Ab initio conformational analysis of flavone and related compounds

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Abstract

Conformational analysis is performed on flavone (2-phenyl-4-H-benzopyran-4-one) and three other related compounds 2-phenyl pyranone, beta-phenyl naphthalene and biphenyl using quantum chemical calculations. For each compound, the rotation of the phenyl group with respect to the rest of the molecule is studied, and conclusions are drawn concerning the relationship of flavone and the other three molecules.

Introduction

Flavonoids belong to the family of polyphenolic compounds, which occur as yellow pigments in plants [1], [2]. The possibility of an essential biological role of flavonoids in mammalian physiology was first suggested in 1936 by Szent-Györgyi [2]. Szent-Györgyi found that flavonoids strengthened capillary walls in ways Vitamin C could not. Since it was thought to enhance permeability of blood vessels, they were referred to as Vitamin P (P for permeability) [2]. Nowadays, more than any other time since the first discovery by Szent-Györgyi, flavonoids have been the main focus of many researchers.

Flavonoids are glycosides of flavones as illustrated in Scheme 1. Note that –OH and –OCH3 functionality may be focused all around the three rings of flavones. This scheme also illustrates that the pyranone ring may also occur in its hydrogenated or reduced form. Scheme 2 also indicates that, in addition, the reduction [RED] of the pyranone ring may also be oxidized [OX] via hydrogenation at position 3. All of these clearly indicate that one may anticipate a large number of structural variants for these polyphenolic aglycones.

Numerous studies have been underway for the isolation of flavonoid related compounds such as flavones, isoflavones and flavanones (cf. Scheme 3). Various flavones and flavanones have been isolated by bio-activity fractionation from plants such as Feijoa sellowiana (the fruit of pineapple guava), and Eriodictyon californicum (a sticky shrub whose dried leaves are used medicinally) [3]. Acacetin and kaempferide are two flavones isolated from these plants and have demonstrated high activity at nontoxic doses in inhibiting Benzo[a]pyrene carcinogenesis [4]. Same studies have shown that flavones are more active inhibitors than their corresponding isoflavones and flavanones [4]. These findings render flavones as the best possible chemopreventive agents on tumor formation. In the same context of anti-cancer activity of flavones, warfarin, a flavone related compound has been used as a drug for its antimetastatic effect in lung cancer [5]. In addition, recent study has been focusing on the anti-HIV activity of flavonoid compounds [6]. Flavonoids are also thought to help reduce heart disease. Experiments done in dogs with stenosed coronary arteries have shown that Provex Plus®, a commercial mixture of flavonoids, inhibits platelet activity significantly [7]. This infers that flavonoids may protect against coronary artery disease, acute occlusive thrombosis and death from myocardial infarction [7].

Many of the beneficial effects of flavonoids are a direct result of their antioxidant properties [1]. The antioxidant activity of α-tocopherol (Vitamin E), considered as a flavone related compound and present in plasma and erythrocyte membranes [8], acts against lipid peroxidation [9], a process which causes aging and various other degenerative diseases [10]. It is not surprising, therefore, that many cosmetic creams have Vitamin E as an essential ingredient. Structural aspects of the antioxidant activity of flavonoids have been the main interest of many researchers [11], [12], [13]. It is also believed that flavonoids can work directly as anti-aging factors by scavenging free radicals—the byproducts of normal metabolism.

It seems that flavonoids have beneficial effects in various aspects of human health, and further study on these compounds will not end up being futile. The focus of this paper is to attempt a conformational analysis of flavone, the parent molecule of the flavonoid compounds. Having analyzed the parent molecule further suggestions and conclusions can be drawn for the reactivity of flavonoids.

Section snippets

Computational methods

gaussian 94 is used to perform Hartree–Fock (HF) calculations on the compounds of interest. Due to the size of the molecules investigated, the HF calculations employed two basis sets of modest size STO-3G and 3-21G. Potential energy curves are plotted using AXUM 5.0. The compounds studied are shown in Scheme 4.

The compounds of interest were first modeled by the semi-empirical AM1 method. After the structures were determined at HF/STO-3G level of theory, a relaxed scan for every 15° of rotation

Results and discussion

The phenyl torsional energies computed as a one-dimensional (1D)-scan at the HF/STO-3G levels for flavone [1], 2-phenyl pyranone [2], β-phenyl naphthalene [3] and biphenyl [4] are summarized in Table 1, Table 2, Table 3, Table 4, respectively. Graphical representations of the phenyl torsional potential for [1], [2], [3] and [4] are shown in Fig. 1, Fig. 2, Fig. 3, Fig. 4, respectively. It is interesting to note that the potentials for the oxygen containing heterocyclic compounds [1] and [2] are

Conclusions

Hydrocarbons (biphenyl and β-phenyl naphthalene) are noticeably different from oxygen containing heterocyclic analogs, such as 2-phenyl pyranone and flavone, as far as phenyl rotation is concerned. By looking at the Mulliken charges, it was concluded that the oxygen containing compounds are expected to have different reactivity than the hydrocarbons. While there are noticeable differences, the topology at the potential energy curves (number of minima and the transition structures) are the same

Acknowledgements

The authors would like to thank the NCI for the use of services of the Frederick Biomedical Supercomputing Center. The continuous financial support of the Natural Science and Engineering Research Council (NSERC) of Canada is gratefully acknowledged.

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