Oxidized Juncuenin B Analogues with Increased Antiproliferative Activity on Human Adherent Cell Lines: Semisynthesis and Biological Evaluation

Abstract

Phenanthrenes have become the subject of intensive research during the past decades because of their structural diversity and wide range of pharmacological activities. Earlier studies demonstrated that semisynthetic derivatization of these natural compounds could result in more active agents, and oxidative transformations are particularly promising in this regard. In our work, a natural phenanthrene, juncuenin B, was transformed by hypervalent iodine(III) reagents using a diversity-oriented approach. Eleven racemic semisynthetic compounds were produced, the majority containing an alkyl substituted p -quinol ring. Purification of the compounds was carried out by chromatographic techniques, and their structures were elucidated by 1D and 2D NMR spectroscopic methods. Stereoisomers of the bioactive derivatives were separated by chiral-phase HPLC and the absolute configurations of the active compounds, 2,6-dioxo-1,8a-dimethoxy-1,7-dimethyl-8-vinyl-9,10-dihydrophenanthrenes ( 1a – d ), and 8a-ethoxy-1,7-dimethyl-6-oxo-8-vinyl-9,10-dihydrophenanthrene-2-ols ( 7a , b ) were determined by ECD measurements and TDDFT-ECD calculations. The antiproliferative activities of the compounds were tested on different (MCF-7, T47D, HeLa, SiHa, C33A, A2780) human gynecological cancer cell lines. Compounds 1a – d , 4a , 6a , and 7a possessed higher activity than juncuenin B on several tumor cell lines. The structure–activity relationship studies suggested that the p -quinol (2,5-cyclohexadien-4-hydroxy-1-one) moiety has a considerable effect on the antiproliferative properties, and substantial differences could be identified in the activities of the stereoisomers.

Antiproliferative Phenanthrenes from Juncus tenuis: Isolation and Diversity-Oriented Semisynthetic Modification

“…While many oxidants are available for the oxidation of phenols, the use of [bis-(trifluoroacetoxy)]iodobenzene (PIFA) was a natural follow-up to our previous work on the diversity-oriented transformation of phenolic natural products. This reagent allows selective transformation of phenolic hydroxyl groups under mild conditions, and we have previously found it to be efficient in the (i) synthesis of functionalized quinol derivatives with antitumor potential [ 27 , 37 ], and (ii) simulation of certain biomimetic oxidative conditions [ 38 ]. The latter is because it may act not only through an aryloxyiodonium(III) intermediate forming a phenoxenium ion that undergoes a nucleophilic attack, but it can also oxidize aromatic compounds via a single-electron transfer mechanism [ 39 , 40 ].…”

“…Juncuenin B, a natural phenanthrene isolated from Juncus inflexus , differs from juncusol in only the position of substituents (hydroxy at C-6, methyl at C-7, and vinyl at C-8) on ring C. In our previous investigation, semisynthetic derivatives of juncuenin B were prepared [ 27 ]. Some of these compounds contain the same structural elements ( o - and p -quinoidal structure; methoxy- and ethoxy-substitution) as juncusol derivatives produced in this experiment.…”

“…Starting from juncuenin B, we prepared and characterized eleven derivatives via hypervalent iodine-catalyzed oxidation. Among these differently substituted compounds bearing p - or o -quinol rings, three showed considerable antiproliferative effects against different tumor cell lines, and their activity was enantiospecific [ 27 ].…”

Unique Phenanthrenes from Juncus ensifolius and Their Antiproliferative and Synergistic Effects with the Conventional Anticancer Agent Doxorubicin against Human Cancer Cell Lines

“…In this investigation, 17 phenanthrenes, among them ensifolins A-M (1-13) as new natural products, four known ones (14)(15)(16)(17), and 4-hydroxybenzaldehyde (18) and luteolin (19), were characterized from the whole plant of J. ensifolius. Their planar structures were elucidated by comprehensive spectroscopic data.…”

“…Juncuenin possessed promising antiproliferative activity (IC 50 2.9 µM) against HeLa cells. One of its semisynthetic derivatives, differing only in the presence of a methoxy group at C-8a and a carbonyl group at ring C, showed an even higher inhibitory effect (IC 50 0.9 µM) [ 15 ]. In a superoxide anion generation assay, remarkable anti-inflammatory activity was determined for juncusol (IC 50 3.1 µM) and juncuenin B (IC 50 4.9 µM).…”