Design and Synthesis of Angucyclinone 5-Aza Analogues

Abstract

A highly efficient one-pot procedure for the synthesis of phenanthridine-1,7,10-triones from acylbenzoquinones and cyclic enaminones is reported. The cycloaddition reactions of these quinones with 1-trimethylsilyloxybutadiene followed by hydrolysis and oxidative processes provide entry to a variety of angucyclinone 5-aza analogues.The substitution of a nitrogen atom for an aromatic CH group in anticancer drugs (e.g. ametantrone and 11-deoxydoxorubicin), 1,2 which provides active antitumor Nanalogues, has shown to be an effective strategy to design new potential antitumor compounds. These N-heterocyclic aromatic congeners could potentially retain the planar shape of the drug chromophore necessary for molecular recognition of the host. Furthermore, the basic and electron-withdrawing properties of the N-heterocycles seem to improve the affinity for the biological target and/or the cyclic redox mechanism. 3,4The synthesis of aza congeners of the benz[a]anthraquinone chromophore of angucyclines and angucyclinones 5,6 has received relatively little attention despite the antitumor activity of several members of this family of antibiotics. In this respect, Guingant et al. 7 have reported the synthesis of angucyclinone aza analogues by a method that involves cycloaddition reactions of 2-bromo-1,4-naphthoquinone derivatives with a push-pull heterodiene.As part of our continuous interest in the synthesis and biological evaluation of quinones 8 we have recently reported studies on azaanthraquinones. 8a The efficient and regioselective access to these compounds along with their promising antitumoral activities on several tumor cell lines encouraged us to extend our studies to the synthesis of aza analogues of benz[a]anthracene-1,7,12-trione, the skeleton of some angucyclines and angucyclinones.We now report our findings which show that phenanthridine-7,10-quinone derivatives can be efficiently obtained via an ionic [3+3] process from commercially available precursors. The applications of these quinones in the synthesis of benzo[j]phenanthridine-7,12-quinones through highly regiocontrolled [4p+2p]-cycloaddition reactions is also described.Based on recent results on the high-yield synthesis of a 5,8-dihydroxyisoquinoline derivative by reaction of acetylbenzoquinone 3b with methyl aminocrotonate, 8a we envisaged the construction of 7,10-dihydroxyphenanthridines by reaction of acyl-1,4-benzoquinones with cyclic enaminones. The following commercially available compounds were employed in this study: 2,5-dihydroxybenzaldehyde (1a), 2,5-dihydroxyacetophenone (1b), 3-amino-2-cyclohexen-1-one (2a), and 3-amino-5,5-dimethyl-2-cyclohexen-1-one (2b).Formylbenzoquinone 3a, prepared by oxidation of 1a with silver(I) oxide, 9 reacts with enaminone 2a at room temperature to give dihydroxyphenanthridine 4a in 87% yield. Similarly, acetylbenzoquinone 3b, prepared from 2,5-dihydroxyacetophenone (1b) and manganese dioxide, 10 was reacted with 2a in dichloromethane to yield dihydroxyphenanthridine 4b in 68% yield. Then, dihydroxyphenanthridines 4a...

Synthetic approaches and in vitro cytotoxic evaluation of 2-acyl-3-(3,4,5-trimethoxyanilino)-1,4-naphthoquinones

“…[5][6][7][8][9][10][11][12][13] The 2-acyl-1,4-benzo-and 1,4-naphthoquinones exhibit remarkable features in terms of their reactivity with nucleophiles due to the fact that the electrophilic centers at the quinone nucleus and acyl substituent are suitably located, thus enabling reactions with compounds such as arylamines [14][15][16] azaenamines 17 enaminones 18,19 and 2-aminobenzothiazoles 20 to give rise to a broad variety of quinonoid compounds such as those depicted in Fig. 1.…”

Hetero-annulation reaction between 2-acylnaphthoquinones and 2-aminobenzothiazoles. A new synthetic route to antiproliferative benzo[g]benzothiazolo[2,3-b]quinazoline-7,12-quinones

“…12 Our synthetic strategy to entry into isoquinoline-containing polycyclic quinones is based on the hetero-annulation reaction of 2-acyl-1,4-quinones with primary acyclic-and endocyclic enaminones, where the electrophilic a,b-unsaturated acyl fragment of the quinone and the ambident nucleophile H 2 NACH@CRA group of the enaminone are involved in the N-heterocyclic ring formation. [13][14][15] Taking into account the similar chemical reactivity of enaminones 16 and 2-aminobenzothiazoles 17 to act as ambident nucleophiles with a,b-unsaturated carbonyl compounds to give heterocycles, we decided to explore the synthesis of benzo[g]benzothiazolo[2,3-b]quinazoline-7,12-quinones from 2-acylnaphthoquinones and 2-aminobenzothiazoles. To the best of our knowledge, the sole precedent regarding the synthesis of antiproliferative benzo[g]benzothiazolo[2,3-b]quinazolinequin ones is the recent report on amberlyst-15 catalyzed three-component condensation of 2-aminobenzothiazole, aromatic aldehydes, and 2-hydroxy-1,4-naphthoquinone.…”

3-Amino-5,5-dimethylcyclohex-2-enone in the synthesis of heterocyclic compounds (review)

“…The one-stage synthesis of phenanthridine-1,7,10-triones 108a,b from the enaminone 1 and 2-acylhydroquinones is proved to be an effective method [59]. …”