**5. Interactions of flavonoids metal complexes with proteins**

Protein binding can influence the blood levels and the pharmacokinetic behavior of a drug and possibly its pharmacologic and toxicologic profiles. Human serum albumin (HSA) is quantitatively ∼55% of total serum proteins. Analyses of the crystal structure of the protein indicate that the main binding sites in HSA are located in the hydrophobic cavities of subdomains II and III of site A. These binding sites are known as Sudlow I and II, respectively. The remaining single tryptophan in HSA structure is located within the site's Sudlow I (Trp‐214) [87]. Serum albumin (SA) is involved in blood transport for many compounds and metal ions. The interactions of a drug with SA play a major role in drug efficacy. Flavonoids and their metal complexes interact in the microenvironment surrounding the tryptophan residue of SA.

Transferrin (Tf) is a monomeric glycoprotein, containing two main metal ion binding sites: the N‐terminal lobe and the C‐terminal lobe, similar in structure, each binding one Fe(III) ion. It has been found that iron‐binding sites in the serum Tf are only saturated to an extent of 39% of Fe(III), meaning that the free lobes can bind other metal ions [88]. Cancer cells, as active and rapidly proliferating cells, express high levels of transferrin receptors. Consequently, transferrin has been explored as a potential drug carrier for targeted delivery into tumor cells [89].

Moreover, human topoisomerase II‐α (topo II‐α) is currently a target for anticancer chemotherapy. Topo II‐α is involved in DNA transcription, replication, and chromosome segregation. Although these biological functions are vital for insuring genomic integrity, the ability to inhibit topo II‐α and generate enzyme‐mediated DNA damage in cancer cells is an effective strategy in antitumor therapy [90]. Electrostatic forces, hydrogen bonds, and van der Waals interactions are involved in the interactions of flavonoid metal complexes and proteins [72].

Flavonoids and their metal complexes bind bovine serum albumin (BSA) or human (HSA), in vitro, with different affinities (**Table 4**).



**Table 4.** Selection of flavonoid metal complexes‐protein interactions studies.

**Complex Comments Ref.**

M−1

The interaction takes place in a ratio of 1:1 compound:protein through a static mechanism. Complexation lowered the binding affinity to BSA of naringenin, probably due to steric hindrance. At 298 K: *K*b nar

55.3 ± 0.07 × 105

*K*b lut = 65.10 ± 0.90 × 10<sup>6</sup>

= 10.20 ± 0.30 × 104

VO (mor)2

Baicalein‐Al(III) complex (ALBC) The results of the competitive binding and molecular-

*K*b BC = 1.73 × 105

*K*b DMY = 1.30 × 105

M−1 *K*b ZnDMY = 7.76 × 104

× 105

Morin‐La(III) complex (La‐Mo) La‐mo‐HSA interaction was studied by means of

(VO)2

albumin (HSA), VO(que)2

when the species (VO)<sup>x</sup>

and VO(morS

Diosmin and VOdios interactions with BSA follow a static mechanism, a ratio of 1: 1 compound: protein; the interaction is enabled via hydrogen bonds and van der Waals forces. At 298 K: *K*b dios = 1.84 ± 0.32 × 104

Luteolin interacts with the microenvironment around tryptophan in BSA, by electrostatic forces; the complex interacts with the protein through hydrogen bonds and van der Waals forces. The interaction takes place in a ratio of 1: 1 compound: protein through a static mechanism. At 298 K:

M−1 *K*b VOdios = 79.43 ± 0.56 × 10<sup>6</sup>

)2

M−1

(HSA) and (VO)(apo‐HTF)/

undergo displacement reactions,

and mor<sup>S</sup>

/VO(QueS )2 does

M−1 *K*b VOnar = 0.31 ± 0.01 × 104

and VO(QueS

In the systems with apo‐human transferrin (apo‐HTF) and

)2

are formed. The complexes interact strongly with the proteins by the formation of hydrogen bonds with polar

docking studies indicate that BC binds to HSA at site I (subdomain IIA), while ALBC binds mainly at site II (subdomain IIIA). BC binding had a greater influence than ALBC on the secondary structure of the protein. At 297 K:

M−1 *K*b ALBC = 1.67 × 105

DMY‐BSA interaction is achieved by van der Waals forces and hydrogen bonds, while complexes bind through hydrophobic and hydrogen‐bonding forces (conclusions based on thermodynamic values for parameters). At 300 K:

M−1 *K*b MnDMY = 2.13 × 105

spectrofluorometry and circular dichroism. It has been found that La‐mo is an efficient interaction with HSA hydrogen bonding and van der Waals forces. The thermodynamic parameters (Δ*G*, Δ*H*, Δ*S*) that characterize the interaction had negative values, implying that the binding is thermodynamically favorable and the degree of reversibility is modest. Circular dichroism spectra show a reduction in the α‐helix‐type structures from 60.0 to 56.9% and an increase in the β‐chain‐type structures from 6.0 to 7.1% in HSA. Molecular‐docking studies show that La‐mo competes with warfarin site Sudlow I of subdomain II in HSA structure. At 299 K: *K*b La‐Mo = 1.5752 ± 0.007 × 105

M−1

(apo‐HTF) and VO‐apo‐HTF‐morS

not interact with hemoglobin, while VO(mor)2

groups on the protein surface. VO(que)2

forms adducts with hemoglobin (Hb).

M−1 *K*b VOdios =

M−1

M−1

are stable, while

/VO(morS )

M−1 *K*b CuDMY = 2.95

M−1

‐VO‐HAS

[35]

[75]

[76]

[91]

[92]

[93]

[94]

Diosmin‐oxovanadyl (IV) complex

Luteolin‐ oxovanadyl (IV) complex

Naringenin‐oxovanadyl (IV) complex

O (VOnar)

O)2 ] Na**·**3H2

]**·**2H2

Quercetin and morin and their sulfonic derivatives-oxovanadyl (IV) complexes VO(que)2

Dihydromyricetin Mn(II), Cu(II) and Zn(II) complexes MnDMY CuDMY

] Na5·6H2

316 Flavonoids - From Biosynthesis to Human Health

O (VOdios)

O (VOlut)

VO(mor)2

[VO(dios)(OH)3

[VO(lut)(H2

[VO(nar)2

VO(queS )2 VO(morS )2

ZnDMY
