Bambang W. Nugroho

Chemistry and Biological Activity of Rocaglamide Derivatives and Related Compounds in Aglaia Species (Meliaceae)

The genus Aglaia is the source of a unique group of natural products featuring a cyclopenta(b)tetrahydrobenzofuran skeleton. Commonly these compounds, which until now include more than 50 naturally occurring derivatives, are named after the parent compound, rocaglamide, which was described for the first time almost twenty years ago. This review highlights the chemical diversity of rocaglamide derivatives and of biogenetically similar compounds from the genus Aglaia and their remarkable biological activity in the fields of insecticides and cytostatic agents. With a few exceptions, all naturally occurring rocaglamide derivatives exhibit striking insecticidal activity against various pest insects. In addition, they display pronounced cytostatic activity against human cancer cell lines in vitro. Furthermore, it was shown recently that rocaglamide and several of its congeners inhibit NF-κB induced gene activation in human T cells and are able to elicit apoptosis in resistant tumor cells. Taken together, these data make rocaglamide derivatives interesting candidates for possible therapeutic agents primarily in the field of cancer chemotherapy. In some Aglaia species, rocaglamide derivatives co-occur with biogenetically similar natural products of the aglain, aglaforbesin or forbaglin type. These latter compounds differ from rocaglamide and its congeners mainly by the nature of their heterocycle. Furthermore, they seem to be devoid of significant biological activity at least in the areas mentioned above, thereby pointing to the cyclopenta(b)tetrahydrobenzofuran core of the rocaglamide skeleton as one essential structural requirement for the pronounced biological activity of the rocaglamides.

An insecticidal rocaglamide derivatives and related compounds from Aglaia odorata (Meliaceae)

Organic extracts of the twigs and leaves of Aglaia odorata yielded eight insecticidal cyclopentatetrahydrobenzofuran rocaglamide derivatives including three congeners which proved to be new natural products. Moreover, four new cyclopentatetrahydrobenzopyran aglain derivatives, as well as the known aminopyrrolidine odorine and odorinol, syringaresinol and flavonoid derivatives were also isolated. Structure elucidation of the new compounds is described and a rationale of the biosynthesis of the rocaglamide and aglain congeners is considered. The isolated rocaglamide derivatives exhibited strong insecticidal activity towards neonate larvae of the polyphagous pest insect Spodoptera littoralis when incorporated into artificial diet with LC50 values varying from 1.0‐8.0 ppm. The most active compounds showed LC50 values between 1.0 and 1.1 ppm, comparable to those of the insecticide azadirachtin, which was used as a positive control. The remaining compounds isolated from A. odorata were inactive with regard to insecticidal activity. # 1999 Elsevier Science Ltd. All rights reserved.

Insecticidal rocaglamide derivatives from Aglaia duppereana

Abstract Twigs of Aglaia duppereana collected in Vietnam yielded the cyclopentatetrahydrobenzofuran, rocaglamide, and also six of its congeners. Whereas three of the isolated compounds were already known, four rocaglamide derivatives were new natural products. Elucidation of their structures and absolute configurations is described. All the rocaglamide derivatives isolated exhibited strong insecticidal activity towards neonate larvae of the polyphagous pest insect Spodoptera littoralis when incorporated into artificial diet. The LC50 for rocaglamide, which was one of the most active compounds encountered in this study, was 0.9 ppm, identical to that of azadirachtin used as a positive control in feeding experiments.

Insecticidal rocaglamide derivatives from Aglaia elliptica and A. harmsiana

Abstract Fruits of Aglaia elliptica and leaves of A. harmsiana yielded seven insecticidal rocaglamide derivatives including five components which proved to be new natural products. Structure elucidation of the new compounds is described. All rocaglamide derivatives isolated exhibited strong insecticidal activity towards neonate larvae of the polyphagous pest insect Spodoptera littoralis when incorporated into an artificial diet with LC 50 values varying from 0.8–19.7 ppm. The known didesmethylrocaglamide was the most active compound encountered. Its LC 50 (0.8 ppm) and EC 50 , (0.05 ppm) were identical to those of azadirachtin which was included as a positive control.

