70476-63-0Relevant articles and documents
Efficient hypoxic activation of the anticancer agent AQ4N by CYP2S1 and CYP2W1
Nishida, Clinton R.,Lee, Melody,Ortiz De Montellano, Paul R.
experimental part, p. 497 - 502 (2011/11/12)
AQ4N [1,4-bis{[2-(dimethylamino-N-oxide)ethyl]amino}-5,8- dihydroxyanthracene-9,10-dione], a prodrug with two dimethylamino N-oxide groups, is converted to the topoisomerase II inhibitor AQ4 [1,4-bis{[2- (dimethylamino)ethyl]amino}-5,8-dihydroxy-anthracene-9,10-dione] by reduction of the N-oxides to dimethylamino substituents. Earlier studies showed that several drug-metabolizing cytochrome P450 (P450) enzymes can catalyze this reductive reaction under hypoxic conditions comparable with those in solid tumors. CYP2S1 and CYP2W1, two extrahepatic P450 enzymes identified from the human genome whose functions are unknown, are expressed in hypoxic tumor cells at much higher levels than in normal tissue. Here, we demonstrate that CYP2S1, contrary to a published report (Mol Pharmacol 76:1031-1043, 2009), is efficiently reduced by NADPH-P450 reductase. Most importantly, both CYP2S1 and CYP2W1 are better catalysts for the reductive activation of AQ4N to AQ4 than all previously examined P450 enzymes. The overexpression of CYP2S1 and CYP2W1 in tumor tissues, together with their high catalytic activities for AQ4N activation, suggests that they may be exploited for the localized activation of anticancer prodrugs. Copyright
Anti-cancer compounds
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, (2008/06/13)
Compounds of formula (I) STR1 in which R1, R2, R3 and R4 are each separately selected from hydrogen, X, NH--A--NHR and NH--A--N(O)R'R" wherein X is hydroxy, halogeno, amino, C1-4 alkoxy or C2-8 alkanoyloxy, A is a C2-4 alkylene group with a chain length between NH and NHR or N(O)R'R" of at least 2 carbon atoms and R, R' and R" are each separately selected from C1-4 alkyl groups and C2-4 hydroxyalkyl and C2-4 dihydroxyalkyl groups in which the carbon atom attached to the nitrogen atom does not carry a hydroxy group and no carbon atom is substituted by two hydroxy groups, or R' and R" together are a C2-6 alkylene group which with the nitrogen atom to which R" and R" are attached forms a heterocyclic group having 3 to 7 atoms in the ring, but with the proviso that at least one of R1 to R4 is a group NH--A--N(O)R'R", and physiologically acceptable salts thereof are of value in the treatment of cancer.
