQ73) The method follows that of HAQ105 using HAQ107 (120 mg, 0.3495 mmol), [1- (2-aminoethyl) - piperidin-3 -ol (150 mg, 1047 mmol), pyridine (1 mL), 30 minutes, 90 ° C. The product was achieved as a dark blue powder (95 mg, 58%). Melting point 228-230 ° C. d? (250 MHz, CDC13): 1.55-1.75 (m, 4H, 4 x H-ring), 1.83-2.0 (m, 2H, 2 x H-ring), 2.28 (2xd, 1H, H-ring), 2.35 ( s, 6H, 2 x NCH3), 2.65-2.75 (2xt, 5H, 2xHNCH2CH2N and OH), 3.46 (m, 4H, HNCH2CH2N), 3.9 (m, 1H, NCH2CH0H), 7.1 (s, 2H, C (2) H and C (3) H), 7.15 (s, 2H, C (6) H and C (7) H), 10.4 (t, 1H, C (l) H), 10.6 (t, 1H, C (4 ) H), 13.4 (s, 1H, C (8) H) and 13.5 (s, 1H, C (5) H); 5C (62.9 MHz, DMSO): 21.48, 31.52, 39.99, 41.26, 45.61, 53.31, 56.14, 58.43, 60.20, 66.03, 109.11, 115.43, 115.48, 123.81, 124.70, 146.29, 155.51, and 185.24; FAB MS, m / z (M + H) + 469; IR v ^ / crn "1: 3,425 (OH), 3,240 (NH), 3,100 (Ar-CH), 2,975-2,800 (CH2, CH3), 1,650, 1,625, 1,575, 1,490, 1,375, and 1,225; Analytical calculation for C28H35N406: C, 64.09; H, 6.88; N, 11.96, Found: C, 63.88; H, 6.89; N, 11.98, Example 50: 1, 4-Bis- { [2- (2-hydroxymethylpiperidine-l- il) ethyl] amino.}. -5, 8 -dihydroxy -anthracene- 9,10 -dione (HAQ105) 1,4 -Difluoro-5,8-hydroxyanthraquinone (0.17 g, 0.601 mmol) and [1- (2- aminoethyl) -piperidin-2-yl] -methanol (0.95 g, 6.01 mmol) were stirred in pyridine (2 mL) at 90 ° C in 1 hour.The reaction mixture was added to ice-cold brine and set aside ° C at night. The precipitated solid was isolated by filtration and lyophilized. The desired product was purified by flash chromatography, initially extracting with CH2Cl2 / CH3OH (95: 5) to remove non-polar impurities, followed by a gradual increase of CH3OH to CH2C12 / CH30H (85:15). The product subjected to chromatography was then crystallized from CH3C1 to obtain the title compound HAQ105 as a dark blue powder (0.11 g, 34%). Melting point 208-210 ° C. d? (250 MHz, CDC13): 1.15-1.65 (m, 12H, 2 x OH and 10 x H-ring), 2.25-2.4 (m, 6H, 6 x H-ring), 2.6-2.7 (t, 4H, 2 x HNCH2CH2N), 2.85 (m, 2H, 2 x H-ring), 3.55 (t, 4H, 2 x HNCH2CH2N), 3.6-3.65 (2xd, 4H, 2 x CHCH2OH), 7.2 (s) , 2H, C (2) H and C (3) H), 7.5 (s, 2H, C (6) H and C (7) H), 10.75 (t, 2H, C (1) NH and C (4 ) NH) and 13.65 (s, 2H, C (5) OH and C (8) OH); 5C (62.9 MHz; DMSO): 22.55, 24.92, 28.14, 50.99, 52.32, 61.94, 62.42, 107.03, 116.11, 123.89, 125.91, 147.07, 154.46, and 182.88; FAB MS, m / z. { M + K) + 553; IR v ^ / cm'1: 3,400 (OH), 3,225 (NH), 3,100 (Ar-CH), 2,960-2,800 (CH2, CH3), 1,650, 1,625, 1,575, 1,480, 1,370 and 1,225; Analytical calculation for C30H40N4Os · 1H20: C, 63.14; H, 7.24; N, 9.82. Found: C, 63.07; H, 7.49; N, 9.77. Example 51: l-. { [(2-Dimethylamino) ethyl] amino} -4-. { [2- (2-hydroxy-methylpyrrolidin-1-yl) ethyl] -amino} - 5,8-dihydroxy-anthracene-9,10-dione (HAQ110) The method follows that of HAQ105 using HAQ107 (75 mg, 0.218 mmol), [1- (2-aminoethyl) -pyrrolidin-2-yl] -methanol (650 mg, 4.114 mmol), pyridine (2 mL), 1 hour, 90 ° C. The product HAQ110 is achieved as a dark blue powder (52 mg, 51%). Melting point 202-203 ° C. d? (250 MHz; DMSO / CDCl3 (1: 1)): 1.55-1.9 (m, 4H, 4 x H-ring), 2.3 (s, 6H, 2 x NCH3), 2.5-2.55 (m, 1H, 1 x H-ring), 3.25-3.4 (m, 7H, 2 x HNCH2CH2N, 2 x H-ring and OH), 3.45-3.6 (m, 6H, 2 x HNCH2CH2N and NCHCH20H), 7.05 (s, 2H, C (2 ) H and C (3) H), 7.2 (m, 2H, C (6) H and C (7) H), 10.6-10.7 (2xt, 2H, C (1) NH and C (4) NH), and 13.5 (s, 2H, C (5) OH, C (8) OH); 5C (62.9 MHz; DMS0 / CDC13 (1: 1)): 22.71, 27.65, 41.58, 44.83, 53.38, 53.53, 57.54, 64.07, 64.94, 107.10, 114.81, 123.73, 125.00, 125.11, 146.52, 154.36, and 183.17; FAB MS, m / z (M + H) + 469; Analytical calculation for C25H32N405: C, 64.09; H, 6.88; N, 11.96. Found: C, 63.83; H, 6.99; N, 12.05. Example 52: 1-. { [2-dimethylamino) ethyl] amino} -4 - . { [2 - (4-Hydroxy-piperidin-1-yl) ethyl] amino} - 5, 8 -dihydroxy -anthracene- 9, 10 -dione (HAQlll) The method follows that of HAQ105 using HAQ107 (18 mg, 0.0523 mmol), N- (2-aminoethyl) -piperidin-4-ol (140 mg, 0.97 mmol), pyridine (1 mL), 1 hour, 90 ° C. The HAQIII product was achieved as a dark blue powder (16.1 mg, 65%). Melting point 231-233 ° C. d? (250 MHz; DMSO / CDCl3 (1: 1)): 1.25-1.8 (m, 6H, 6 x H-ring), 2.2-2.25 (m, 2H, 2 x H-ring), 2.35 (s, 6H, 2 x NCH3), 2.5-2.8 (m, 5H, 2 x HNCH2CH2N and 1 x OH), 3.5-3.55 (m, 5H, 2 x HNCH2CH2N and NCH2CHOH), 7.1 (s, 2H, C (2) H and C (3) H), 7.25 (m, 2H, C (6) H and C (7) H), 10.65 (t, 2H, C (1) NH and C (4) NH), and 13.65 (s, 2H , C (5) OH, C (8) OH); 5C (62.9 MHz; DMS0 / CDCl3 (1: 1)): 27.78, 32.15, 43.72, 49.49, 54.73, 56.39, 65.09, 106.48, 113.66, 122.55, 123.12, 123. 