71582-53-1Relevant articles and documents
Formation and Reaction of the Quinone Methide from Reductive Cleavage of the Antitumor Drug Menogaril
Boldt, Marybeth,Gaudiano, Giorgio,Haddadin, Makhluf J.,Koch, Tad H.
, p. 2283 - 2292 (2007/10/02)
Anaerobic reduction of menogaril (1), a semisynthetic antiumor drug in clinical trials, with d,l-bi(3,5,5-trimethyl-2-oxomorpholin-3-yl) (TM-3 dimer) in methanol gave 7-deoxynogarol (5) and stereoisomers of bi(7-deoxynogarol-7-yl) (6) and, in the presence of N-acetylcysteine, 7-(N-acetylcysteinyl)-7-deoxynogarol (10) via an observed quinone methide intermediate (8).In the presence of excess reducing agent, 5 was formed relatively rapidly as the major product in its hydroquinone state.The rate-controlling step, tautomerization of the quinone methide, was autocatalyzed; the product, the hydroquinone of 5, catalyzed the reaction.In fact, several anthracycline-derived hydroquinones were effective catalysts.Uncatalyzed tautomerization of the quinone methide yielded little if any 5, in contrast with facile unimolecular formation of 7-deoxyaglycons from reduction of other anthracyclines.In the absence or presence of excess reducing agent, the rate of formation of 6 or formation of 6 in its bishydroquinone state, respectively, was second order in quinone methide concentration and relatively slow.The rate constants for the autocatalyzed tautomerization and the dimerization of the quinone methide are 27 +/- 2 and 11+/-1 M-1s-1, respectively.Reduction of menogaril in aqueous medium gave predominantly 7-deoxynogarol (5) relatively rapidly with excess reducing agent and a mixture of 5 and the aglycon dimer 6 slowly with substoichiometric amounts of reducing agent.Under both sets of conditions, the quinone methide transient was not observed.Reduction in aqueos medium with 0.3 equiv of reducing agent in the presence of N-acetylcysteine gave high yields of adduct 10, suggesting a relatively longlifetime for the unobservable quinone methide transient even in aqueous medium in the absence of hydroquinones and reactive nucleophiles.A possible in vivo consequence of the relatively slow uncatalyzed tautomerization of the quinone methide is efficient nucleophilic trapping.
Trapping of the Quinone Methide from Reductive Cleavage of Menogaril with the Nitrogen Nucleophile Imidazole
Gaudiano, Giorgio,Egholm, Michael,Haddadin, Makhluf J.,Koch, Tad H.
, p. 5090 - 5093 (2007/10/02)
Anaerobic reduction of menogaril, 7-con-O-methylnogarol (1), a semisynthetic antitumor drug in clinical trials, with 10 mol percent of meso-bi(3,5,5-trimethyl-2-oxomorpholin-3-yl) (meso-TM-3 dimer, 4) in methanol at ambient temperature in the presence of a large excess of imidazole yielded 58percent of a mixture of con- and dis-7-imidazoyl-7-deoxynogarol (8) and 13percent 7-deoxynogarol (7).Similar reduction of 1 with 30 mol percent of a mixture of the diastereoisomers of bi(3,5-dimethyl-5-(hydroxymethyl)-2-oxomorpholin-3-yl) (DHM-3 dimers, 9) in water yielded 54percent 8 and 33percent 7.The reaction isproposed to occur by the Fisher chain mechanism with reductive activation to the quinone methide state 2 followed by nucleophilic addition of imidazole and subsequent oxidation of adduct hydroquinone 14 by starting menogaril.These experiments represent the first trapping of an anthracycline quinone methide state with a nitrogen nucleophile.
SYNTHETIC STUDIES ON NOGALAMYCIN CONGENERS ; TOTAL SYNTHESES OF (+)-NOGARENE, (+)-7-DEOXYNOGAROL, AND (+)-7-CON-O-METHYLNOGAROL
Kawasaki, Motoji,Matsuda, Fuyuhiko,Terashima, Shiro
, p. 5727 - 5744 (2007/10/02)
According to the retrosynthetic perspective, the title total syntheses were accomplished by employing the regioselective Diels-Alder reactions of the (+)-naphthoquinone (5), the CDEF-ring system of nogalamycin congeners, with various structural types of dienes (8, 16, and 26).The highly functionalized dienes (16 and 26) incorporating all the functionalities present in the A-rings of (+)-7-deoxynogarol (3) and (+)-7-con-O-methylnogarol (2), were prepared efficiently by way of the 1,4-cyclohexadiene and 2-cyclohexanone derivatives (6 and 21), respectively.Reaction mechanism of the key Diels-Alder reaction was also discussed in terms of its stereoselectivity.
Structure-Activity Relationships of Nogalamycin Analogues
Wiley, Paul F.,Elrod, David W.,Houser, David J.,Richard, Floyd A.
, p. 560 - 567 (2007/10/02)
Nogalamycin (1) has been modified by changes at C-10 and C-7 and in the dimethylamino group to prepare an extensive series of analogues.The chemistry involved in the modifications and structure-activity relationships among these nogalamycin analogues are discussed, as well as comparisons with previously reported compounds 1, 7-con-O-methylnogarol (2), and disnogamycin (11).
