Redox chemistry of anthracycline antitumor drugs and use of captodative radicals as tools for its elucidation and control

Abstract

The oxomorpholinyl radicals are unique materials in organic and medicinal chemistry. Their closest parallel lies in inorganic chemistry with dithionite, which exists in equilibrium with sulfur dioxide radical anion, also a one-electron reducing agent. However, dithionite is a more powerful reducing agent and is probably more toxic. The rate of release of the oxomorpholinyl radical from its dimer is medium and is structure dependent, which provides for some level of control. The oxomorpholinyl radicals TM-3 and DHM-3 are selective one-electron reducing agents for the anthracyclines, generating sequentially semiquinone and hydroquinone redox states. Formation of the reduced states of the anthracyclines is probably relevant to their cytotoxic activity. Semiquinones and hydroquinones react rapidly with molecular oxygen to yield superoxide. Hydroquinone redox states with anaerobic conditions in protic media at pH 7-8 undergo glycosidic cleavage to form quinone methides; in aprotic media or at pH less than 4, they tautomerize to leuco forms. Quinone methides react with protons from solvent to form 7-deoxyaglycons, with some nucleophiles to form adducts, and with molecular oxygen to form semiquinone methide. The reactivity of the quinone methide is a function of substitution; nucleophilic addition is facilitated by the absence of a hydroxyl group at the 11-position and by proper location of the nucleophile. Quinone methides and semiquinone methides are both viable transients for covalently linking anthracycline aglycons to biological macromolecules. DHM-3 dimer is of possible pharmaceutical value for the detoxification of quinone antitumor drugs and for the improvement of chemotherapy through modulating the redox chemistry of the quinone antitumor drugs.

Time‐related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function

“…However, in our preparation, caffeine (1 mM), which rapidly depressed contractility, failed to produce significant time-related changes, despite its wellknown ability to release SR Ca2" (Palade, 1987;Pessah et al, 1987) and increase muscle stiffness (Sutko et al, 1986;Schouten, 1990). Similarly, ruthenium red, a negatively inotropic agent that inhibits Ca2" release from SR (Zimanyi & Pessah, 1991 (Boucek et al, 1987b;Olson et al, 1981;Floreani & Carpandeo, 1989;Averbuch et al, 1988;Olson & Mushlin, 1990;Gaudiano & Koch, 1991) (Table 2). On this basis, for doxorubicin and doxorubicinol to make equal contributions to dysfunction associated with doxorubicin treatment, doxorubicinol would need to be 74 fold to 778 fold more potent than doxorubicin to impair subcellular functions (Table 4).…”

Ferrocenyl compounds possessing protected phenol and thiophenol groups: Synthesis, X-ray structure, and in vitro biological effects against breast cancer

“…The formation of QMs is an important pathway for the metabolism of many compounds, including natural products [12][13][14], selective estrogen receptor modulators [15][16][17][18], and drugs [19][20][21][22]. However, to our knowledge, only one example of an isolable p-thioquinone methide has been reported, 10-(dicyanomethylene)thioanthrone, which is stabilized by electron withdrawing cyano groups and an annelated phenyl ring [23].…”

Um panorama atual da química e da farmacologia de naftoquinonas, com ênfase na beta-lapachona e derivados

“…Foi observado que muitas quinonas possuem um grupo de saí-da que pode ser ativado por redução das carbonilas quinonoídicas, gerando intermediários alquilantes 22 (agentes antineoplásicos biorredutores). Atualmente, existem sólidas evidências de que este mecanismo de ação é o que mais se aproxima das ações farmacológicas das mitomicinas e antraciclinas 23 . A quimioterapia baseada num planejamento racional de fármacos tem, então, no sistema redox das quinonas um bom modelo para estudos teóricos.…”