New Cytotoxic Naphthohydroquinone Dimers from Rubia alata

Abstract

Two novel naphthohydroquinone dimers with unprecedented skeletons, rubialatins A (1) and B (2), were isolated from the herbal plant Rubia alata together with their precursor, mollugin (3). The structures were elucidated on the basis of NMR spectra and crystal X-ray diffraction. Compound 1, a racemate, was separated by chiral column chromatography, and the absolute configurations of the enantiomers were determined by the computational methods. Cytotoxicity of 1-3 was evaluated as well as the effect on the NF-κB pathway. Compound (+)-1 showed cytotoxicity and could inhibit NF-κB pathway. Meanwhile, 2 showed cytotoxicity and a synergistic effect with TNF-α on NF-κB activation.

Natural Naphthohydroquinone Dimer Rubioncolin C Exerts Anti-Tumor Activity by Inducing Apoptotic and Autophagic Cell Death and Inhibiting the NF-κB and Akt/mTOR/P70S6K Pathway in Human Cancer Cells

“…The roots and rhizomes of several Rubia plants have been widely used for the treatment of cancer, menoxenia, rheumatism, and tuberculosis, especially R. cordifolia, which was recorded as a traditional Chinese medicine in all editions of Chinese Pharmacopeia. In previous studies, we have obtained nearly 200 compounds from nine Rubia plants, including R. cordifolia, R. yunnanesis, R. podantha, R. schumanniana, R. alata, R. wallichiana, R. oncotricha, R. sylvatica, and R. ovatifolia, and investigated their bioactivities and mechanisms of action, including Rubiaceae-type cyclopeptides [6][7][8][9][10], quinones [5,15,16,[27][28][29], triterpenes [27,30,31]. For their unique structures and preferable bioactivities, naphthohydroquinone dimers have attracted our attention, especially rubioncolin C (RC) which exhibits the best cytotoxicity among them.…”

“…The roots and rhizomes of Rubia plants, especially R. cordifolia, R. yunnanensis and R. podantha, have been widely used as traditional Chinese medicines for treating cancer, menoxenia, rheumatism and tuberculosis [6][7][8][9][10]. To date, 17 naphthohydroquinone dimers have been isolated from Rubia plants [5,[11][12][13][14][15][16][17] (Figure S1), and some of 2 of 17 them have been synthesized totally [18][19][20]. These isolated compounds possessed anti-tumor activities, particularly rubioncolin C (RC) ( Figure 1A).…”

“…But most of them have not been used in clinical therapy, except Bortezomib (Velcade), a reversible 26S proteasome inhibitor approved by the US FDA for treating multiple myeloma. In the last decade, we performed phytochemical investigations on nine Rubia plants and obtained ten naphthohydroquinone dimers containing seven novel ones [5,15,16]. Our previous studies also showed that naphthohydroquinone dimers possessed cytotoxic activities against ten tumor cell lines [5].…”

Naphthohydroquinones, naphthoquinones, anthraquinones, and a naphthohydroquinone dimer isolated from the aerial parts of Morinda parvifolia and their cytotoxic effects through up-regulation of p53

“…In addition, naphthohydroquinone dimers like compound 5 have not been isolated previously from the genus Morinda. As far as we know, naphthohydroquinone dimers were previously isolated only from Rubia cordifolia, Rubia oncotricha, and Rubia alata (Itokawa et al, 1993;Qiao et al, 1990;Zhao et al, 2014).…”

(+)/(−)-Phaeocaulin A-D, four pairs of new enantiomeric germacrane-type sesquiterpenes from Curcuma phaeocaulis as natural nitric oxide inhibitors

“…Owing to their central role in the biosynthesis of other sesquiterpenes and their potent bioactivities, germacrane-type sesquiterpenes have stimulated efforts in their isolation, synthesis and structural modification for drug discovery4567. It is not uncommon for natural products to have one or more stereogenic centers with a significant influence on biological activity8910. Different single enantiomers may have different pharmacokinetic properties (absorption, distribution, biotransformation, and excretion) and quantitatively or qualitatively different pharmacologic or toxicologic effects11.…”