38554-25-5Relevant articles and documents
Reaction of anthracycline antitumor drugs with reduced glutathione. Formation of aglycon conjugates
Gaudiano, Giorgio,Resing, Katheryn,Koch, Tad H.
, p. 6537 - 6544 (1994)
Anaerobic reduction of adriamycin (1) with bi(3,5-dimethyl-6-(hydroxymethyl)-2-oxomorpholin-3-yl) (DHM-3-dimer), bi(3,5,5-trimethyl-2-oxomorpholin-3-yl) (TM-3-dimer), or dithionite in the presence of excess reduced glutathione (GSH, 9) yielded the aglycon conjugate, 7-deoxy-7-S-glutathionyladriamycinone (11 a,b), as a mixture of diastereoisomers together with 7-deoxyadriamycinone (12) via 7-deoxyadriamycinone quinone methide. Anaerobic reaction of adriamycin with reduced glutathione also yielded, in a slower reaction, the conjugates with the glutathione serving both as the reducing agent and as the nucleophile reacting with the quinone methide, as proposed in Scheme 2. A separate reductive cleavage of 11a,b to 12 established reversibility of the nucleophilic addition. The proposed mechanism was further supported by the reaction composition at termination as a function of conditions. At higher concentrations of 1 and 9, a 99% yield of salt 13, consisting of the anion of 11b and adriamycin cation, precipitated and was characterized spectroscopically. The conjugate 11b was subsequently separated from adriamycin by extraction. The anthracyclines daunomycin (2) and menogaril (10) also reacted with glutathione with and without an additional reducing agent to yield the respective aglycon conjugates, 7-deoxy-7-S-glutathionyldaunomycinone (14a,b) and 7-deoxy-7-S-glutathionylnogarol (15a,b), characterized predominantly by HPLC electrospray mass spectrometry. Enzyme catalyzed formation of 11a,b may be relevant to tumor cell resistance to adriamycin.
Arachidonic Acid Metabolism by Human Cardiovascular CYP2J2 Is Modulated by Doxorubicin
Arnold, William R.,Baylon, Javier L.,Tajkhorshid, Emad,Das, Aditi
, p. 6700 - 6712 (2017)
Doxorubicin (DOX) is a chemotherapeutic that is used in the treatment of a wide variety of cancers. However, it causes cardiotoxicity partly because of the formation of reactive oxygen species. CYP2J2 is a human cytochrome P450 that is strongly expressed in cardiomyocytes. It converts arachidonic acid (AA) into four different regioisomers of epoxyeicosatrienoic acids (EETs). Using kinetic analyses, we show that AA metabolism by CYP2J2 is modulated by DOX. We show that cytochrome P450 reductase, the redox partner of CYP2J2, metabolizes DOX to 7-deoxydoxorubicin aglycone (7-de-aDOX). This metabolite then binds to CYP2J2 and inhibits and alters the preferred site of metabolism of AA, leading to a change in the ratio of the EET regioisomers. Furthermore, molecular dynamics simulations indicate that 7-de-aDOX and AA can concurrently bind to the CYP2J2 active site to produce these changes in the site of AA metabolism. To determine if these observations are unique to DOX/7-de-aDOX, we use noncardiotoxic DOX analogues, zorubicin (ZRN) and 5-iminodaunorubicin (5-IDN). ZRN and 5-IDN inhibit CYP2J2-mediated AA metabolism but do not change the ratio of EET regioisomers. Altogether, we demonstrate that DOX and 7-de-aDOX inhibit CYP2J2-mediated AA metabolism and 7-de-aDOX binds close to the active site to alter the ratio of cardioprotective EETs. These mechanistic studies of CYP2J2 can aid in the design of new alternative DOX derivatives.
