Flavones, Flavonols, Lignans, and Caffeic Acid Derivatives from Dracocephalum moldavica and Their In Vitro Effects on Multiple Myeloma and Acute Myeloid Leukemia

Abstract

Phenolic plant constituents are well known for their health-promoting and cancer chemopreventive properties, and products containing such constituents are therefore readily consumed. In the present work, we isolated 13 phenolic constituents of four different compound classes from the aerial parts of the Moldavian dragonhead, an aromatic and medicinal plant with a high diversity on secondary metabolites. All compounds were tested for their apoptotic effect on myeloma (KMS-12-PE) and AML (Molm-13) cells, with the highest activity observed for the flavone and flavonol derivatives. While diosmetin (6) exhibited the most pronounced effects on the myeloma cell line, two polymethylated flavones, namely cirsimaritin (1) and xanthomicrol (3), were particularly active against AML cells and therefore subsequently investigated for their antiproliferative effects at lower concentrations. At a concentration of 2.5 µM, cirsimaritin (1) reduced proliferation of Molm-13 cells by 72% while xanthomicrol (3) even inhibited proliferation to the extent of 84% of control. In addition, both compounds were identified as potent FLT3 inhibitors and thus display promising lead structures for further drug development. Moreover, our results confirmed the chemopreventive properties of flavonoids in general, and in particular of polymethylated flavones, which have been intensively investigated especially over the last decade.

Evaluation of the Cytotoxic, Antioxidative and Antimicrobial Effects of Dracocephalum moldavica L. Cultivars

“…The chemical compositions of the three cultivars were dominated by the presence of flavonoids and phenolic acids. Almost all these compounds were previously identified in the composition of the species [ 6 , 11 , 12 , 13 , 14 , 22 , 25 , 49 , 53 ]. The novelty of the present study consists in the identification and quantification of ellagic, salycilic, and carnosic acids, together with naringenin and vitexin, which, to the best of our knowledge, are reported for the first time in this study.…”

“…Due to the high abundance and availability of polyphenols from D. moldavica , they have been the subject of numerous investigations for their cytotoxic and anticancer effects [ 14 ].…”

“…Its aerial parts are traditionally used for the treatment of stomach and liver pathologies, headaches, snake bites, stomatitis, or fungal infections [ 2 , 5 , 6 , 7 ]. Essential oils found in the vegetal medicinal product have a citruslike flavor and are rich in oxygenated acyclic monoterpenes, such as geranial, neral, and geranyl acetate [ 1 , 2 , 8 , 9 , 10 , 11 ]; however, the species is also known for its polyphenolic composition, among which phenolic acids (rosmarinic and caffeic acids) and flavonoids (apigenin, luteolin, and kaempferol) are the main compounds [ 6 , 11 , 12 , 13 , 14 ]. Among flavonoids, tilianin is an interesting glycoside with important biological properties that was firstly isolated from this species [ 15 , 16 , 17 ].…”

“…Among flavonoids, tilianin is an interesting glycoside with important biological properties that was firstly isolated from this species [ 15 , 16 , 17 ]. Both classes of compounds are correlated to the biological activities of the species, such as its antioxidant [ 1 , 6 , 11 , 12 , 13 , 18 , 19 , 20 ], antimicrobial [ 1 , 18 , 21 , 22 ], and cardioprotective [ 15 , 23 , 24 , 25 , 26 , 27 ] effects, which are the most studied ones, together with its anti-inflammatory [ 28 , 29 ], neuroprotective [ 16 , 30 ], sedative [ 31 ], cytotoxic [ 14 , 32 ], and antidepressant [ 33 ] effects, which are lesser known. The antimicrobial potential of the species was attributed to its essential oils, linked to its antioxidant capacity and demonstrated against Staphylococcus aureus , Escherichia coli , Salmonella Typhimurium , and Listeria monocytogenes [ 1 , 18 ].…”

“…A hydroalcoholic extract obtained from the aerial parts of the species produced significant results against even antibiotic-resistant strains of E. coli and Klebsiella pneumoniae [ 21 ] and Staphylococcus aureus [ 22 ]. On the other hand, the cytotoxic activity of the species is less documented in previously performed studies, being attributed to flavonoids and studied on multiple myeloma and acute myeloid leukemia cell lines [ 14 ], but also to triterpenes and tested against cervical, lung, and hepatic cancerous cell lines [ 32 ]. The vast majority of the biological activities of this species are strongly related to its antioxidative mechanisms [ 16 , 34 ].…”