Insecticidal constituents from rhizomes of Zingiber cassumunar and Kaempferia rotunda

Abstract Rhizomes from 18 different species of the Zingiberaceae were screened for insecticidal constituents against neonate larvae of the pest insect, Spodoptera littoralis . Extracts from rhizomes of Kaempferia rotunda and Zingiber cassumunar , when incorporated into artificial diets, displayed significant insecticidal activity in chronic feeding bioassays at concentrations of 2500 ppm and 1250 ppm, respectively. Bioassay-guided isolation afforded two phenylbutanoids from rhizomes of Z. cassumunar which had LC 50 values against neonate larvae of 121 and 127 ppm, respectively, in the chronic feeding bioassay. Both compounds were also active in the residue-contact bioassay (LC 50 values of 0.5 and 3.6 μg cm −2 , respectively). The presence of oxygenated substituents (−OH or −OAc groups) in the side-chain nullified insecticidal activity. Rhizomes of K. rotunda yielded two active metabolites: benzyl benzoate and the cyclohexane derivative, crotepoxide. Compared to the bioactive phenylbutanoids from Z. cassumunar , crotepoxide was less active in the chronic feeding bioassay (LC 50 , 1450 ppm) and was inactive in the residue-contact bioassay. Benzyl benzoate, however, exhibited insecticidal activity only when applied topically (LC 50 , 5.6 μg cm −2 ) suggesting detoxification in the larval gut when applied orally.

1H-cyclopenta[b]benzofuran lignans from Aglaia species inhibit cell proliferation and alter cell cycle distribution in human monocytic leukemia cell lines.

Thirteen naturally occurring 1H-cyclopenta[b]benzofuran lignans of the rocaglamide type as well as one naturally occurring aglain congener all of them isolated from three Aglaia species (Aglaia duperreana, A. oligophylla and A. spectabilis) collected in Vietnam were studied for their antiproliferative effects using the human monocytic leukemia cell lines MONO-MAC-1 and MONO-MAC-6. Only rocaglamide type compounds showed significant inhibition of [3H-]thymidine incorporation and the most active compound didesmethylrocaglamide inhibited cell growth in a similar concentration range as the well-known anticancer drug vinblastine sulfate. Detailed structure-activity analysis indicated that the OH-group at C-8b which is a common structural feature of most naturally occurring rocaglamide compounds is essential for the described antiproliferative activity since replacement of this group by methylation led to a complete loss of the inhibitory activity for the resulting derivative. Rocaglamide derivatives rapidly inhibited DNA as well as protein biosynthesis of MONOMAC- 6 cells at concentrations well below those of actinomycin D or cycloheximide which were used as positive controls in the respective experiments. Didesmethylrocaglamide was furthermore able to induce growth arrest of MONO-MAC-1 cells in the G2/M and probably G0/Gl-phase of the cell cycle with no morphological indication of cellular damage. Our data suggests that 1H-cyclopenta[b]benzofuran lignans of the rocaglamide type act primarily by a cytostatic mechanism.

New insecticidal rocaglamide derivatives from flowers of Aglaia duperreana (Meliaceae)

Abstract Flowers of Aglaia duperreana collected in Vietnam yielded thirteen insecticidal cyclopentatetrahydrobenzofuran derivatives of the rocaglamide type including five compounds which proved to be new natural products. Structure elucidation of the new compounds and their insecticidal activity against larvae of the pest insect Spodoptera littoralis are described. Most of the isolated rocaglamide derivatives exhibited strong to moderate insecticidal activity. The most active compounds were similar with regard to their bioactivity to the well known natural insecticide azadirachtin. However, replacement of the OH-group at C-8b (that is a characteristic structural feature of most known rocaglamide congeners) by an OC 2 H 5 -substituent as present in two of the isolated new derivatives was found to result in a loss of insecticidal activity.

Structure Activity Relationships of Antiproliferative Rocaglamide Derivatives from Aglaia Species (Meliaceae)

Eleven rocaglamide derivatives (cyclopentatetrahydrobenzofurans) and one structurally related aglain congener all isolated from different Aglaia species (Meliaceae) were tested for growth inhibiting properties using the human cancer cell lines MONO-MAC-6 and MEL-JUSO. Proliferation of both cell lines was efficiently inhibited in a dose and compound dependent manner. Applying a MTT-Assay, the IC50 of the most active compound didesmethyl-rocaglamide (1) was observed at 0.002 and 0.006 μg/ml (0.004 and 0.013 μM) depending on the cell line investigated. Bulky aminoacyl substituents at C-2, acetylation of the OH substituent at C-1 or insertion of a OH or OMe substituent at C-3 ’of the rocaglamide skeleton all diminished the activity of the compounds investigated. The aglain derivative 12 was inactive up to a concentration of 3 μg/ml (4.6 μᴍ) . This loss of activity is assumed to be mainly due to the presence of a pyran ring in the aglains vs. a furan ring as found in rocaglamide derivatives. Rocaglamide derivatives may act primarily by inhibition of cell proliferation as evidenced by the absence of a significant cytotoxic effect in long-term cultures of MONO-MAC-6 cells treated with high doses of didesmethylrocaglamide. Our data suggest that rocaglamide derivatives could exert a potential role in the treatment of malignant diseases and are worth to be investigated in further studies of experimental medicine and pharmacology