39, 144.97, 153.33, 182.56; FAB MS, m / z (M + E) + 469; Analytical calculation for C25H32N405 · 1 H20: C, 61.17; H, 6.84; N, 11.52. Found: C, 61.27; H, 6.64; N, 11.40. Example 53: 1, 4-Bis-. { [2- (3-hydroxypyrrolidin-1-yl) ethyl] amino} -5,8-dihydroxy-anthracene-9,10-dione (HAQ115) Although not shown in scheme 3 (figure 4), the method follows that of HAQ105 using 1,4-difluoro-5,8-hydroxy-anthraquinone (75 mg, 0.272 mmol), 1- (2-aminoethyl) -pyrrolidin-3 -ol (1 g, 7.7 mmol), pyridine (2 mL), 1 hour, 100 ° C. The product HAQ115 was achieved as a dark blue powder (59.2 mg, 44%). Melting point 197-199 ° C. d? (250 MHz; DMS0 / CDC13 (1: 1)): 1.55-1.65 (m, 2H, 2 x H-ring), 2.0-2.1 (m, 2H, 2 x H-ring), 2.45-2.9 (m, 10H, 8 x H-ring and 2 x OH), 2.75-2.85 (t, 4H, 2 x HNCH2CH2N), 3.55-3.65 (q, 4H, 2 X HNCH2CH2N), 4.05-4.15 (m, 2H, 2 x CH2CH0H ), 7.05 (s, 2H, C (2) H and C (3) H), 7.3 (m, 2H, C (6) H and C (7) H), 10.55 (t, 2H), C (1 ) NH and C (4) NH), and 13.55 (s, 2H, C (5) OH, C (8) OH); 5C (62.9 MHz; DMSO / CDCl3 (1: 1)): 28.01, 34.73, 41.22, 52.18, 54.42, 62.33, 69.26, 107.01, 115.04, 123.79, 124.90, 146.43, 154.38, and 183.21; FAB MS, m / z (M + H) + 497; Analytical calculation for C26H32N406: C, 62.88; H, 6.51; N, 11.28. Found: C, 62.50; H, 6.54; N, 11.00 Example 54: 1, 4-Bis-. { [2- (4-hydroxypiperidin-1-yl) ethyl] amino} -5,8-dihydroxy-anthracene-9,10-dione (HAQ116) The method follows that of HAQ105 using 1,4-difluoro-5,8-hydroxy-anthraquinone (45 mg, 0.163 mmol), 1 - (2 - aminoethyl) - piperidin-4 -ol (1 g, 42.6 mmol), pyridine (2 mL), 1 hour, 90 ° C. The HAQ116 product was achieved as a dark blue powder (36.2 mg, 42%). Melting point 241-244 ° C. d? (250 MHz, CDC13): 1.25-1.65 (m, 12H, 12 x H-ring), 1.7-2.0 (m, 4H, 4 x H-ring), 2.65-3.0 (m, 6H, 2 x NCH2CH2N and 2 x OH), 3.6-3.8 (q, 4H, 2 x HNCH2CH2N), 4.1 (m, 2H, 2 x CH2CHOH), 7.2 (s, 2H, C (2) H and C (3) H), 7.6 (m , 2H, C (6) H and C (7) H), 10.5 (t, 2H, C (1) NH and C (4) NH), and 13.6 (s, 2H, C (5) OH, C ( 8) OH); £ c (62.9 MHz, CDCl3): 3.167, 39.45, 41.56, 49.56, 54.66, 109.22, 115.40, 124.82, 5 125.45, 146.39, 154.70, 164.022, and 183.54; FAB MS, / z (M + H) + 525. Example 55: 1-. { [(2-Dimethylamino) ethyl] amino} -4-. { [2- (3-hydroxy-pyrrolidin-1-yl) ethyl] amino} - 5,8-dihydroxy -anthracene- 9,10 -dione (HAQ120) The method follows that of HAQ105 using HAQ107 (45 mg, 0.13 mmol), 1- (2-amino-yl) -pyrrolidin-3-ol (880 mg , 6.77 mmol), pyridine (1 mL), 30 minutes, 100 ° C. The HAQ120 product was achieved as a dark blue powder (24 mg, 41%). Melting point 195-198 ° C. d? (250 MHz; DMSO / CDCl 3 (1: 1)): 1.55-1.7 (m, 1H, 1 X-H ring), 1.95-2.05 (m, 2H, 2 x H-ring), 2.3 (s, 6H, 2 x NCH3), 2.35-2.4 (m, 1H, 1 x H-ring), 2.5-2.6 (t, 4H, 2 x HNCH2CH2N), 2.6-2.85 (m, 2H, 1 x H-ring and OH), 3.5-3.55 (q, 4H, 2 x HNCH2CH2N), 4.25 (m, 1H, CH2CHOH), 7.1 (s, 2H, C (2) H and C (3) H), 7.4 (m, 2H, C (6 ) H and C (7) H), 10.5 (t, 2H, C (1) H and C (4) NH), and 13.5 (s, 2H, C (5) OH, C (8) OH); 5C (62.9 MHz; DMSO / CDCl3 (1: 1)): 34.19, 41.22, 52.18, 54.42, 62.33, 69.26, 107.18, 114.78, 123.79, 124. 90, 146.90, 154.38, and 183.16; FAB MS, m / z (M + H) + 455. Example 56: 1-. { [(2-Dimethylamino) ethyl] amino} -4-. { [2- (2-hydroxy-methylpiperidin-1-yl) ethyl] -amino} -5,8-dihydroxy-anthracene-9,10-dione (HAQ121) The method follows that of HAQ105 using HAQ107 (30 mg, 0.0872 mmol), [1- (2-aminoethyl) -piperidin-2-yl] -methanol (700 mg, 4.43 mmol), pyridine (1 mL), 30 minutes, 100 ° C. The product HAQ121 was produced as a dark blue powder (21.3 mg, 51%). Melting point 201-203 ° C. d? (250 MHz, CDC13): 1.7-2.1 (m, 7H, 6 x H-ring and OH), 2.6 (s, 6H, 2 x NCH3), 2.8 (m, 2H, 2 x H-ring), 2.9 ( t, 4H, 2 x HNCH2CH2N), 2.9-3.1 (m, 1H, 1 x NCHCH2), 3.6-3.65 (t, 4H, 2 x HNCH2CH2N), 3.9-4.1 (2x, 2H, CHCH2OH), 7.05 (s, 2H, C (2) H and C (3) H), 7.15 (m, 2H, C (6) H and C (7) H), 10.5 (t, 2H, C (1) NH and C (4) NH), and 13.65 (s, 2H, C (5) OH, C (8) OH); 5C (62.9 MHz; CDCl3): 23.06, 23.93, 26.94, 40.57, 41.13, 45.59, 50.42, 51.88, 58.35, 61.44, 62.65, 108.67, 115.43, 123.45, 124.12, 146.11, 155.24, and 184.63; FAB MS, m / z (M + H) + 483; Analytical calculation for C26H34N405: C, 64.71; H, 7.10; N, 11.61. Found: C, 64.45; H, 6.85; N, 11.79. Example 57: 1, 4 -Bis -. { [2 - (2-Hydroxymethylpyrrolidin-1-yl) ethyl] amino} -5, 8-dihydroxy-anthracene-9, 10-dione (HAQ125) As shown in scheme 3 (figure 4), the method follows that of HAQ105 using 1,4-difluoro-5,8-hydroxyanthraquin Na (75 mg, 0.272 mmol), [1- (2-aminoethyl) -pyrrolidin-2-yl] -methanol (1.5 g, 10.42 mmol), pyridine (2 mL), 2 hours, 100 ° C. The product HAQ125 was achieved as a dark blue powder (58.1 mg, 41%). Melting point 202-204 ° C. d? (250 MHz; DMS0 / CDC13 (1: 1)): 1.6-1.9 (m, 8H, 8 x H-ring), 2.2-2.3 (m, 2H, 2 x H-ring), 2.6-2.75 (m, 6H, 2 x HNCH2CH2N and 2 x H-ring), 3.1-3.2 (m, 2H, 2 x H-ring), 3.3-3.6 (m, 10H, 2 x HNCH2CH2N, 2 x NCHCH2OH and 2 x OH), 7.1 (s, 2H, C (2) H and C (3) H), 7.5 (m, 2H, C (6) H and C (7) H), 10.7 (t, 2H, C (1) NH and C (4) NH), and 13.55 (s, 2H, C (5) OH, C (8) 0H); 5C (62.9 MHz; DMSO / CDCI3 (1: 1)): 22.75, 27.65, 41.59, 53.56, 64.08, 64.96, 107.14, 114.92, 123.79, 125.30, 146.65, 154.37, and 183.15; FAB MS, m / z (M + H) + 525; Analytical calculation for C28H36N406: C, 64.14; H, 6.87; N, 10.69. Found: C, 64.09; H, 6.98; N, 10.77. Example 58: 1-. { [2 - (2,6-Dihydroxymethylpiperidin-1-yl) ethyl] amino} -4-. { [(2-dimethylamino) ethyl] amino} -5, 8-dihydroxy.traceno-9, 10-dione (HAQ143) The method follows that of HAQ105 using HAQ107 (78 mg, 0.227 mmol), [1- (2-aminoethyl) -piperidine-bis-2,6- il] -methanol (420 mg, 2283 mmol), pyridine (2 mL), 30 minutes, 100 ° C. The HAQ143 product was achieved as a dark blue powder (63 mg, 54%). Melting point 216-218 ° C. d? (250 MHz; CDCl3): 1.4-1.8 (m, 6H, 6 x H-ring), 2.35 (s, 6H, 2 x NCH3), 2.65 (t, 2H, 1 x HNCH2CH2N), 2.75-2.85 (s, 2H, 2 x NCHCH2), 3.0 (t, 2H, HNCH2CH2N), 3.35-3.45 (m, 6H, 2 x HNCH2CH2N and 2 x OH), 3.7 (d, 4H, 2 x CHCH2OH), 7.05 (s, 2H, C (2) H and C (3) H), 7.15 (m, 2H, C (6) H and C (7) H), 10.5 (t, 2H, C (1) NH and C (4) NH), and 13.65 ( s, 2H, C (5) OH, C (8) OH); 5C (62.9 MHz; CDC13): 20.90, 24.85, 41.27, 42.35, 45.63, 50.50, 58.42, 61.95, 64.60, 107. 