The dichapetalins and dichapetalin-type compounds: structural diversity, bioactivity, and future research perspectives.

Covering mainly from 2013 up to 2023 with relevant references to work done before 2013First reported in 1995, the dichapetalins and analogous compounds constitute a novel class of natural dammarane-type merotriterpenoids characterized by their unique 2-phenylpyrano moiety annellated to ring A of the dammarane skeleton. They have been reported from only two genera: Dichapetalum (Dichapetalaceae) and Phyllanthus (Phyllanthaceae). About 100 novel dichapetalins and dichapetalin-type compounds, including the acutissimatriterpenes and their antitumour and other bioactivities have been reported. In the present review, we cover the distribution, ethnobotanical and medicinal importance and the diversity of secondary metabolites reported from the two genera Dichapetalum and Phyllanthus from 2013 to date, with appropriate reference to relevant information prior to 2013. We also propose and discuss possible biosynthetic pathways, antitumour activity against a broad range of human and murine cancer cell lines, structure activity relationships, and other biological activities and mechanisms of action. Finally, the review deals with future perspectives which include expansion of the structural diversity and bioactivity scope, possible simplification of the structural complexity of the compounds to enhance their drug-likeness, in silico studies, and continuation of the search for new dichapetalins and dichapetalin-type compounds from the over 200 Dichapetalum and over 1200 Phyllanthus species yet to be investigated. It is envisaged that the present review will stimulate further multidisciplinary and interdisciplinary studies.

Constituents of the Roots of Dichapetalum pallidum and Their Anti-Proliferative Activity.

As part of our search for bioactive compounds from the Dichapetalaceae, repeated chromatographic purification of the roots of a hitherto unexamined species, Dichapetalum pallidum, led to the isolation of the newly occurring 7-hydroxydichapetalin P (1) and the known dichapetalins A (2) and X (3). Also isolated were the known compounds friedelin-2,3-lactone (4), friedelan-3-one (6), friedelan-3ß-ol (7) and pomolic (8), as well as the dipeptide aurantiamide acetate (5). The compounds were characterized by direct interpretation of their IR, 1D NMR and 2D NMR spectral data and by comparison of their physico-chemical data, including their chromatographic profiles, with the literature and authentic samples in our compound library for the genus Dichapetalum. The compounds were assayed for their anti-proliferative activities against the human T-lymphocytic leukemia (Jurkat), acute promyelocytic leukemia (HL-60) and T-lymphoblast-like leukemia (CEM) cell lines. Overall, dichapetalin X showed the strongest (3.14 µM) and broadest cytotoxic activities against all the leukemic cell lines tested, exhibiting even stronger activities than the standard compound, curcumin.

Isolation, characterization, and anthelminthic activities of a novel dichapetalin and other constituents of Dichapetalum filicaule.

CONTEXT: Dichapetalum filicaule Breteler (Dichapetalaceae) is a rare species occurring only in Côte d'Ivoire and Ghana. Although research on several species of the genus has produced interesting bioactive compounds, particularly the Dichapetalins, a novel class of triterpenoids with antineoplastic properties, there is virtually no information on the ethnobotanical uses and chemical constituents of D. filicaule. OBJECTIVE: The phytochemical and anthelminthic activities of the constituents of D. filicaule were investigated. MATERIALS AND METHODS: Chemical constituents of the petroleum ether, chloroform-acetone, and methanol root extracts of D. filicaule were isolated by column chromatography and characterized by their physico-chemical properties, 1-D and 2-D NMR spectroscopy and mass spectrometry. In vitro anthelminthic activity of the extracts and compounds against the human hookworm, Necator americanus, Stiles 1902 (Nematoda: Ancylostomatidae) was determined within a concentration range of 2500-250 µg/ml using the Egg Hatch Inhibition (EHI) Assay. The hookworm species were identified using a published polymerase chain reaction (PCR) method. RESULTS: A new dichapetalin, dichapetalin X (1), together with the known dichapetalin A (2), pomolic acid (3), glycerol monostearate (4), D:A-friedooleanan-3ß-ol (5), and D:A-friedooleanan-3-one (6) were isolated. Compounds 1, 2, and 4 exhibited EHI with IC50 values of 523.2, 162.4, and 306.0 µg/ml, respectively, against the hookworm. The positive control albendazole gave an IC50 value of 93.27 µg/ml. DISCUSSION AND CONCLUSION: This is the first report of the phytochemical investigation of D. filicaule. The study has yielded a new dichapetalin and also demonstrated the potential anthelminthic properties of the constituents.

