Influence of amide versus ester linkages on the anticancer properties of the new flavone–biotin conjugates

Abstract

Novel biotinylated C-6 substituted flavones were synthesised by a one-step method that connects biotin to 6-hydroxyflavone and 6-aminoflavone by esterification and amidation of hydroxyl and amino groups, respectively. The obtained compounds, 6-O-biotinylflavone and 6-biotinylamidoflavone, are the bifunctional molecules composed of a flavone moiety as a fluorescent reporter and biotin as a cancer-targeting unit. Antiproliferative activity was evaluated using SRB assays in MCF-7, MCF-10A, HepG2, MDA-MB-231, 4T1, and Balb/3T3 cell lines. In vitro evaluation revealed that compounds with biotin moiety displayed better cell selectivity between the cancer and normal cells than the parental substrates. These results indicate that anticancer effect is not related to the position of biotin moiety, but it is related to the presence of ester or amide bond. 6-O-Biotinylflavone was more active than 6-hydroxyflavone against human breast (MDA-MB-231) and liver (HepG2) cancer cells with IC50 (concentration of tested agent that inhibits proliferation of the cell population by 50%) values equal to 78.5 ± 18.8 μM and 133.2 ± 14.2 μM, respectively. Non biotinylated 6-aminoflavone was more active than 6-biotinylamidoflavone against all tested cell lines, with IC50 values between 34.3 ± 9.1 μM (4T1) and 173.86 ± 24.3 μM (MCF-7).

A Facile Conjugation of 6-Hydroxylflavone Biomolecule with Polyethylene Glycol for Enhancing Conjugate Stability

“…The synthesis of PEG-6HF conjugate is based on methodology from Dey et al (2015) and Stompor et al (2019) with few modifications. PEG solution was synthesized with a ratio of 1:1 v/v in 4 ml of a mixture of DMSO and water by dissolving 30 mg of mPEG-COOH.…”

“…6-Hydroxyflavone (6HF) is a group of naturally derived bioactive polyphenolic compounds that possess tremendous medicinal assets that have potential roles in preventing chronic diseases, including effectiveness against some neurological disorders paraplegia or sciatica (Wang et al, 2021). 6HF has pharmacologically significant biological characteristics such as neuroprotection, antimicrobial, anti-inflammatory, anticancer, and antioxidants and has been discovered to be an effective treatment for diabetic patients against glomerulonephritis and glomerulosclerosis (Iwakiri et al, 2013;Wang et al, 2015;Das et al, 2018;Das et al, 2019;Stompor et al, 2019;Wang et al, 2021). Stompor et al (2019) and Mikell et al (2015) revealed that the hydroxyl group or the propionyl group located in the A ring of the flavones at the C-6 positions has an inhibitory effect on hormone production in the process of steroidogenesis and has cytotoxic solid and apoptotic activities against cancer cell (Iwakiri et al, 2013;Mikell et al, 2015;Wang et al, 2015;Stompor et al, 2019).…”

“…6HF has pharmacologically significant biological characteristics such as neuroprotection, antimicrobial, anti-inflammatory, anticancer, and antioxidants and has been discovered to be an effective treatment for diabetic patients against glomerulonephritis and glomerulosclerosis (Iwakiri et al, 2013;Wang et al, 2015;Das et al, 2018;Das et al, 2019;Stompor et al, 2019;Wang et al, 2021). Stompor et al (2019) and Mikell et al (2015) revealed that the hydroxyl group or the propionyl group located in the A ring of the flavones at the C-6 positions has an inhibitory effect on hormone production in the process of steroidogenesis and has cytotoxic solid and apoptotic activities against cancer cell (Iwakiri et al, 2013;Mikell et al, 2015;Wang et al, 2015;Stompor et al, 2019). A hydroxyl group at the sixth carbon in the 6HF compound chemical structure makes 6HF easily esterifiable.…”

Diversity-Oriented Synthesis: Amino Acetophenones as Building Blocks for the Synthesis of Natural Product Analogs

“…Among the structural modifications operated on flavonoids, the introduction of amino groups at the flavone scaffold was one of the most frequent [29][30][31][32]. For example, flavone derivatives bearing amino groups were studied as anticancer compounds [33][34][35][36]. Among them, flavopiridol was the first cyclin-dependent kinase inhibitor to enter human clinical trials [36].…”

“…For example, flavone derivatives bearing amino groups were studied as anticancer compounds [33][34][35][36]. Among them, flavopiridol was the first cyclin-dependent kinase inhibitor to enter human clinical trials [36]. Another aminoflavone, known under the name Alvocidib (AFP 464, NSC710464), has been developed by the National Cancer Institute (NCI) investigational drug program and has entered clinical trials as a promising antitumor drug candidate for the treatment of acute myeloid leukemia [37][38][39][40].…”