01, 115.38, 123.89, 124.92, 146.39, 155.85, and 185.21; FAB S, m / z (M + H) + 513; Analytical calculation for C27H36N4Os: C, 63.26; H, 7.08; N, 10.93. Found: C, 62.93; H, 7.12; N, 10.84. Example 59: H- [2 - (2-Hydroxymethylpyrrolidin-1-yl) ethyl] amino} -anthracene- 9, 10 -dione (HAQ163) (scheme 2) A [1- (2-aminoethyl) -pyrrolidin-2-yl] -methanol (1.63 g, 11.3 mmol) in pyridine (10 mL) was added 1- chloroanthraquinone (1.37 g, 5.646 mmol), and the mixture was stirred at 65 ° C for 24 hours. Pyridine was removed in vacuo and the resulting mixture of oil and solid was dissolved in CH2C12 and washed with H20 (3 x 50 mL) to remove any unreacted amine. The separated organic layer was removed in vacuo and the crude product was chromatographed using CH2C12 / CH30H (97: 3). The desired product was produced as a red powder (0.21 g, 11%). Melting point 113-115 ° C. d? (250 MHz, CDC13): 1.75-2.0 (m, 4H), 2.25-2.35 (m, 1H), 2.6-2.8 (m, 2H), 3.15-3.3 (m, 2H), 3.35-3.55 (m, 4H ), 3.75-3.85 (2xd, 1H), 7.0 (2xd, 1H), 7.45-7.6 (m, 2H), 7.65-7.8 (m, 2H), 8.2 (2xd, H), 8.45 (2xd), and 10.05 (s, 1H, C (l) NH); 5C (62.9 MHz; CDC13): 24.11, 27.15, 41.64, 52.99, 53.82, 62.61, 65.26, 113.15, 115.60, 126.57, 132.86, 133.81, 135.32, 151.49, 183.77, and 184.49; FAB MS, m / z (M + H) + 351; Analytical calculation for C21H22N203: C, 71.98; H, 6.33; N, 8.00 Found: C, 71.79; H, 6.13; N, 8.07. Example 60: l-. { [2- (3-chloropiperidin-1-yl) ethyl] amino} -4-. { [(2-dimethylamino) ethyl] amino} - 5, 8 -dihydroxyanthracene- 9,10 -dione (CAQ166M) Preparation of CAQ166M involved 5 steps, where none of the intermediate products were isolated and purified. The preparation generally follows scheme 5 (figure 6) then scheme 3 (figure 4). (i): Boc protection of mono-hydroxylated diamine side chains (ii): esylation of Boc-protected monohydroxylated diamine side chains (iii): Cloration of mono-mesylated diamine secondary chains (iv): Group deprotection Boc of secondary chain of chlorinated diamine (v): ipso substitution of l - [[2- (dimethylamino) ethyl] amino] -4-fluoro-5,8-dihydroxyanthraquinone by chlorinated diamine (i) 1- (2 - Aminoethyl) -piperidin-3 -ol (1 g, 6.94 mmol) and Et3N (1.16 mL, 8.33 mmol) were stirred together with CH3OH (10 mL) for 5 minutes before Boc20 (1.82 g, 8.33 mmol), dissolved in CH30H (5 mL), was added in drops over 15-20 minutes. The reaction mixture was then stirred for 20 hours at 45 ° C, before being concentrated in vacuo. The oil was diluted in EtOAc (40 mL) and washed with 2 x H20 (20 mL) and brine (20 mL). The organic phase was dried with magnesium sulfate (MgSOj) and after filtration it was concentrated in vacuo to yield a straw-colored oil that did not need further purification (1.35 g, 80%) FAB MS m / z (M + H) + 245. (ii) MsCl (420 μ? _, 5.41 mmol) was added dropwise to a freeze-protected solution of amine Boc (880 mg, 3.61 mmol) and Et3N (755 pL, 5.41 mmol) in dry CH2C12 (10 mL) under N2 . After the reaction mixture was stirred for 1 hour at 0 ° C, the solution was diluted with cold CH2C12, washed with ice-cold NaHCO3 and ice-cold brine. The organic phase was dried with MgSO 4, filtered and concentrated in vacuo at room temperature. The mesylated product was achieved as a crude straw-colored oil (965 mg, 83%). FAB MS m / z (M + H) + 323. (iii) Tetra-n-butylammonium chloride (2 g, 7.20 mmol) was added to a stirred solution of crude mesylate (965 mg, 3.01 mmol) in dry DMF ( 5 mL). The reaction mixture was heated at 90 ° C for 30 minutes before DMF was removed in vacuo. The residual oil was taken up in CH2C12 and washed with ice-cold NaHCO3 and ice-cold brine. The organic phase was dried (MgSO 4), filtered and the solvent was concentrated in vacuo at room temperature. The crude product was achieved as a yellow straw colored oil (624 mg, 79%). FAB MS m / z (M + H) + 263. (iv) The crude chloride (624 mg, 2.38 mmol) was stirred in 4 M HCl in EtOAc for one hour to remove the Boc group. To the acid EtOAc solution, cooled in an ice bath, a solution of brine and NH3 (pH = 12) was added slowly until the aqueous phase was pH ~ 11. The chlorinated diamine was then extracted into the organic phase, the which was dried with (MgSO4). The solvent it was removed in vacuo and the crude product was produced as a brown oil (175 mg, 45%) which was used directly in the next step FAB MS m / z (M + H) + 163. (v) A mixture of HAQ107 ( 36 mg, 0.105 mmol) and the crude Boc-deprotected chloride (175 mg, 1.08 mmol) was reacted in pyridine (2 mL) at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by extracting initially with CH2C12 to remove non-polar impurities, followed by a gradual increase of CH3OH to CH2Cl2 / CH3OH (97: 3). The product subjected to chromatography was crystallized from CHC13. The title compound CAQ166M was produced as a dark blue solid (35 mg, 60%). Melting point desc. > 300 ° C. d? (250 MHz, CDC13): 1.5-1.9 (m, 4H, 4 x H-ring), 2.15-2.25 (m, 3H, 3 x H-ring), 2.35 (s, 6H, 2 x NCH3), 2.65- 2.8 (2xt, 4H, 2 x HNCH2CH2N), 3.15-3.2 (2xd, 1H, H-ring), 3.45 (t, 4H, 2 x HNCH2CH2N), 4.1 (m, 1H, CH2CHCl), 7.05 (s, 2H, C (2) H and C (3) H), 7.15 (s, 2H, C (6) H and C (7) H), 10.45 (t, 2H, C (1) NH and C (4) NH), and 13.5 (s, 2H, C (5) OH, C (8) 0H); 5C (62.9 MHz, CDC13): 24.95, 29.65, 34.88, 40.37, 41.26, 45.63, 52.85, 55.78, 56.28, 58.39, 61.43, 109.23, 115.39, 123.64, 123.78, 124.66, 146.05, 146.24, 155.41, 185.28, and 