Djaja D. Soejarto

Novel Strategies for the Discovery of Plant-Derived Anticancer Agents.

Work has continued on the investigation of plants, collected mainly from tropical rainforests, as potential sources of new cancer chemotherapeutic agents. About 400 primary samples are obtained each year, with the chloroform-soluble extract of each being screened against a battery of in vitro assays housed at the three consortial sites in our current National Cooperative Drug Discovery Group (NCDDG) research project. An HPLC-MS dereplication procedure designed to screen out “nuisance” compounds has been refined. Several hundred secondary metabolites that are active in one or more of the primary assays utilized have been obtained in the project to date, and are representative of wide chemical diversity. Some of these are also active in various in vivo assays, inclusive of the hollow fiber assay, which was installed recently as part of our collaborative research effort. A number of bioactive compounds of interest to the project are described.

Biodiversity prospecting and benefit-sharing: perspectives from the field

Searching for new biologically active compounds from natural sources starts, obviously, in the field. Plant, microbial or animal materials to be sought and investigated may be selected through a number of approaches. No matter what selection criterion(a) is (are) used, the first step in obtaining the organism concerned is to undertake field collecting work to search for and to collect the organism. Good knowledge on the ecogeographic distribution and precision in the taxonomic identification of the organism(s) sought are crucial if the field work involves the search for a pre-determined organism or set of organisms. Such knowledge and precision during field work are of secondary importance, however, if the search and collection are based on biodiversity or ethnomedical uses, since accurate taxonomic identification may be made at a later date, in a Museum or Herbarium environment. When an individual or institution from a biotechnologically developed country wishes to obtain indigenous raw biological material from a biotechnologically less developed country, an agreement for the procurement of such raw material may be negotiated. Since the effort to search and develop a biologically active compound(s) from natural sources is a long-term process that involves teamwork between field and laboratory scientists, the success of the endeavor will depend in large part on the continued flow of raw material from the field. Goodwill to maintain such a flow may be achieved through appropriate scientific and monetary compensations, both in real-time and in long-term sharing of the benefits of discovery. Only with the prospect of financial return to the supplying country will there be an incentive for the protection of the natural resources towards sustainable use and development, as well as to allow time for continuing explorations and discoveries.

Traditional herbal drugs of southern Uganda, I

One-hundred four plant species used medicinally by herbalists from three southern Ugandan tribes were collected and identified. The collection includes a large portion of the materia medica of the Abayanda of the southwest region, as well as species used by herbalists of the Baganda and Bakiga Tribes. Literature searches were performed in preparation for further collections, and for collaborative laboratory validation of in vitro antimicrobial activity. Literature data provide support for ethnomedical claims for a number of species used in Uganda for disease treatment.

Sweetening agents of plant origin

The most important sweet substance known is sucrose, which is obtained commercially from sugar cane and sugar beet. Because the intake of sucrose has been associated with a number of adverse effects on health, an intensive search has been undertaken to find alternative substances to satisfy the human craving for a sweet taste. Many other plant‐derived compounds are sweet, ranging in structural complexity from sugars and polyhydric alcohols through diterpene and triterpene glycosides to proteins; some of these compounds are intensely sweet, being hundreds or even thousand times sweeter than sucrose, and offer potential for commercial use in dietetic and diabetic foodstuffs. The present review examines the role of ethnobotany in the discovery of sweet‐tasting plants, the chemical isolation and elucidation of the sweet compounds, and some safety and sensory evaluation aspects of these compounds. A discussion on the future prospects of discovering and developing new plant‐derived sweeteners concludes the review.

Koenoline, a further cytotoxic carbazole alkaloid from Murraya koenigii

Abstract Koenoline, a carbazole alkaloid, has been isolated from the root bark of Murraya koenigii for the first time as a natural product. Its structure was established as 1-methoxy-3-hydroxymethylcarbazole by analysis of spectroscopic data and was confirmed by partial synthesis from murrayanine isolated from M. siamensis roots. Koenoline exhibited cytotoxic activity against the KB cell-culture test system.

Peltogynoids and homoisoflavonoids from Caesalpinia pulcherrima

Abstract From the stem part of Caesalpinia pulcherrima Swartz (Leguminosae) two new peltogynoids, pulcherrimin and 6-methoxypulcherrimin and two homoisoflavonoids, the recently reported compound bonducellin and a new derivative 8-methoxy-bonducellin, were isolated. The structures of these constituents were deduced by consideration of their spectral data. Also isolated were the known compounds, 2,6-dimethoxybenzoquinone and 4′-methylisoliquiritigenin, which displayed cytotoxic activity.

