Elsevier

Bioorganic & Medicinal Chemistry

Volume 11, Issue 18, 1 September 2003, Pages 4069-4081
Bioorganic & Medicinal Chemistry

Synthesis of daidzin analogues as potential agents for alcohol abuse

https://doi.org/10.1016/S0968-0896(03)00397-3Get rights and content

Abstract

Daidzin, the active principle of an herbal remedy for ‘alcohol addiction’, has been shown to reduce alcohol consumption in all laboratory animals tested to date. Correlation studies using structural analogues of daidzin suggests that it acts by raising the monoamine oxidase (MAO)/mitochondrial aldehyde dehydrogenase (ALDH-2) activity ratio (J. Med. Chem. 2000, 43, 4169). Structure–activity relationship (SAR) studies on the 7-O-substituted analogues of daidzin have revealed structural features important for ALDH-2 and MAO inhibition (J. Med. Chem. 2001, 44, 3320). We here evaluated effects of substitutions at 2, 5, 6, 8, 3′ and 4′ positions of daidzin on its potencies for ALDH-2 and MAO inhibition. Results show that analogues with 4′-substituents that are small, polar and with hydrogen bonding capacities are most potent ALDH-2 inhibitors, whereas those that are non-polar and with electron withdrawing capacities are potent MAO inhibitors. Analogues with a 5-OH group are less potent ALDH-2 inhibitors but are more potent MAO inhibitors. All the 2-, 6-, 8- and 3′-substituted analogues tested so far do not inhibit ALDH-2 and/or have decreased potencies for MAO inhibition. This, together with the results obtained from previous studies, suggests that a potent antidipsotropic analogue would be a 4′,7-disubstituted isoflavone. The 4′-substituent should be small, polar, and with hydrogen bonding capacities such as, –OH and –NH2; whereas the 7-substituent should be a straight-chain alkyl with a terminal polar function such as –(CH2)n–OH with 2≤n ≤6, –(CH2)n–COOH with 5≤n ≤10, or –(CH2)n–NH2 with n ≥4.

Daidzin reduces alcohol intake in alcohol preferring Syrian golden hamsters by raising the mitochondrial MAO/ALDH-2 activity ratio. The synthesis of 36 new daidzin analogues and their effect on liver MAO and ALDH-2 activity is described.

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Introduction

Alcohol dependence and abuse are among the most serious drug problems of Western societies. In the US, about 10% of the population abuse alcohol.1 The economic cost to the nation is more than $185 billion per year.2 Therefore, safe and effective treatments for this drug problem are sorely needed. Recent success in the development of pharmaotherapies for addictive disorders such as nicotine addiction and a more widespread recognition that alcohol dependence is a medical rather than moral problem have harnessed growing support in the search for and development of pharmaceutical agents for this medical condition. However, such efforts have been greatly hampered by (i) the lack of a thorough understanding of the molecular basis for alcohol craving, (ii) an adequate animal model for human ‘alcohol addiction’, and (iii) a truly predictive model for drug screening. We have taken an alternative approach to the problem, searching for effective agents from traditional Chinese medicines that have been used apparently safely and effectively for the treatment of ‘alcohol addiction’.3 This approach has led to the discovery of daidzin, the active principle of the medicinal plant Pueraria lobata, that selectively reduces ethanol intake in ethanol-preferring Syrian golden hamsters.4, 5 Since then, the antidipsotropic (ethanol intake suppressive) activity of daidzin has been confirmed in all ethanol drinking animal models tested to date.6, 7, 8, 9