Tilapia consumption patterns and consumer preferences: Predictors and perspectives of consumers in Ghana.

The objective of this study was to assess consumer behaviour towards tilapia and tilapia products and provide information linking production with consumption patterns and preferences as well as to predict factors that influence consumer preference, purchase behaviour, and willingness to patronize tilapia fillets using classification and regression trees. A total of 960 responses were obtained using convenient sampling. The findings of this survey indicate that tilapia is eaten mainly because of its taste. Regarding the various cooked tilapia options available in Ghana, 58.5 % preferred charcoal-grilled tilapia while sixty-six per cent (66 %) preferred to purchase their tilapia in the fresh state. Furthermore, sixty-five per cent (65 %) of the participants revealed that they consume tilapia at least once a month, indicating a link between production and consumption, as well as a continuous market for tilapia fish farmers. Most respondents (85 %) would prefer an easier way to prepare tilapia. The availability of tilapia in a fillet form appealed to about 50.8 % of respondents with 78 % indicating that they would purchase tilapia fillets if they were available on the market. For the parts of tilapia consumed, 70 % indicated that the head of tilapia was important to them and only 49 % of respondents indicated they would buy fillets without the head. The top three preferred fillet options in increasing order were chilled, frozen, and spiced. From the study of associations, income was the most important factor determining whether a consumer would purchase tilapia fillets or not. However, with regards to preference of head or tail region, age was the most important determining factor. Thus, consideration of all these factors would serve as a guide to businesspeople and actors within the tilapia value chain in Ghana and beyond.

The workshops on computational applications in secondary metabolite discovery (CAiSMD).

We report the outcomes of the second session of the free online open-access workshop "Computational Applications in Secondary Metabolite Discovery (CAiSMD) 2022" that took place from 09 to 11 March 2022. The first session was held from 08 to 10 March 2021 and drew the attention of many early career scientists from academia and industry. The 23 invited speakers of this year's workshop also came from academia and industry and 222 registered participants from five continents (Africa, Asia, Europe, South, and North America) took part in the workshop. The workshop highlighted the potential applications of computational methodologies in the search for secondary metabolites or natural products as drug candidates and drug leads. For three days, the participants of this online workshop discussed modern computer-based approaches for exploring NP discovery in the "omics" age. The invited experts gave keynote lectures, trained participants in hands-on sessions, and held round table discussions. These were followed by oral presentations during which much interaction between the speakers and the audience was observed. Selected applicants (early-career scientists) were offered the opportunity to give oral presentations (15 min) upon submission of an abstract. The final program available on the workshop website (https://indiayouth.info/index.php/caismd) comprised three keynote lectures, 14 oral presentations, two round table discussions, and four hands-on sessions. This meeting report also references internet resources for computational biology around secondary metabolites that are of use outside of the workshop areas and will constitute a long-term valuable source for the community.

Antimicrobial and in silico studies of the triterpenoids of Dichapetalum albidum.

Here we report a new polyhydroxylated triterpene, 2ß,6ß,21α-trihydroxyfriedelan-3-one (4) isolated from the root and stem bark of Dichapetalum albidum A. Chev (Dichapetalaceae), along with six known triterpenoids (1-3, 5, 6, 8), sitosterol-3ß-O-D-glucopyranoside (9), a dipeptide (7), and a tyramine derivative of coumaric acid (10). Friedelan-3-one (2) showed an antimicrobial activity (IC50) of 11.40 µg/mL against Bacillus cereus, while friedelan-3α-ol (1) gave an IC50 of 13.07 µg/mL against Staphylococcus aureus with ampicillin reference standard of 19.52 µg/mL and 0.30 µg/mL respectively. 3ß-Acetyl tormentic acid (5) showed an IC50 of 12.50 µg/mL against Trypanosoma brucei brucei and sitosterol-3ß-O-d-glucopyranoside (9) showed an IC50 of 5.06 µg/mL against Leishmania donovani with respective reference standards of IC50 5.02 µg/mL for suramin and IC50 0.27 µg/mL for amphotericin B. Molecular docking of the isolated compounds on the enzyme glucose-6-phosphate dehydrogenase (G6PDH) suggested 3ß-acetyl tormentic acid (5) and sitosterol-3ß-O-D-glucopyranoside (9) as plausible inhibitors of the enzyme in accordance with the experimental biological results observed.