185.35; FAB MS, m / z (M +) + 487. Example 61: 1-. { [2- (4-Chloropiperidin-1-yl) ethyl] amino} -4-. { [(2-dimethylamino) ethyl] amino} -5,8 -dihydroxyanthracene -9,10 -dione (CAQ172) The method follows that of CAQ166M. (i) 1- (2-Aminoethyl) -piperidin-4-ol (2 g, 13.89 mmol), Et 3 N (2.32 mL, 16.65 mmol), CH 3 OH (20 mL), Boc 20 (3.63 g, 16.65 mmol), dissolved in CH 3 OH (5 mL). The reaction mixture was stirred for 18 hours. The product was obtained as a straw colored oil that did not need additional purification (2.35 g, 69%). FAB MS m / z (M + H) + 245. (ii) Boc-protected amine (1.70 g, 6.94 mmol), MsCl (810 yL, 10.41 mmol), Et 3 N (1.45 mL, 10.41 mmol), dry CH 2 Cl 2 (20). mL). The mesylated product was produced as a crude straw colored oil (1.39 g, 62%). FAB MS m / z. { M + H) + 323. (iii) Crude mesylated (1.39 g, 4.29 mmol), tetra-n-butylammonium chloride (2.38 g, 8.58 mmol), dry DMF (10 mL), 120 ° C, 30 minutes. The crude chloride was achieved as a straw / yellowish oil (0.73 g, 65%). FAB MS m / z. { M + H) + 263. (iv) Crude Chloride (0.73 g, 2.78 mmol), 4 M EtOAc HCl, 1 hour. Raw Boc-protected amine was produced as a brown oil (160 mg, 35%). FAB MS m / z (M + H) + 163. (v) HAQ107 (36 mg, 0.105), crude deprotected secondary chain (160 mg, 0.98 mmol), pyridine (2 mL), 5 hours, 45 ° C. The title compound (CAQ172) was produced as a dark blue solid (31.4 mg, 54%). Melting point 200-202 ° C. d? (250 ???, - CDC13): 1.3-1.75 (m, 6H, 6 x H-ring), 1.95-2.1 (m, 2H, 2 x H-ring), 2.35 (s, 6H, 2 x NCH3) , 2.6-2.8 (t, 4H, 2 x HNCH2CH2N), 3.3 (q, 4H, 2 x HNCH2CH2N), 3.45 (m, 1H, CH2CHCl), 7.05 (s, 2H, C (2) H and C (3) H), 7.1 (s, 2H, C (6) H and C (7) H), 10.45 (t, 2H, C (1) NH and C (4) NH), and 13.55 (s, 2H, C (5) 0H, C (8) 0H); 5C (62.9 MHz; CDC13): 24.06, 34.69, 45.38, 50.79, 56.25, 58.96, 109.09, 115.31, 123.77, 123.95, 124.61, 146.12, 146.22, 155.34, 161.33, and 185.29; FAB MS, m / z (M + H) + 487; Analytical calculation for C 25 H 31 ClN 40 4 · 3 H 20: C, 48.90; H, 6.24; N, 9.12. Found: C, 48.77; H, 6.00; N, 9.10. Example 62: l-. { [2- (2-Chloromethylpyrrolidin-1-yl) ethyl] -amino} -4-. { [(2-dimethylamino) ethyl] amino} -5, 8-dihydroxyanthracene-9, 10-dione (CAQ176M) The method follows that of CAQ166M. (i) [1- (2-Aminoethyl) -pyrrolidin-2-yl] -methanol (5 g, 34. 72 mmol), Et 3 N (5.8 mL, 41.67 mmol), CH 3 OH (40 mL), Boc 20 (9.10 g, 41.67 mmol), dissolved in CH 3 OH (10 mL). The reaction mixture was stirred for 18 hours. The product was achieved as a straw colored oil that did not need further purification (6.9 g, 82%). (ii) Boc-protected amine (5.1 g, 20.9 mmol), MsCl (2.43 mL, 31.35 mmol), Et3N (4.32 mL, 31.35 mmol), dry CH2C12 (50 mL). The mesylated product was achieved as a crude straw colored oil (5.63 g, 84%). FAB MS n? / Z (M + H) + 245. (iii) Crude mesylated (5.63 g, 17.48 mmol), tetra-n-butylammonium chloride (9.72 g, 11.26 mmol), dry DMF (30 mL), 90 ° C, minutes. The crude chloride was achieved as a straw / yellowish oil (2.2 g, 48%). FAB MS T / Z (M + H) + 323. (iv) Crude Chloride (2 g, 7.58 mmol), 4M EtOAc HCl, 1 hour. The crude Boc-deprotected amine was obtained as a brown oil (675 mg, 55%). FAB MS m / z (M + H) + 263. (v) HAQ107 (95 mg, 0.276 mmol), crude deprotected secondary chain (675 mg, 4.15 mmol), pyridine (2 mL), 2 hours, 30 ° C. The title compound CAQ176M was achieved as a dark blue solid (63.8 mg, 41%). FAB MS m / z (M + H) + 163. Melting point 253-255 ° C. d? (250 MHz, CDC13): 1.5-1.85 (m, 4H, 4 x H-ring), 2-2.25 (m, 3H, 3 x H-ring), 2.35 (s, 6H, 2 x NCH3), 2.6-2.8 (2xt, 4H, 2 x HNCH2CH2N), 3.15 (d, 1H, 1 x NCHCH2C1), 3.4 (m , 5H, 2 x HNCH2CH2N and 1 x NCHCH2C1), 7.05 (s, 2H, C (2) H and C (3) H), 7.1 (s, 2H, C (6) H and C (7) H), 10.45 (t, 2H, C (1) NH and C (4) NH), and 13.55 (s, 2H, C (5) 0H, C (8) 0H); 5C (62.9 MHz; CDC13): 24.93, 34.86, 40.33, 41. 19, 45.59, 52.82, 55.78, 56.03, 56.27, 58.35, 61.43, 109.02, 115.40, 123.55, 123.69, 124.49, 146.01, 146.2, 155.32, and 185.11; FAB MS, m / z (M + H) + 487. Analytical calculation for C25H31C1N404 | 2 HCl • 2 H20: C, 50.38; H, 6.60; N, 9.40. Found: C, 49.81; H, 6.23; N, 9.29. Example 63: 1, 4-Bis. { [2- (2-chloromethylpyrrolidin-1-yl) ethyl] amino} -5, 8-dihydroxyanthracene-9, 10-dione (CAQ177M) The method follows that of CAQ166M. (i) [1- (2-Aminoethyl) -pyrrolidin-2-yl] -methanol (7 g, 48.61 mmol), Et 3 N (8.12 mL, 58.33 mmol), CH 3 OH (50 mL), Boc 20 (12.73 g, 58.33 mmol), dissolved in CH3OH (15 mL). The reaction mixture was stirred for 20 hours. The product was achieved as a straw-colored oil that did not need further purification (9.36 g, 79%). FAB MS m / z (M + H) + 245. (ii) Boc-protected amine (8 g, 32.8 mmol), MsCl (3.81) mL, 49.2 mmol), E 3 N (6.85 mL, 49.2 mmol), dry CH 2 C 12 (50 mL). The product was achieved as a raw straw colored oil (9.06 g, 86%). FAB MS m / z (M + H) + 323. (iii) Crude mesylated (9 g, 28 mmol), tetra-n-butylammonium chloride (13.34 g, 42 mmol), dry DMF (50 mL), 90 ° C, 30 minutes. The crude product was achieved as a straw colored oil (6.78 g, 61%). FAB MS m / z (M + H) + 263. (iv) Crude chloride (6.78 mg, 25.7 mmol), 4M EtOAc HCl, 1 hour. The crude Boc-unprotected amine was obtained as a brown oil (1.98 g, 47%). FAB MS m / z (M + E) + 163. (v) HAQ107 (125 mg, 0.363), crude deprotected secondary chain (1.98 mg, 12.1 mmol), pyridine (5 mL), 4 hours, 30 ° C. The title compound CAQ177M was produced as a dark blue solid (88.5 mg, 39%). Melting point desc. > 300 ° C. d? (250 MHz, DMSO): 1.45-1.85 (m, 6H, 6 x H-ring), 2.15-2.35 (m, 6H, 6 x H-ring), 2.65-2.85 (m, 6H, 2 x HNCH2CH2H and 2 x H-ring), 3.15 (d, 2H, 2 x NCHCH2C1), 3.45-3.55 (q, 4H, 2 x HNCH2CH2N), 4.15 (m, 2H, 2 x NCHCH2C1), 7.05 (s, 2H, C (2 ) H and C (3) H), 7.15 (s, 2H, C (6) H and C (7) H), 10.45 (t, 2H, C (1) NH and C (4) NH), and 13.45 (s, 2H, C (5) 0H, C (8) 0H); 5C (62.9 MHz; DMSO): 28.11, 35.05, 41.78, 50.83, 55. 