Cytotoxic and NF-κB inhibitory constituents of the stems of Cratoxylum cochinchinense and their semisynthetic analogues.

A new caged xanthone (1), a new prenylxanthone (2), seven known xanthones, and a known sterol glucoside were isolated from the stems of Cratoxylum cochinchinense, collected in Vietnam. Compounds 1 and 2 were determined structurally by analysis of their spectroscopic data. In addition, five new (10 and 16-19) and eight known prenylated xanthone derivatives were synthesized from the known compounds α-mangostin (3) and cochinchinone A (6). Several of these substances were found to be cytotoxic toward HT-29 human colon cancer cells, with the most potent being 3,6-di-O-acetyl-α-mangostin (8, ED50, 1.0 μM), which was tested further in an in vivo hollow fiber assay, but found to be inactive at the highest dose used (20 mg/kg; ip). Of the substances evaluated in a NF-κB p65 inhibition assay, 1,3,7-trihydroxy-2,4-diisoprenylxanthone (5) exhibited the most potent activity (IC50, 2.9 μM). In a mitochondrial transmembrane potential assay, two new compounds, 1 (IC50, 3.3 μM) and 10 (IC50, 1.4 μM), and two known compounds, 3 (α-mangostin, IC50, 0.2 μM) and 11 (3,6-di-O-methyl-α-mangostin, IC50, 0.9 μM), were active. A preliminary analogue development study showed that 3,6-diacetylation and 6-benzoylation both slightly increased the cytotoxicity of α-mangostin (3), whereas methylation reduced such activity. In contrast, neither acetylation, benzoylation, nor methylation enhanced the cytotoxicity of cochinchinone A (6).

Bioactive constituents of the stem bark of Mitrephora glabra

Bioactivity-guided fractionation of the stem bark of Mitrephora glabra yielded nine compounds, comprising three ent-kaurenoids (1-3), five polyacetylenic acids/esters (4-8), and one aporphine alkaloid, liriodenine (9). The structures of the six new compounds (1-3, 5, 7, and 8) were determined by spectroscopic data interpretation. All compounds were evaluated for their inhibitory activities against a panel of cancer cell lines and a battery of microorganisms.

Bioactive Flavaglines and Other Constituents Isolated from Aglaia perviridis

Eight new compounds, including two cyclopenta[b]benzopyran derivatives (1, 2), two cyclopenta[b]benzofuran derivatives (3, 4), three cycloartane triterpenoids (5-7), and an apocarotenoid (8), together with 16 known compounds, were isolated from the chloroform-soluble partitions of separate methanol extracts of a combination of the fruits, leaves, and twigs and of the roots of Aglaia perviridis collected in Vietnam. Isolation work was monitored using human colon cancer cells (HT-29) and facilitated with an LC/MS dereplication procedure. The structures of the new compounds (1-8) were determined on the basis of spectroscopic data interpretation. The Mosher ester method was employed to determine the absolute configurations of 5-7, and the absolute configuration of the 9,10-diol unit of compound 8 was established by a dimolybdenum tetraacetate [Mo2(AcO)4] induced circular dichroism procedure. Seven known rocaglate derivatives (9-15) exhibited significant cytotoxicity against the HT-29 cell line, with rocaglaol (9) being the most potent (ED50 0.0007 μM). The new compounds 2-4 were also active against this cell line, with ED50 values ranging from 0.46 to 4.7 μM. The cytotoxic compounds were evaluated against a normal colon cell line, CCD-112CoN. In addition, the new compound perviridicin B (2), three known rocaglate derivatives (9, 11, 12), and a known sesquiterpene, 2-oxaisodauc-5-en-12-al (17), showed significant NF-κB (p65) inhibitory activity in an ELISA assay.

Bioactivity-guided isolation of cytotoxic constituents of Brucea javanica collected in Vietnam

Five new triterpenoids (1-5), together with two known quassinoids, bruceantin (6) and bruceine A (7), and a known flavonolignan, (-)-hydnocarpin (8), were isolated from the chloroform-soluble subfraction of a methanol extract of the combined twigs, leaves, and inflorescence of Brucea javanica collected in Vietnam. The structures of the new compounds 1-5 were established on the basis of spectroscopic methods. All isolates were evaluated for cytotoxicity against a small panel of human cancer cell lines. Quassinoids 6 and 7 were found to be highly active against these cell lines. (-)-Hydnocarpin (8) showed a potentiating effect when combined with both 6 and 7, during cytotoxicity testing using the MCF-7 human breast cancer cell line.