Assessment of toxicity and anti-plasmodial activities of chloroform fractions of Carapa procera and Alchornea cordifolia in murine models.

Background: Plant as a source of medicine has gained international popularity in recent times because of its natural origin, availability in local communities, cheaper to purchase, ease of administration, and its usefulness as an alternative treatment in case of numerous side effects and drug resistance. However, the use of herbal formulations can also result in short-term and long-term organ damage or dysfunction to the host. In this study, chloroform fractions of the leaves of two medicinal plants, Alchornea cordifolia (ACL) and Carapa procera (CPL), were investigated for their toxicological and anti-malarial effects in murine models. Method: Acute (14-day) and sub-acute (28-day) studies were conducted based on the Organization for Economic Cooperation and Development (OECD) Guidelines in Institute for Cancer Research (ICR) mice and Sprague Dawley (SD) rats respectively. A dosage of 2000 mg/kg body weight was administered orally to each ICR mouse during the acute study and 100, 300, and 1000 mg/kg body weight to each SD rat during the sub-acute study. A 5-day curative anti-plasmodial activity was assessed in ICR mouse model. Results: The assessment of toxicity revealed that all three fractions did not influence mortality, clinical appearance, body weight gain, or necropsy at the various doses. Hematological and serum biochemical analysis indicated no significant elevations in liver and renal function parameters. Histopathological examinations of the liver indicated reversible liver degeneration with the chloroform fraction of the 100% ethanol extract of Carapa procera leaves (CPL100%) at 1000 mg/kg. Anti-plasmodial assessments showed CPL100% exhibiting dose-dependent anti-plasmodial activity from 16% to 26.67%. On the other hand, chloroform fraction of the 100% ethanol extract of Alchornea cordifolia leaves (ACL100%) showed declining anti-plasmodial activity from 21.1% to 15.1%. Conclusion: These preliminary findings demonstrate that chloroform fractions of the leaves of Carapa procera and Alchornea cordifolia may be safe agents for treating malaria hence further development for drug discovery must be pursued.

Antiproliferative Activities of Methanolic Extract and Fractions of Tetrapleura Tetraptera Fruit.

Most of the current cancer chemotherapeutics are associated with harsh and undesirable side effects, including toxicity and chemoresistance, driving the need for safer and more effective alternatives. In this study, the antiproliferative activities of the methanolic extract of Tetrapleura tetraptera fruits and nine different fractions (C1-C9) from the column chromatographic separation of the extract against leukemia (Jurkat) and human breast cancer (MCF-7) cell lines were investigated using a tetrazolium-based colorimetric assay. Phytochemical screening of the extract and fractions found alkaloids, carbohydrates, flavonoids, glycosides, phenols, saponins, steroids, tannins, and terpenoids in the methanolic extract. Most of the fractions exhibited antiproliferative activity (>100 µg/mL) with the Jurkat cells being more susceptible than the MCF-7 cells. Four of the collected fractions C4, C3, C5, and C2 had good selective indices in decreasing order of activity, in the case of Jurkat cells. Liquid chromatography-mass spectrometry analysis of all samples (except for C4 and C9) revealed that C1, C2, C3, and C5 each had a single component. More importantly, fractions C2, C3, and C5, which were selective to Jurkat cells, also had the same retention time of 1.846 min. Fractions C6 and C8 had two components, with C7 having four components. This study serves as a basis for further work to isolate and characterize potential anticancer agents from the fractions of extracts of T. tetraptera fruits.

Towards understanding antimicrobial activity, cytotoxicity and the mode of action of dichapetalins A and M using in silico and in vitro studies.