43, 60.52, 65.26, 107.91, 114.93, 124.33, 127.56, 144.33, 156.69, 183.28; FAB MS, m / z (M + K) + 561; Analytical calculation for C28H34C12N404 · 2 HCl: C, 53.05; H, 5.72; N, 8.84. Found: C, 53.35; H, 5.84; N, 8.72. Example 64: l-. { [2- (3-Chloropyrrolidin-1-yl) ethyl] amino} -4-. { [ (2- tell me you lamino) ethyl] amino} -5,8 -dihydroxyanthracene- 9, 10-dione (CAQ188M) The method follows that of CAQ166M. (i) 1- (2-Aminoethyl) -pyrrolidin-3 -ol (1 g, 7.94 mmol), Et 3 N (1.32 mL, 9.52 mmol), CH 3 OH (10 mL), Boc 20 (2.08 g, 9.52 mmol), dissolved in CH 3 OH (5 mL). The reaction mixture was stirred for 16 hours. The product was achieved as a straw colored oil that did not need additional purification (1.54 g, 86%). FAB MS m / z (M + H) + 230. (ii) Boc-protected amine (960 mg, 4.16 mmol), MsCl (483 ih, 6.24 mmol), Et 3 N (868 L, 6.24 mmol), dry CH 2 C 12 (10) mL). The crude product was obtained as a straw colored oil (1 g, 78%). FAB MS m / z (M + H) + 308. (iii) Crude mesylated (1 g, 3.24 mmol), tetra-n-butylammonium chloride (1.35 g, 4.86 mmol), dry DMF (10 mL), 100 ° C, 30 minutes. The product was achieved as a straw / yellowish oil (705 mg, 81%). FAB MS m / z (M + H) + 248. (iv) Crude chloride (705 mg, 2.88 mmol), HC1 EtOAc 4 M, 1 hour. The crude Boc-deprotected amine was obtained as a brown oil (124 mg, 30%). FAB MS m / z (M + H) + 148. (v) HAQ107 (50 mg, 0.18 mmol), crude deprotected secondary chain (124 mg, 0.86 mmol), pyridine (2 mL), 2 hours, 60 ° C. The CAQ188M product was achieved as a dark blue powder (15 mg, 15%). Melting point desc. >; 300 ° C. d? (250 MHz; DMS0 / CDC13 (1: 1)): 1.8-2.15 (m, 2H, 2 x H-ring), 2.3 (m, 1H, H-ring), 2. 35 (s, 6H, 2 x NCH3), 2.85-3.05 (m, 7H), 3.8-4.1 (m, 5H), 7.1 (s, 2H, C (2) H and C (3) H), 7.2 ( s, 2H, C (6) H and C (7) H), 10.45 (t, 2H, C (1) NH and C (4) NH), and 13.55 (s, 2H (C5) OH, C (8 ) OH); 5C (62.9 MHz; CDC13): 37.19, 42.31, 52.01, 55.05, 62.05, 68.95, 107.65, 114.40, 124.91, 125.15, 146.09, 154.74, 184.44; FAB MS, m / z (M + H) + 473; Analytical calculation for C24H29C1N404 · 2 HC1 | 4 H20: C, 46.65; H, 6.04; N, 9.07. Found: C, 47.10; H, 5.80; N, 9.07. Hydroxylated Anthraquinone Chlorination using Ph3P-CCl4 Complex Example 65: 1,4-Bis-. { [2- (3-chloromethylpiperidin-1-yl) ethyl]] amino} -anthracene-9, 10-dione (CAQ39) Ph3P (377.7 mg, 1.44 mmol) and CC14 (425 pL, 432 mmol) were stirred for 15 minutes before they were added in drops to a solution of HAQ38 (125 mg, 0.24 mmol) in dry CH2C12 (5 mL) under N2 at reflux temperature. The reaction mixture was maintained at reflux temperature for 4 hours before it was cooled to room temperature. Ethereal HCl was added to the solution and after 1 hour of stirring, the precipitated solid was filtered. To remove excess Ph3P and Ph3PO, the precipitated solid was dissolved in hot CH3OH (10 mL). While the dark blue solution was stirred at reflux, a mixture of EtOAc and EtOH (1: 1) was added until the precipitation of solid was observed. The solution was kept on its side for 1 hour before the precipitated product was isolated by filtration; the excess Ph3P and Ph3PO remained in the EtOAc / EtOH solution. The title compound was achieved as a dark blue solid (98.3 mg, 65%). Point of fusion desc. > 300 ° C. d? (250 MHz, CDC13): 1.1 (m, 2H, 2 x CH2CHCH2C1), 1.75 (m, 6H, CH2CH2CH and 2 x CH2CH2CH2), 2.05 (m, 4H, H-ring), 2.18 (3xd, 2H, J = 3 Hz and 10 Hz, 2 x NCH2CH2), 2.73 (t, 4H, J = 9 Hz, 2 x HNCH2CH2N), 2.8 (m, 2H, H-ring), 2.96 (2xd, 2H, 2 x NCH2CH), 3.5 (m, 8H, 2 x CHCH2C1 and 2 x HNCH2CH2N), 7.25 (s, 2H, C (2) H and C (3) H), 7.7 (m, 2H, C (6) H and C (7) H ), 8.3 (m, 2H, C (5) H, C (8) H) and 10.75 (t, 2H C (1) NH and C (4) NH); 5C (62.9 MHz, CDCl3): 24.42, 28.34, 38.47, 40.56, 48.14, 54.22, 57.52, 57.60, 110.30, 123.52, 126.12, 132.01, 134.56, 145.82 and 182.65; FAB MS, m / z (M + H) + 557; IR v ^ / cm'1: 3,400 (NH), 3,090, 2,960-2,825 (CH2, CH3), 1,650, 1,600, 1,585, 1,525, 1,275, 1,025 and 740. Analytical calculation for C30H38Cl2N4O2 | 2 HCl · 2 H20: C , 54.06; H, 6.65; N, 8.41. Found: C, 54.07; H, 6.27; N, 8.14. Example 66: 1-. { [2 - (3-chloropiperidin-1-yl) ethyl] amino} -4 - . { [(2-dimethylamino) ethyl] amino} -anthracene- 9, 10-dione (CAQ46M) The method follows that of CAQ39 using HAQ22 (167 mg, 0.384 mmol), Ph3P (302 mg, 0.152 mmol), CC14 (333 yL, 3.456 mmol) and dry CH2C12 (2 mL ). The reaction was stopped after 6 hours of reflux. The title compound was achieved as a dark blue solid (131 mg, 75%). d? (250 MHz, CDC13): 1.4-1.8 (m, 4H, CH2CH2CH2 and CH2CH2CH), 2.2 (3xd, 1H, J = 3 Hz and 11 Hz, 1 x NCH2CH2), 2.75 (t, 2H, J = 7Hz, HNCH2CH2N ), 2.9 (m, 1H, 1 x NCH2CH2), 3.15 (2xd, 1H, J = 3 Hz and 11 Hz, 1 x NCH2CH), 3.5 (m, 4H, 2 x HNCH2CH2N), 4.05 (m, 1H, CH2CHC1 ), 7.1 (d, 2H, C (2) H, C (3) H), 7.6 (m, 2H, C (6) H, C (7) H), 8.3 (m, 2H, C (5) H, C (8) H), and 10.75 (t, 2H, C (1) NH and C (4) NH); 5C (62.9 MHz; CDC13): 24.50, 34.95, 40.42, 41.02, 45.65, 52.99, 55.88, 56.85, 58.55, 