Cytotoxic Flavaglines and Bisamides from <em>Aglaia edulis</em>

Soyoung Kim

Young Chin

Bao Su

Soedarsono Riswan

Geoffrey Cordell+2 authors

Program for Collaborative Research in the Pharmaceutical Sciences and Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, Herbarium Bogoriense, Research and Development Center for Biology, Indonesian Institute of Science, 16122 Bogor, Indonesia, Research and Development Chemistry, Indonesian Institute of Science, Serpong, 15310 Tangerang, Indonesia

* Corresponding author. Tel: +1-614-247-8094; Fax: +1-614-247-8642; E-mail: ude.uso@4.nrohgnik

^{University of Illinois at Chicago.}

^{The Ohio State University.}

^{Herbarium Bogoriense, Research and Development Center for Biology, Indonesian Institute of Science.}

^{Research and Development Chemistry, Indonesian Institute of Science.}

Abstract

Two new cyclopenta[b]benzofurans, aglaroxin A 1-O-acetate (2) and 3′-methoxyaglaroxin A 1-O-acetate (3), a new benzo[b]oxepine, 19,20-dehydroedulisone A (4), and five new cyclopenta[bc]benzopyrans, edulirin A (5), edulirin A 10-O-acetate (6), 19,20-dehydroedulirin A (7), isoedulirin A (8), and isoedulirin B (9), were isolated from the bark of Aglaia edulis, along with one known cyclopenta[b]benzofuran, aglaroxin A (1). Additionally, four new amides, aglamides A–D (10–13), as well as three known compounds, aglalactone, scopoletin, and 5-hydroxy-3,6,7,4′-tetramethoxyflavone, were isolated from the leaves and/or twigs of this species. The structures of the new compounds (2–13) were elucidated by interpretation of their spectroscopic data. All isolates obtained in this study were evaluated for cytotoxicity against both several human cancer cell lines (Lu1, LNCaP, and MCF-7) and a non-tumorigenic (HUVEC) cell line. Among these isolates, the cyclopenta[b]benzofurans (1–3) exhibited potent in vitro cytotoxic activity (ED₅₀ range 0.001 to 0.8 μg/mL). Aglaroxin A 1-O-acetate (2) was further evaluated in the in vivo P388 lymphocytic leukemia model, by intraperitoneal injection, but found to be inactive in this model.

Abstract

The cyclopenta[b]benzofurans have been isolated only from the genus Aglaia (Meliaceae) and occur in two structurally related groups of compounds, the benzo[b]oxepines and cyclopenta[bc]benzopyrans.¹2 These classes of compounds have been termed as “flavaglines” because their mutual biogenetic origin is postulated to involve a flavonoid unit linked to a cinnamic acid moiety.³6 Among the flavaglines, cyclopenta[b]benzofurans have received considerable recent attention as interesting lead compounds for cancer chemotherapy,⁶20 as a result of the cyclopenta[b]benzofuran derivative, rocaglamide from Aglaia elliptifolia, being found to exhibit antineoplastic activity in an in vivo model.²⁰ As a part of a National Cooperative Drug Discovery Group (NCDDG) program to discover new antitumor agents from plants,²¹22 the leaves, twigs, and bark of Aglaia edulis (Roxb.) Wall. (Meliaceae) were separately collected in Indonesia. The chloroform-soluble partitions of the three methanol extracts of these three plant parts were subjected to detailed investigation due to their cytotoxic activities demonstrated against a small panel of human cancer cell lines. Bioassay-guided purification of the bark of A. edulis led to the isolation of two new cyclopenta[b]benzofurans (2 and 3), a new benzo[b]oxepine (4), and five new cyclopenta[bc]benzopyrans (5–9), along with one known compound, aglaroxin A (1). Additionally, four new amides (10–13), as well as three known compounds were isolated from the leaves and/or twigs of this species. All isolates obtained in this study were evaluated for cytotoxicity against several human cancer cell lines and the new cyclopenta[b]benzofuran (2) was further tested in an in vivo model. In a preliminary investigation, two new benzo[b]oxepines and their hydrolytic derivatives were characterized from the bark of A. edulis.²³

References and Notes

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