Dichapetalum madagascariense Poir (Dichapetalaceae) is traditionally used to treat bacterial infections, jaundice, urethritis and viral hepatitis in Africa. Its root contains a broad spectrum of biologically active dichapetalins. To evaluate the plant's effect on human MCF-7 cells and its' antibacterial and antiparasitic potentials, we isolated and identified the known dichapetalins A and M from the roots. Both dichapetalins were tested on six bacterial strains (Shigella flexneri, Bacillus cereus, Salmonella paratyphi B, Listeria monocytogenes, Escherichia coli, Staphylococcus aureus) and two parasite strains; Trypanosoma brucei brucei, and Leishmania donovani using the Alamar Blue assay system. Dichapetalins A and M were more potent against B. cereus with IC50 values of 11.15 and 3.15 µg/ml, respectively, compared to the positive control ampicillin (IC50 = 19.50 µg/ml). Dichapetalins A (IC50 = 74.22 µg/ml) and M (IC50 = 72.34 µg/ml) were less active against T. b. brucei, compared to the standard Suramin (IC50 = 4.96 µg/ml). Dichapetalin M showed moderate activity against L. donovani (Amphotericin B: IC50 = 0.21 µg/ml) with an IC50 of 16.80 µg/ml. In human MCF-7 cells expressing the NR1I2 receptor, the activity of dichapetalin M was higher (IC50 = 4.71 µM and 3.95 µM) for 48 and 72 h of treatment, respectively compared to Curcumin with IC50 of 17.49 µM and 12.53 µM for 48 and 72 h of treatment, respectively. Results from in vitro expression studies with qPCR confirmed an antagonistic effect of dichapetalin M on PXR (NR1I2) signaling; supporting the PXR signaling pathway as a possible mode of action of dichapetalin M as predicted by in silico results. These findings confirm previous studies that D. madagascariense can be a source of potential lead compounds for development of novel antibiotic, antiparasitic and anticancer medicines, and provide further insights into the mechanism of action of the dichapetalins.

In vitro activities of crude extracts and triterpenoid constituents of Dichapetalum crassifolium Chodat against clinical isolates of Schistosoma haematobium.

Dichapetalum crassifolium Chodat (Dichapetalaceae) is widely distributed in Africa, Tropical Asia and Latin America. As part of our quest for potential bioactive lead compounds for various neglected tropical diseases, we report the anti-schistosomal potential of the crude extracts and chemical constituents of the stems and roots of Dichapetalum crassifolium. Column chromatography of extracts of the stems and roots led to the isolation and identification of three oleanane-type triterpenoids, friedelan-3ß-ol (1), friedelan-3-one (2), and maslinic acid (3); the ursane-type tritepenoid, pomolic acid (4) and the dammarane-type tetracyclic triterpenoids, dichapetalin A (5) and dichapetalin M (6). Dichapetalin A was isolated from only the roots. Isolated compounds were identified by comparison of their physico-chemical and spectral data with published data. The highest in vitro anti-schistosomal activity (IC50) of the crude extracts against clinical isolates of Schistosoma haematobium (Bilharz 1852) was 248.6 µg/ml for the ethyl acetate extract of the root while dichapetalin A gave the highest activity at 151.1 µg/ml among the compounds compared with the 15.5 µg/ml for the standard drug, praziquantel. The rest of the compounds showed activities in the order 177.9, 191.0, and 378.1 µg/ml respectively for mixture of ß-sitosterol/stigmasterol, dichapetalin M and friedelan-3-one. The least active extract was the methanol extract of the stem (893.7 µg/ml). The constituents of D. crassifolium showed activity against the S. haematobium that are below praziquantel. It is envisaged that the presence of multiple layers and the minute sizes of pores in the egg shells, may preclude penetration of eggs by the compounds.

Bi- and bisbibenzyls from the roots of Dichapetalum heudelotii and their antiproliferative activities.

Two new bisbibenzyls, heudelotol A (1) and B (2), along with the known bibenzyls, (E)-combretastatin A-1 (3) and combretastatin B-1 (4) have been isolated from the ethyl acetate extract of the roots of Dichapetalum heudelotii. Structure elucidation of all four isolated compounds was achieved using UV, IR, 1D and 2D NMR spectroscopy and HR-Mass Spectrometry. The compounds exhibited varying antiproliferative activity against six cancer cell lines using the CellTiter-Glo® Luminiscent Cell Viability Assay. Compound 3 was found to be the most active with sub-micromolar growth inhibition concentrations against all the cell lines (GI50 0.03-0.72µM). However, it was about ten-fold less active than the positive control, taxol. The new bisbibenzyls heudelotol A and B exhibited good activity against human pancreatic adenocarcinoma (GI50 9.04µM) and Burkitt's lymphoma (GI50 4.67µM) respectively, and average activity against the other cancer cell lines.