61.61, 110.23, 123.41, 126.12, 132.03, 134.48, 145.73 and 182.62; FAB MS, m / z (M + H) + 455. Example 67: 1, 4-Bis-H-. { [2- (3-chloromethylpiperidin-1-yl) ethyl] amino} - 5, 8 -dihydroxyanthracene- 9, 10 -dione (CAQ74) The method follows that of CAQ39 using HAQ70 (142 mg, 0.26 mmol), Ph3P (404 mg, 1.54 mmol), CC14 (447 mL, 4.63 mmol) and mL of CHC13 / CH3CN (4: 1) as solvent. The reaction was stopped after 5 hours of reflux. The title compound was produced as a dark blue solid (117 mg, 68%). Melting point desc. > 300 ° C. d? (250 MHz, CDC13 / D20 (10: 1)): 1.4 (m, 2H, 2 X CH2CHCH2OH), 1.85-2.3 (m, 2H, 8 x H-ring), 3.0 (m, 4H, H-ring) , 3.4-3.8 (m, 16H, 2 x HNCH2CH2N, 2 x HNCH2CH2N and 8 x H-ring), 6.96 (s, 2H, C (2) H and C (3) H) and 7 (s, 2H, C (6) H and C (7) H); 5C (62.9 MHz; CDC13 / D20 (10: 1)): 27.99, 38.45, 40.04, 48.97, 56.36, 58.40, 111. 43, 117.38, 126.78, 127.37, 148.32, 156.32, and 187.18; FAB MS, m / z (M + H) + 589. Analytical calculation for C 30 H 38 Cl 2 N 4 O 4 · 2 HCl · 2 H20: C, 51.59; H, 6.35; N, 8.02. Found: C, 51.49; H, 6.14; N, 8.22. Example 68: l-. { [2- (2-Chloromethylpiperidin-1-yl) ethyl] amino} -4-. { [(2-dimethylamino) ethyl] amino} -5,8 - dihydroxyanthracene -9,10-dione (CAQ75) The method follows that of CAQ39 using HAQ71 (48 mg, 0.1 mmol), Ph3P (78.7 mg, 0.3 mmol), CC14 (300 L, 3.11 mmol) and CH2C12 dry (10 mL). The reaction was stopped after 5 hours of Reflux. The product (CAQ75) was achieved as a dark blue powder (46.3 mg, 81%). Melting point desc. > 300 ° C. d? (250 MHz, DMSO: CDCl3 (1: 1)): 1.3-1.45 (m, 3H, 3 x H-ring), 1.45-1.6 (m, 2H, 2 x H-ring), 2.35 (s, 6H, 2 x NCH3), 2.9-3 (m, 6H), 3-3.2 (m, 2H), 3.9 (m, 4H), 4.1 (d, 2H, CHCH2C1), 7.15 (s, 2H, C (2) H and C (3) H), 7.6 (s, 2H, C (6) H and C (7) H), 10.45 3 (t, 2H, C (1) NH and C (4) NH), and 13.35 ( s, 2H, C (5) OH, C (8) OH); 5C (62.9 MHz; CDCl3): 22.45, 25.33, 41.70, 42.56, 54.63, 54.95, 61.95, 107.94, 114.43, 124.41, 125.03, 145.03, 145.81, 155.05, and 184.03; FAB MS, m / z (M + K) + 501. Analytical calculation for C 26 H 33 ClN 40 4 · 2 HCl | 2 H20: C, 51.20; H, 6.44; N, 9.19. Found: C, 51.30; H, 6.18; N, 9.01. Example 69: l-. { [2- (2-Chloromethylpiperidin-1-yl) ethyl] -amino} -4-. { [2-dimethylamino) ethyl] amino} -5,8 -dihydroxyanthracene- 9,10 -dione (CAQ183M) The method follows that of CAQ39 using HAQ121 (105 mg, 0.21 mmol), Ph3P (165.23 mg, 0.63 mmol), CC14 (500 L, 5.25 mmol) and CH2C12 dry (10 mL). The reaction was stopped after 3 hours of reflux. The product (CAQ183M) was achieved as a dark blue powder (88.8 mg, 73%). Melting point 233-235 ° C. d? (250 MHz, CDC13): 1.55-2.1 (m, 8H, 8 x H-ring), 2.8 (s, 6H, 2 x NCH3), 3.2-3.35 (m, 4H), 3.6-3.75 (m, 2H) , 3.9-4.15 (m, 4H), 4.2 (m, 1H), 7.15, (s, 2H, C (2) H and C (3) H), 7.6 (s, 2H, C (6) H and C (7) H), 10.45 (t, 2H, C (1) NH and C (4) NH), and 13.35 (s, 15 2H, C (5) OH, C (8) OH); 5C (62.9 MHz, CDCl3): 21.60, 26.03, 36.70, 42.21, 51.73, 54. 85, 62.25, 108.34, 114.23, 124.81, 124.93, 145.83, 145.90, 154.65, and 184.20; FAB MS, / n / z (M + H) + 501. Analytical calculation for C26H33C1N404 · 2 HC1 | 3 H20: C, 49.73; H, 6.58; N, 8.92. Found: C, 50.09; H, 6.27; N, 8.96. Example 70: l-. { [2- (2,6-Dichloromethylpiperidin-1-yl) ethyl] -amino} -4-. { [(2-dimethylamino) ethyl] amino} -5,8-dihydroxyanthracene-9,10-dione (CAQ187M) The method follows that of CAQ39 using HAQ143 (14 mg, 0.0273 mmol), Ph3P (43 mg, 0.164 mmol), CC1"(79 yL, 0.82 mmol) and Dry CH2C12 (5 mL). The reaction was stopped after 5 hours of reflux. The product (CAQ187M) was achieved as a dark blue powder (12.2 mg, 81%). d? (250 MHz, CDC13): 1.3-1.65 (m, 6H, 6 x H-ring), 2.35 (s, 6H, 2 x NCH3), 2.7 (t, 2H, 1 x HNCH2CH2N), 2.8-2.9 (m, 2H, 2 x NCHCH2), 3.0 (t, 2H, 1 x HNCH2CH2N), 3.35-3.45 (q, 4H, 2 x HNCH2CH2N), 3.8-3.9 (d, 4H, 2 x CHCH2Cl), 7.1 (s, 2H, C (2) H and C (3) H), 7.15 (m, 2H, C (6) H and C (7) H), 10.55 (t, 2H, C (1) NH and C (4) NH) , and 13.65 (s, 2H, C (5) OH, C (8) OH); FAB MS, m / z (M + K) + 549. Example 71: 1, 4-Bis-. { [2 - (2-chloromethylpiperidyl-1-yl) ethyl] amino} -5,8-dihydroxyanthracene-9,10-dione (CAQ190M) The method follows that of CAQ39 using HAQ105 (60 mg, 0.109 mmol), Ph3P (171.5 mg, 0.654 mmol), CC14 (190 μ? _, 1.96 mmol) and dry CH2Cl2 (5 mL). The reaction was stopped after 5 hours of reflux. The product (CAQ190M) was achieved as a dark blue powder (49.8 mg, 78%). Melting point decomposes to > 300 ° C. d? (250 MHz, DMSO): 1.5-1.65 (m, 4H, 4 x H-ring), 1.75-2.15 (m, 10H, 10 x H-ring), 3.4-3.8 (m, 8H, 2 x HNCH2CH2N and 4 x H-ring), 4-4.1 (q, 4H, 2 x HNCH2CH2N), 4.15 (2xd, 4H, 2 x CHCH2Cl), 7.2 (s, 2H, C (2) H and C (3) H), 7.65 (s, 2H, C (6) H and C (7) H), 10.45 (t, 2H, C (1) NH C ( 4) NH), and 13.45 (s, 2H, C (5) OH, C (8) 0H); 5C (62.9 MHz; DMSO): 26.11, 37.05, 42.78, 50.78, 51.83, 60.32, 62.26, 108.41, 114.33, 125.00, 126.56, 145.93, 154.69, 184.28; FAB MS, m / z (M + H) + 589. Example 72: l-. { [2- (2-chloromethylpyrrolidin-1-yl) ethyl] amino} -anthracene-9, 10-dione (CAQ191M) The method follows that of CAQ39 using HAQ163 (115 mg, 0.329 mmol), Ph3P (260 mg, 0.99 mmol), CC14 (100 μL, 9.86 mmol) and dry CH2C12 (5 mg). mL). The reaction was stopped after 3 hours of reflux. The product (CAQ191M) was achieved as an orange powder (91.9 mg, 69%). Melting point 250-253 ° C. 5H (250 MHz; CDC13): 1.6-2.1 (m, 4H), 2.15-2.35 (m, 1H), 2.65-2.75 (m, 2H), 3.05-3.15 (m, 2H), 3.4-3.6 (m, 4H), 