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  • Previously we have shown that

    2022-01-15

    Previously, we have shown that the natural flavonoid compounds that possess C-4 ketone group and C-5 hydroxy group, such as baicalein, luteolin, myricetin and quercetin, effectively inhibit human GLO I. Considering our interest in inhibitors of GLO I and based on the rationale mentioned above, structurally related compounds, anthocyanidins, were considered to have inhibitory effects on the human GLO I. Our working hypothesis was that similar to flavonoid compounds, the polyphenolic compounds may active to the human GLO I.
    Results
    Discussion In this study, we first demonstrated the inhibitory effects of anthocyanidins, delphinidin, cyanidin and pelargonidin, on the human GLO I activity. Among them, delphinidin was found to be the most effective inhibitor of the human GLO I. Previously, we have shown that several natural flavonoid compounds which possess C-4 ketone and C-5 hydroxy groups effectively inhibit the human GLO I. The analysis of structure–activity relationships of the flavonoid compounds showed that the hydroxy groups on the B ring contribute to the inhibitory effects on the human GLO I. Consistent with the previous observations, the present results of in vitro GLO I assay (Fig. 2) revealed that the hydroxy groups on the B ring of anthocyanidins, especially at the R1 position (Fig. 1), greatly contribute to the inhibitory activities on the human GLO I. The comparison of the computationally predicted binding modes of these three anthocyanidins suggests that delphinidin can form more hydrogen bonds to bind one more amino STK393606 mg (Asn103B) of the human GLO I than cyanidin and pelargonidin via its hydroxy group at the R1 position (Fig. 3). Thus, the three hydroxy groups on the B ring of delphinidin are considered to be involved in the specific interaction with the hot spot constructed especially by Asn103B, Arg122A and Arg37B on the human GLO I molecule. Since GLO I is an attractive target for development of new anticancer drugs, we next evaluated the effects of the anthocyanidins on the proliferation of HL-60 cells. As expected, delphinidin that possessed strong inhibitory activity to the human GLO I activity in vitro suppressed the growth of HL-60 cells in a dose- and time-dependent manner (Fig. 4). In contrast, cyanidin and pelargonidin which have less inhibitory effects on the human GLO I had little suppressive effects on the cell growth. Furthermore, delphinidin was appeared to induce cell death by apoptosis (Fig. 5). Since the kinetics of delphinidin-induced apoptosis is slow, it is likely that the onset of apoptosis by delphinidin treatment is the consequence of the accumulation of MG by GLO I inhibition. These observations indicate that the GLO I inhibition is an important contribution to the antiproliferative and apoptosis inducing activities. It should be emphasized that more experiments are necessary to further elucidate whether delphinidin actually enters the cells, inhibits GLO in cells and induced the accumulation of MG. These issues should be addressed in future studies. It is now widely appreciated that agents capable of inducing apoptosis in cancer cells can potently lead to the development of mechanism-based prevention and treatment approaches for cancer. Our results suggest that delphinidin could be an important natural lead compound for the development of GLO I inhibitory anticancer drugs. That is, the structure of delphinidin could provide a valuable scaffold to design the human GLO I specific inhibitors. In the predicted binding mode shown in Figure 3, the four polar atoms (O atom on Asn103B, N–H atom on Arg122A, two N–H atoms on Arg37B) on the human GLO I (PDB code 1FRO) are capable of forming hydrogen bonds to delphinidin. Taken together with these in silico and in vitro data, we tried to construct a delphinidin/GLO I pharmacophore illustrated in Figure 6. Probably, the specific interaction of delphinidin/GLO I is due to the flavylium ion in delphinidin and Phe67B in the human GLO I and the A aromatic ring and Leu69B. This pharmacophore may be useful for computational screening and design of novel GLO I specific inhibitors.