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.

New Amidated 3,6-Diphenylated Imidazopyridazines with Potent Antiplasmodium Activity Are Dual Inhibitors of Plasmodium Phosphatidylinositol-4-kinase and cGMP-Dependent Protein Kinase.

Recent studies on 3,6-diphenylated imidazopyridazines have demonstrated impressive in vitro activity and in vivo efficacy in mouse models of malaria infection. Herein, we report the synthesis and antiplasmodium evaluation of a new series of amidated analogues and demonstrate that these compounds potently inhibit Plasmodium phosphatidylinositol-4-kinase (PI4K) type IIIß while moderately inhibiting cyclic guanidine monophosphate (cGMP)-dependent protein kinase (PKG) activity in vitro. Using in silico docking, we predict key binding interactions for these analogues within the adenosine triphosphate (ATP)-binding site of PI4K and PKG, paving the way for structure-based optimization of imidazopyridazines targeting both Plasmodium PI4K and PKG. While several derivatives showed low nanomolar antiplasmodium activity (IC50 < 100 nM), some compounds, including piperazine analogue 28, resulted in strong dual PI4K and PKG inhibition. The compounds also demonstrated transmission-blocking potential, evident from their potent inhibition of early- and late-stage gametocytes. Finally, the current compounds generally showed improved aqueous solubility and reduced hERG (human ether-a-go-go-related gene) channel inhibition.

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.

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.