The carcinogenicity of 15,16-dihydro-11-methyl-cyclopenta[a]phenanthren-17-one

Abstract

Fig. 1) is the most active, and that its activity depends upon 2 structural features: the presence of a small electron-releasing group at C-11, and further coniuLyation of the phenanthrene ring system at C-17. Of the monomethyl isomers, only the 11-methyl-17-ketone (1)

A stereospecific total synthesis of the anthracyclinones (.+-.)-daunomycinone and (.+-.)-isodaunomycinone

“…sequently converted as described in Scheme XIV to isodaunomycinone (6). The physical and spectral properties of our isodaunomycinone (6) are consistent with those reported by Krohn et al35 Since methods for the introduction of the hydroxyl function at C-14 have been described,30 this route also formally constitutes the synthesis of adriamycinone and isoadriamycinone.…”

“…This effort has been further stimulated by the fact that small structural differences can produce dramatic activity effects. For example, the synthetic analogue 4-desmethoxydaunorubicin (idarubicin ( 4)) is between 4 and 8 times more active than daunorubicin.6 7 The anthracycline structures are composed of a tetracyclic aglycon attached to the amino sugar L-daunosamine.8,9 Since a variety of syntheses of this sugar10 and its coupling to daunomycinone (5) have been described,11 (6) Lenaz, L.; Page, J. A.…”

“…In particular we were interested in developing a synthetic strategy that would not only generate both isomeric daunomycinones 5 and 6 but be general enough for analogue preparation and additionally incorporate a high-yielding stereospecific introduction of the 7-hydroxyl function. This previously difficult hydroxylation has been accomplished in our synthesis of 4-desmethoxydaunomycinone.12 In this paper we report the full details of our total synthesis of both daunomycinone 5 and its regioisomer 6. Following the first synthesis of l,13 a number of general approaches for the construction of the tetrahydro-5,12naphthacenedione ring system, some demonstrating regiochemical control in the orientation of the Aand D-ring substituents, have been described.14 In our approach, we chose 5-methoxy-1,4,9,10-anthradiquinone (29)15 as our Diels-Alder dienophile and irans-4-(trimethylsilyl)-2acetoxy-1, 3-butadiene (31)12a,b as the diene for ultimate conversion to isodaunomycinone (6) and daunomycinone (5), respectively. We noted that relatively electron rich dienes add to the internal double bond (Scheme I) of anthradiquinones (7) to produce 10 while relatively electron deficient dienes prefer the terminal double bond, generating (9).15-17,22 Since diene 31 is electron poor, we expected it to add predominantly to the terminal double bond.…”

Potentially Carcinogenic Cyclopenta[a]phenanthrenes. Part 12.1 Synthesis of metabolites of the Carcinogen 16,17-Dihydro-11-methoxy-15H-cyclopenta[a]-phenanthrene

“…In the cyclopenta[a]phenanthrene series carcinogenicity is induced by the presence of a small electron-releasing group at C-11 in the bay-region, 2,3 and is greatly enhanced by further unsaturation in the ®ve-membered ring. Thus the 11-methyl-17-ketone is a carcinogen with potency similar to that of the classic polycyclic aromatic hydrocarbon benzo[a]pyrene in the mouse, 4 whereas the 11-methyl hydrocarbon lacking unsaturation in this ring is only very weakly active. 5 Not unexpectedly the 11-methoxy-17-ketone 3b is also a strong carcinogen, 2 but here there is a dierence because the 11-methoxy hydrocarbon 3a is almost equally active.…”

SHORT COMMUNICATION: The in vitro metabolic activation of the 11-trifluoromethyl analogue of the potent carcinogen 15, 16-dihydro-11-methyl-cyclopenta[a]-phenanthren-17-one to mutagens

“…This 11-methyl derivative (2) has been found to induce skin tumours in a number of mouse strains (1 -5) as well as a variety of other soft tissue tumours following s.c. injection in rats and mice (2,3,6). More recently it has been observed to increase the rate of myeloid leukaemia in male Sprague -Dawley rats; in addition the compound was found to act as a potent initiator of silica-induced mesothelioma (7).…”