3.8 ( 2xd, 1H), 7.2 (2xd, 1H), 7.45-7.65 (m, 2H), 7.75-7.95 (m, 2H), 8.1-8.3 (m, 2H), and 9.95 (s, 1H, C (l) NH); 5C (62.9 MHz; CDC13); FAB MS, m / z (M + H) + 351. Analytical calculation for C28H3SN4Os: C, 62.23; H, 5.47; N, 6.91. Found: C, 62.15; H, 5.11; N, 6.77. N-Oxide Derivation (Scheme 4, Figure 3) Example 73: l-. { [2- (2-Hydroxymethylpyrrolidin-1-yl-N-oxide) ethyl] amino} -4-. { [(2-dimethylamino-N-oxide) ethyl] amino} -5, 8-dihydroxy-anthracene-9, 10-dione (HAQ132N) The oxidizing agent m-chloroperoxy benzoic acid m-CPBA (25 mg, 0.145 mmol) dissolved in dry dimethyldioxyrine DCM (1 mL) it was added dropwise to a stirred solution of HAQllO (20 mg, 0.043 mmol) in dry CH2C12 (5 mL) under N2. After 15 minutes of stirring at -10 ° C (ice-acetone bath), the reaction was stirred for 3 hours at 4 ° C. The solution was then diluted with hexane and after 2 hours, the precipitated solid was filtered and washed successively with ice-cold hexane, ether, CH2C12 and EtOAc. The crude product HAQ132N was achieved as a crude dark blue solid (15.5 mg, 73%). Analytical calculation for C25H32N407: C, 59.99; H, 6.44; N, 11.19. Found: C: 52.94; H, 6.15; N: 10.01. Example 74: l-. { [2- (3-Chloropiperidin-1-yl-N-oxide) ethyl] amino} -4- . { [(2-dimethylamino-N-oxide) ethyl] amino} -5,8-dihydroxyanthracene-9,10-dione (CAQ167MN) The method follows that of HAQ132N using CAQ166M (19 mg, 0.0391 mmol), m-CPBA (21.6 mg, 0.125 mmol), dry CH2C12 (5 mL). The product CAQ167MN was achieved as a crude dark blue solid (12.5 mg, 62%). Analytical calculation for C25H31N406: C, 57.86; H, 6.02; N, 10.8. Found: C: 54.82; H, 4.93; N: 7.43. Example 75: 1-. { [2 - (4-Chloropiperidin-1-yl-N-oxide) ethyl] amino} -4 -. { [(2-dimethylamino-N-oxide) ethyl] amino} -5,8-dihydroxyanthracene-9,10-dione (CAQ179N) The method follows that of HAQ132N using CAQ172 (17 mg, 0.035 mmol), m-CPBA (21.5 mg, 0.119 mmol), dry CH2C12 (5 mL). The CAQ179N product was achieved as a crude dark blue solid (15.5 mg, 86%). Analytical calculation for C25H31C1N406: C, 57.86; H, 6.02; N, 10.80. Found: C: 54.62; H, 4.84; N: 6.80.

Example 76: 1-. { [2 - (2-Chloromethylpyrrolidin-1-yl-N-oxide) ethyl] amino} -4-. { [(2-dimethylamino-N-oxide) ethyl] amino} -5, 8-dihydroxy-anthracene-9, 10-dione (CAQ181MN) The method follows that of HAQ132N using CAQ176M (48.3 mg, 0.0994 mmol), m-CPBA (58.3 mg, 0.338 mmol), dry CH2C12 (10 mL) . The CAQ181MN product was achieved as a crude dark blue solid (46.2 mg, 90%). Analytical calculation for C25H31C1N406: C, 57.86; H, 6.02; N, 10.80. Found: C: 54.66; H, 4.51; N: 6.81. Example 77: 1, 4 -Bis-. { [2 - (2-chloromethylpiperidin-1-yl-Af-oxide) ethyl] amino} -5, 8-dihydroxyanthracene-9, 10-dione (CAQ192MN) The method follows that of HAQ132N using CAQ90M (11 mg, 0.0187 mmol), m-CPBA (12.9 mg, 0.075 mmol), dry CH2Cl2 (5 mL). The CAQ192MN product was achieved as a crude dark blue solid (10.2 mg, 83%). Analytical calculation for C 30 H 38 Cl 2 N 4 O 6: C, 57.97; H, 6.16; N, 9.01. Found: C: 55.46; H, 4.49; N: 6.93. Example 78: 1, 4 -Bis-. { [2 - (piperidin-1-yl) ethyl] amino} - 5,8-dihydroxy -anthracene-9,10-dione (HAQ145) The method follows that of HAQ105 using 1,4-difluoro-5,8-hydroxy-anthraquinone (50 mg, 0.181 mmol), 1 - (2 - aminoethyl) -piperidine (232 mg, 1.81 mmol), pyridine (1 mL), 30 minutes, 100 ° C. The product HAQ145 was achieved as a dark blue powder (31.7 mg, 35%). Melting point 219-221 ° C. d? (250 MHz, CDC13): 1.45-1.55 (m, 4H, 4 x H-ring), 1.55-1.7 (m, 8H, 8 x H-ring), 2.55 (m, 8H, 2 x NCH2H2), 2.65 ( t, 4H, 2 x HNCH2CH2N), 3.55 (q, 4H, 2 x HNCH2CH2N), 7.05 (s, 2H, C (2) H and C (3) H), 7.15 (s, 2H, C (6) H and C (7) H), 10.5 (t, 2H, C (1) NH and C (4) NH), and 13.65 (s, 2H, C (5) OH, C (8) OH); 5C (62.9 MHz; CDC13): 24.37, 26.09, 40.72, 54.64, 57.63, 109.21, 115.48, 123.63, 124.63, 146.31, 155.46, 30 and 185.35; FAB MS, m / z (M + K) + 493. Analytical calculation for C28H36N406: C, 64.66; H, 7.27; N, 10.78. Found: C, 64.70; H, 7.55; N, 10.67. Example 79: l-. { [(2-Dimethylamino) ethyl] amino} -4-. { [2- (piperidin-1-yl) ethyl] amino} -5,8-dihydroxyanthracene-9,10-dione (HAQ148) The method follows that of HAQ105 using HAQ107 (62 mg, 0.18 mmol), 1- (2-aminoethyl) -piperidine (250 mg, 1953 mmol), pyridine ( 1 mL), 30 minutes, 100 ° C. The HAQ148 product was achieved as a dark blue powder (42.9 mg, 65%). Melting point 220-223 ° C. d? (250 MHz, CDCl 3): 1.45-1.7 (m, 6H, 6 x H-ring), 2.35 (s, 6H, 2 x NCH3), 2.55 (m, 4H, 2 x CH2CH2), 2.75 (2xt, 4H, 2 x HNCH2CH2N), 3.5 (q, 4H, 2 x HNCH2CH2N), 7.05 (s, 2H, C (2) H and C (3) H), 7.1 (m, 2H, C (6) H and C (7 ) H), 10.45 (t, 2H, C (1) NH and C (4) NH), and 13.55 (s, 2H, C (5) OH, C (8) OH); 5C (62.9 MHz; CDC13): 24.28, 25.93, 40.51, 41.24, 45.63, 54.62, 57.50, 58.39, 109.23, 115.41, 123.73, 123.99, 124.75, 146.24, 155.44, and 185.41; FAB MS, m / z (M + H) + 453. Example 80: Super-coiled DNA test of super-coiled plasmid pBR322 was treated with 50 nM of a chloroethylaminoanthraquinone or 100 nM of the corresponding N-oxide, as described in the preceding examples. After 90 minutes of incubation, the resulting complexes were analyzed by gel-based super-winding test. agarose. The chloroethylaminoanthraquinones were observed to unfold DNA, which is consistent with DNA intercalation. The corresponding N-oxides, however, were inactive in this assay. Example 81: Cytotoxicity of N-oxide Derivatives of Chloroethylaminoanthraquinone