Anti-HIV benzylisoquinoline alkaloids and flavonoids from the leaves of Nelumbo nucifera, and structure–activity correlations with related alkaloids

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Abstract

(+)-1(R)-Coclaurine (1) and (−)-1(S)-norcoclaurine (3), together with quercetin 3-O-β-d-glucuronide (4), were isolated from the leaves of Nelumbo nucifera (Nymphaceae), and identified as anti-HIV principles. Compounds 1 and 3 demonstrated potent anti-HIV activity with EC50 values of 0.8 and <0.8 μg/mL, respectively, and therapeutic index (TI) values of >125 and >25, respectively. Compound 4 was less potent (EC50 2 μg/mL). In a structure–activity relationship study, other benzylisoquinoline, aporphine, and bisbenzylisoquinoline alkaloids, including liensinine (14), negferine (15), and isoliensinine (16), which were previously isolated from the leaves and embryo of Nelumbo nucifera, were evaluated for anti-HIV activity. Compounds 14–16 showed potent anti-HIV activities with EC50 values of <0.8 μg/mL and TI values of >9.9, >8.6, and >6.5, respectively. Nuciferine (12), an aporphine alkaloid, had an EC50 value of 0.8 μg/mL and TI of 36. In addition, synthetic coclaurine analogs were also evaluated. Compounds 1, 3, 12, and 1416 can serve as new leads for further development of anti-AIDS agents.

Graphical abstract

(+)-1(R)-Coclaurine (1) and (−)-1(S)-norcoclaurine (3), together with quercetin 3-O-β-d-glucuronide (4), were isolated from the leaves of Nelumbo nucifera (Nymphaceae), and identified as anti-HIV principles. These compounds can serve as new leads for further development of anti-AIDS agents.

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Introduction

Nelumbo nucifera Gaertn. (Nymphaceae) is a perennial aquatic crop grown and consumed throughout Asia. All parts of N. nucifera have been used for various medicinal purposes in oriental medicine. In particular, the leaves are known for diuretic and astringent properties, and are used to treat fever, sweating, and strangury and as a styptic.1 During our continuing search for plant-derived anti-HIV agents from natural products, the 95% EtOH extract of the leaves of N. nucifera was found to display significant anti-HIV activity (EC50 < 20 μg/mL, TI > 5). Bioassay-guided fractionation and repeated chromatography of this extract has led to the isolation and identification of (+)-1(R)-coclaurine (1)2 and (−)-1(S)-norcoclaurine (3),3 together with quercetin 3-O-β-d-glucuronide (4),4 as anti-HIV principles. We report herein the anti-HIV activity of 1, 3, and 4, as well as related alkaloids isolated from N. nucifera and synthetic coclaurine analogs.

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Results and discussion

The leaves of N. nucifera were extracted successively with n-hexane, CHCl3 and 95% EtOH, and anti-HIV activity was found in the 95% EtOH extract (EC50 < 20 μg/mL). The 95% EtOH extract was further partitioned between n-BuOH and water yielding an anti-HIV active n-BuOH-soluble fraction. Subsequent bioassay-guided fractionation and repeated chromatography of this fraction led to the isolation of two benzylisoquinoline alkaloids (1 and 3) and a flavonoid glycoside (4) as anti-HIV principles.

General experimental procedures

Melting points were measured on a Yanako micro melting point apparatus, and are uncorrected. Optical rotations were measured on a Perkin–Elmer 241 polarimeter. Mass spectra were determined on a JEOL HX-110 spectrometer. 1H and 13C NMR spectra were measured on JEOL JNM-A-400 and JNM-FX200 spectrometers with TMS as an internal standard.

Isolation of alkaloids and flavonoids from the leaves of Nelumbo nucifera

The dried leaves of N. nucifera (3.0 kg) were extracted successively with n-hexane, CHCl3, and 95% EtOH, three times at reflux for 2 h. The combined extracts were

Acknowledgements

This investigation was supported by the Promotion and Mutual Aid Corporation for Private Schools of Japan (Y.K.), as well as Grant AI-33066 from the National Institute of Allergies and Infectious Diseases (K.H.L.).

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