# Flavone Hybrids and Derivatives as Bioactive Agents
## 2 Flavone Hybrids with Different Pharmacophores
### Flavone Hybrids with Amino Acids  
Most often, the amino acid side chain was formed in position 7 of flavones, and chrysin proved to be the most used flavone among them. Thus, several amino acids were coupled to chrysin for metabolic studies, e.g., glycine, alanine, valine, leucine, methionine, etc. [49].  
Two methods were used known from peptide chemistry. In the first one, after hydrolysis of **24**, hybrids were obtained. In compound **26**, the amino acid was coupled to the flavone via a short linker (Figure 11).  
Figure 10: Triphenylphosphonium-containing side chains in positions 3 and 5 of quercetin.  
Figure 9: Synthesis of 7-O-(4-triphenylphosphoniumbutyl) quercetin iodide (**21**).  
The hybrids of **27** (Figure 12) were prepared employing similar procedures; however, at the coupling reaction with amino acids, the well-known \(N\)-hydroxybenzotriazole-EDCI system was used [21].  
The most potent antiproliferative activity was obtained in the case of compound **27** (R=butane-2-yl, R\({}^{1}\)=Me, \(n=1\); isoleucine ester hybrid; \(IC_{50}\) = 3.78 uM against human gastric carcinoma MGC-803 cell lines).  
Compounds with a similar structure were also prepared with a longer linker (Figure 12). Amongst these, **27** (R=2-Me-propyl, R\({}^{1}\)=H, \(n=4\); leucine hybrid) proved to be an effective anticancer molecule. On the breast cancer MCF-7 cell line, \(IC_{50}\) = 16.6 uM was obtained; moreover, the compound displayed moderate inhibition of EGFR [22].  
Further derivatives of flavones combined with amino acids are compounds where the short linker is substituted with a long carbon chain alkyl group (Figure 12). Compound **28**, where the amino acid component is leucine in methyl ester form (R\({}^{1}\)=Me) showed good activities on breast cancer cells MCF-7 cell line (\(IC_{50}\) = 32.7 uM) and on MDA-MB-231 (\(IC_{50}\) = 8.2 uM) [50]. In addition, compound **28** had outstanding selectivity between other cancer cells and human vascular endothelial cells.  
Amino acids containing apigenin (**29**) and quercetin derivatives (**30**) were also synthesized using protected amino acids. From the apigenin hybrids, the Lys-coupled molecule proved to be the best on the biological tests, having a sedative effect on mouse brain tissues (single dose 0.4 mg/g) passing through the blood-brain barrier [51]. In the case of the quercetin-glutamic acid conjugate (\(IC_{50}\) = 0.14 uM on drug-resistant human MES-SA uterine sarcoma cell line), a potent Pgp-based MDR-modulating effect was found [23].  
Figure 11: Chrysin derivatives containing amino acids.  
Figure 12: Chrysin (**27,28**)-, apigenin (**29**)- and quercetin (**30**)-amino acid hybrids.  
Flavone-amino acid hybrids (**32**) were prepared from 7-bromo derivative (**31**) employing the Buchwald-Hartwig reaction conditions (Figure 13). Not only were single amino acid-containing derivatives (**32a**) synthesized, but also dipeptide hybrids (**32b**).  
The products were investigated on several cancer types [24], and hybrids coupled with single-amino acid esters hydrolyzed to the corresponding carboxylic acids proved to be the most effective, especially **32a** (A=Val, R=H). However, it should be noted that the authors did not use a positive control in the course of the screening, which is a non-recommended practice.