131401-54-2Relevant academic research and scientific papers
A large-scale synthesis of the bioreductive drug 1,4-bis{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione bis-N-oxide (AQ4N)
Lee, Ho H.,Denny, William A.
, p. 2755 - 2758 (1999)
A large-scale synthesis of the bis-bioreductive drug 1,4-bis{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxy-anthracene-9,10-dione bis-N-oxide (AQ4N) has been developed. This six-step synthesis provides AQ4N in 20% overall yield from readily available tetrachlorophthalic anhydride. The key step was a KF-NaF-mediated conversion of 3,6-dichlorophthalic anhydride to 3,6-difluorophthalic anhydride, which could be achieved in 77% yield on a 100 g scale. A trace impurity in AQ4N was determined (by LC-MS and independent synthesis) to be the mono-N-oxide 1-amino-4-[2-(dimethylamino)ethyl]amino-5,8-dihydroxyanthracene-9,10-dione N-oxide. This is formed spontaneously from AQ4N under a number of conditions, including during HPLC on reversed-phase columns. The Royal Society of Chemistry 1999.
New anthracenedione derivatives with improved biological activity by virtue of stable drug-DNA adduct formation
Mansour, Oula C.,Evison, Benny J.,Sleebs, Brad E.,Watson, Keith G.,Nudelman, Abraham,Rephaeli, Ada,Buck, Damian P.,Collins, J. Grant,Bilardi, Rebecca A.,Phillips, Don R.,Cutts, Suzanne M.
, p. 6851 - 6866 (2010)
Mitoxantrone is an anticancer agent that acts as a topoisomerase II poison, however, it can also be activated by formaldehyde to form DNA adducts. Pixantrone, a 2-aza-anthracenedione with terminal primary amino groups in its side chains, forms formaldehyde-mediated adducts with DNA more efficiently than mitoxantrone. Molecular modeling studies indicated that extension of the "linker" region of anthracenedione side arms would allow the terminal primary amino greater flexibility and thus access to the guanine residues on the opposite DNA strand. New derivatives based on the pixantrone and mitoxantrone backbones were synthesized, and these incorporated primary amino groups as well as extended side chains. The stability of DNA adducts increased with increasing side chain length of the derivatives. A mitoxantrone derivative bearing extended side chains (7) formed the most stable adducts with ～100-fold enhanced stability compared to mitoxantrone. This finding is of great interest because long-lived drug-DNA adducts are expected to perturb DNA-dependent functions at all stages of the cell cycle.
NEW COMPOUNDS AND USES THEREOF
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Page/Page column 32, (2014/03/21)
The present invention provides an anthraquinone compound of formula I (such as the compounds of formulae II to X) and processes for making the same. The invention further provides pharmaceutical compositions for use in the treatment of cancer, optionally in combination with an agent capable of reducing the level of oxygenation of a tumour. Additionally the invention provides an option for combination with chemotherapeutic and radiotherapeutic modalities to enhance overall tumour cell kill. The invention additionally provides methods for the detection of cellular hypoxia, both in vivo and in vitro.
ANTHARQUINONE COMPOUNDS AS ANTI CANCER COMPOUNDS
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Page/Page column 19, (2008/06/13)
Anthraquinone compounds of the general formula (I) or a salt thereof (Formula I) in which R1 to R4 are each selected from the group consisting of H, C1-4 alkyl, X1, -NHR0N (R5)2 in which R0 is a C1-12 alkanediyl and each R5 is H or optionally substituted C1-4 alkyl, and a group of formula (II) in which at least one of R6,R7 and R8 is selected from X2 , and X2 substituted C1-4 alkyl and any others are H or C1-4 alkyl; R9 is selected from H, C1-4 alkyl, X2 and X2 substituted C1-4 alkyl; 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 alkoxyl group, an aryloxy group or an acyloxy group; provided that at least one of R1 to R4 is a group of formula (II). The N-oxides are useful prodrugs which are selectively bioreduced in hypoxic tumours to the corresponding cyclic amine derivatives. The amine compounds are cytotoxic and may be used as alkylating agents having topoisomerase II inhibiting activities in cancer therapy.
PROCESS FOR THE PREPARATION OF AQ4N
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Page/Page column 14-16; 22, (2008/06/13)
A process for the preparation of compound AQ4N of formula (2) or a salt or solvate thereof wherein the said process includes the reaction step: Formula (1), Formula (2), where compound AQ4 of formula (1) is oxidised to compound AQ4N of formula (2) with an oxidising agent at a reaction temperature not exceeding 10°C.
Synthetic method
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, (2008/06/13)
A process for the preparation of the compound AQ4 of formula 3: or a salt or N-oxide thereof, includes the step:
The Synthesis of 1,4-Difluoro-5,8-dihydroxyanthracene-9,10-dione and Ipso Substitutions of the Fluorides by Diamines Leading to 1,4-Bis--5,8-dihydroxyanthracene-9,10-diones
Krapcho, A. Paul,Getahun, Zelleka,Avery, Kenneth J.
, p. 2139 - 2146 (2007/10/02)
Two synthetic pathways to 1,4-difluoro-5,8-dihydroxyanthracene-9,10-dione (2) are described.The ipso substitution of the fluorides of 2 by diamines is a valuable preparative route to 1,4-bis-5,8-dihydroxyanthracene-9,10-diones related t