Recently, we have shown that daidzin inhibits the conversion of monoamines, such as serotonin (5-HT) and dopamine (DA), into their respective acid metabolites, 5-hydroxyindole-3-acetic acid (5-HIAA) and 3, 4,-dihydroxyphenylacetic acid (DOPAC), in isolated hamster and rat liver mitochondria.10 Further, daidzin does not affect the rates of mitochondria-catalyzed oxidative deamination of these monoamines. These findings suggest that its antidipsotropic activity may not be mediated by the monoamines themselves but rather by their respective metabolic intermediates, 5-hydroxyindole-3-acetaldehyde (5-HIAL) and/or 3, 4-dihydroxyphenylacetaldehyde (DOPAL) which accumulate in the presence of daidzin.10 Later correlation studies using structural analogues of daidzin revealed a link between their antidipsotropic activities and their abilities to accumulate a biogenic aldehyde in isolated liver mitochondria preparations.11 Daidzin analogues that potently inhibit ALDH-2 but have no or little effect on MAO are most antidipsotropic, whereas those that also inhibit MAO exhibit little, if any, antidipsotropic activity. This result, although not conclusive, lends support to the idea that one or more biogenic aldehyde derived from the action of MAO mediates the antidipsotropic action of daidzin (Fig. 1).11, 12 Further, it provided a molecular target based on which a simple in vitro screening assay was developed.13 The potential role(s) of biogenic aldehyde(s) in the control of alcohol use and abuse has been proposed and thoroughly reviewed.14

The levels of biogenic aldehydes attained during mitochondria-catalyzed monoamine metabolism are regulated by the relative activities of MAO and ALDH-2. Therefore, in the design of more efficacious antidipsotropic analogues, structural features important for the inhibition of both ALDH-2 and MAO must be taken into consideration. Since the molecular details of daidzin binding to ALDH-2 and MAO are unknown at this time, studying the classical structure–activity relationship (SAR) remains a valuable approach for this purpose. In a recent study, we have studied the SAR of 7-O-substitued analogues of daidzin and documented a sufficient set of criteria for a potent antidipsotropic analogue.15 As a continuing effort, we here evaluated effects of substitutions at the 2, 5, 6, 8, 3′, and 4′ positions of daidzin on the potencies for ALDH-2 and MAO inhibition.

Section snippets

Synthesis, purification and structural identification of analogues of daidzin

The 7-O-substituents of the derivatives of daidzein (Figure 2, Figure 3, Figure 5, Figure 8, Scheme 1, Figure 2, Figure 5, Figure 7), puerarin (8e, 19), 7-hydroxyisoflavone (Figure 2, Figure 3, Figure 5, Figure 8, Scheme 1, 6, 7b, Figure 2, Figure 7), 7-hydroxy-2-ethoxycarbonylisoflavone (8c, 9b), and the 7-hydroxy-4′-fluoro (11b)-, -bromo (12b)-, -nitro (13b)-, and methyl (14b)-isoflavone were introduced by the general method of Williamson synthesis as described in previous reports (Table 1).11

Conclusion

We have prepared a series of daidzin analogues in which their 4′-OH groups were replaced with H (Figure 2, Figure 3, Figure 5, Figure 8, Scheme 1, 6, Figure 2, Figure 5, Figure 7), F (11a,b), Br (12a,b), CH3 (14a,b), NH2 (16a,b), NO2 (13a,b), or OCH3 (24) substituents. Their potencies for ALDH-2 and MAO inhibition were determined and compared among each other and with those of their respective 7-O-substituted derivatives of daidzein. Results reveal that the potency for ALDH-2 inhibition of a

Experimental

General chemicals were purchased from either Aldrich Chemical Co. (Milwaukee, WI, USA) or Lancaster Synthesis Inc. (Windham, NH, USA). All organic solvents used were of HPLC grade and were supplied by J.P. Baker (Phillipsburg, NJ, USA) or Fisher Scientific Company (Pittsburgh, PA, USA). Daidzin (Figure 5, Figure 6, Figure 8) and Glycitin (30) were purchased from LC Laboratories (Woburn, MA, USA). Daidzein (Figure 4, Figure 7, Figure 8) was first synthesized by Tyger Scientific Inc. (Princeton,

Acknowledgements

This work was supported by the Endowment for Research in Human Biology, Inc. The continuous support of Dr. Bert L. Vallee is greatly appreciated.

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