Compounds HT29 cells were treated with a chloroethylaminoanthraquinone or the corresponding N-oxide, as described in the preceding synthetic examples, at various concentrations up to 100 μ ?. As summarized below in Table 2, the parent chloroethylamino- and hydroxyethylaminoanthraquinones exhibited potent cytotoxic effects (IC50 1-5μ?) While the corresponding N-oxides were inactive (IC50> 100μ?) A the maximum tested concentration (100 μ). Table 2. Cytotoxicity of Chloroethylaminoanthraquinones and IT- Chloroethylaminoanthraquinones oxides Example 82: Location of Derivatives of N-Oxides of Chloroethylaminoanthraquinone Compounds and Hydroxyethylaminoanthraquinone Multicellular spheroids of HT29 cells, which have a hypoxic fraction as measured by GLUT-1, are treated with chloroethylaminoanthraquinone or the corresponding N-oxide (described in the preceding synthetic examples). The treated cells were then observed using confocal microscopy with HeNe laser excitation at 633 nm. Chloroethylamino-anthraquinones were observed binding only to the periphery of the multicellular spheroids. In contrast, the N-oxides were observed in the inner layers of the spheroids and absent from the outer layers of the spheroids. This result indicates that the N-oxides of the non-covalent and covalent ligation anthraquinones with DNA affinity can be prepared and that such compounds can be used as molecular delivery devices by directing potent cytotoxic agents to hypoxic tumor cells.

Claims (16)

1. CLAIMS 1. A method for directing a cytotoxic anthraquinone related to DNA inside a cell mass, comprising contacting an N-oxide of a cytotoxic anthraquinone related to DNA with the cell mass, where the interior of the cell mass is hypoxic and where the N-oxide is reduced under hypoxic conditions, thereby directing a cytotoxic anthraquinone related to DNA inside a cell mass.
2. 2. The method of claim 1, wherein the cell mass is a cellular spheroid.
3. 3. The method of claim 1, wherein the cell mass is a tumor.
4. 4. The method of claim 3, wherein the tumor is a carcinoma or a sarcoma.
5. 5. The method of claim 3, wherein the tumor is a tumor of the lung, breast, ovary, stomach, pancreas, larynx, esophagus, testes, liver, parotid, biliary tract, colon, rectum, cervix, uterus, endometrium, kidney, bladder, prostate, or thyroid gland.
6. The method of claim 3, wherein the tumor is squamous cell carcinoma, adenocarcinoma, small cell carcinoma, melanoma, glioma, neuroblastoma, Wilms tumor, Ewing's sarcoma, neuroblastoma, rhabdomyosarcoma, or osteosarcoma.
7. 7. The method of claim 1, wherein the N-oxide locates the interior of the cell mass.
8. The method of claim 1, wherein the DNA-related cytotoxic anthraquinone is a chloroethylaminoanthrachynone.
9. The method of claim 1, wherein the DNA-related cytotoxic anthraquinone is a compound of the formula (l) where R1 to R4 are each selected from the group consisting of H, C1_i alkyl, X1, -NHR ° N (R5) 2 in which R ° is a C1.12 alkanediyl and each R5 is H or optionally C1 alkyl -4 substituted, and a group of formula II: (II) in which at least one of R6, R7 and R8 is selected from of X2, and C1-4 alkyl substituted with X2 and any other are H or C1-4 alkyl; R 9 is selected from H, C 1 alkyl, X 2 and C 1-4 alkyl substituted with X 2; m is 0 or 1; n is 1 or 2; X 1 is a halogen atom, a hydroxyl group, a C 1 alkoxy group, an aryloxy group or an acyloxy group; and X2 is a halogen atom, a hydroxyl group, an alkoxyl group an aryloxy group or an acyloxy group; provided that at least one of R1 to R4 is a group of formula II.
10. A method for treating a solid tumor in a subject, comprising: administering to the subject an N-oxide of a cytotoxic anthraquinone afin DNA, where the incorporation of N-oxidation to the cytotoxic anthraquinone prevents DNA affinity, where the reduction of N-oxide generates a therapeutically effective cytotoxin; thereby treating a solid tumor in a subject.
11. 11. A pro-drug directed to hypoxia comprising an N-oxide of an anthraquinone related to DNA.
12. 12. A molecular delivery device for directing a deactivated therapeutic agent to a cell, comprising a DNA directed cytotoxic agent of claim 9 having an N-oxide component.
13. 13. A method to treat a solid tumor in a subject, comprising: administering to the patient a therapeutically effective amount of an N-oxide derivative of an alkylating or non-alkylating anthraquinone, wherein the N-oxide derivative of the alkylating or nonalkylating anthraquinone does not display affinity to DNA and is inactive until which is reduced in a hypoxic environment, thereby treating a solid tumor in a subject.
14. 14. A method for directing a cytotoxic agent to the DNA of a cell, comprising: a. preparing a complex of an N-oxide and an alkylating chloroethylaminoanthraquinone or a nonalkylating hydroxyethylaminoanthraquinone, wherein the N-oxide of the alkylating or nonalkylating anthraquinone does not display affinity to DNA; and b. contacting a cell with the complex, thereby directing the cytotoxic agent to the cell's DNA.
15. 15. The method of claim 14, wherein the N-oxide of the alkylating anthraquinone or non-alkylating anthraquinone does not induce cross-linking of substantial DNA.
16. 16. The method of claim 14, wherein the N-oxide of the alkylating anthraquinone or non-alkylating anthraquinone does not display cytotoxicity in the presence of normal oxygen tension.