Bufadienolides and anti-angiogenic homoisoflavonoids from 'Rhodocodon cryptopodus', 'Rhodocodon rotundus' and 'Rhodocodon cyathiformis'

Background: Homoisoflavonoids have been shown to have potent anti-proliferative activities in endothelial cells over other cell types and have demonstrated a strong antiangiogenic potential in vitro and in vivo in animal models of ocular neovascularization. Three species of Rhodocodon (Scilloideaea subfamily of the Asparagaceae family), endemic to Madagascar, R. cryptopodus, R. rotundus and R. cyathiformis, were investigated. Purpose: To isolate and test homoisoflavonoids for their antiangiogenic activity against human retinal microvascular endothelial cells (HRECs), as well as specificity against other ocular cell lines. Methods: Plant material was extracted at room temperature with EtOH. Compounds were isolated using flash column chromatography and were identified using NMR and CD spectroscopy and HRESIMS. Compounds were tested for antiproliferative effects on primary human microvascular retinal endothelial cells (HRECs), ARPE19 retinal pigment epithelial cells, 92–1 uveal melanoma cells, and Y79 retinoblastoma cells. HRECs exposed to compounds were also tested for migration and tube formation ability. Results: Two homoisoflavonoids, 3S-5,7-dihydroxy-(3′-hydroxy-4′-methoxybenzyl)-4-chromanone (1) and 3S-5,7-dihydroxy-(4′-hydroxy-3′-methoxybenzyl)-4-chromanone (2), were isolated along with four bufadienolides. Compound 1 was found to be non-specifically antiproliferative, with GI50 values ranging from 0.21–0.85 μM across the four cell types, while compound 2 showed at least 100-fold specificity for HRECs over the other tested cell lines. Compound 1, with a 3S configuration, was 700 times more potent that the corresponding 3R enantiomer recently isolated from a Massonia species. Conclusion: Select homoisoflavonoids have promise as antiangiogenic agents that are not generally cytotoxic

The chemistry of African Croton species

The genus Croton consists of an important group of trees, with several of its species being commercially exploited either as medicines, biofuels or for the cosmetics industry. Plaunotol, an anti-peptic ulcer drug marketed as Kelnac® is isolated from the leaves of Croton stellatopilosus, Sangre De Drago from Croton lechleri is commercially available for the treatment of wounds and diarrhoea, and Croton megalocarpus seed oil is commercially available as a biofuel and for cosmetic uses. Several species of the Croton genus have been reported as being used ethnomedicinally to treat hypertension, rheumatism, inflammation, bleeding gums, malaria, diarrhoea, syphilitic ulcers, asthma, pain and diabetes. The genus Croton is one of the largest genera of the Euphorbiaceae sensu stricto, and consists of over 1300 species of shrubs and trees that are distributed in the warm tropics and sub-tropics. In Africa, there are more than 292 Croton species where 124 are reported to occur in continental Africa, 156 in Madagascar and 12 in the Indian Ocean islands of Reunion, Comoros, Mauritius and Sao Tome and Principe. This study focussed on the chemistry and pharmacological activity of three Central and East African Croton species, Croton mubango Mull. Arg. and Croton haumanianus J. Leonard from the Democratic Republic of Congo and Croton dictyophlebodes Radcl.-Sm from Tanzania. These species are traditionally used in the treatment of a variety of diseases. A total of seventy-five compounds were isolated from these species, including sixty diterpenoids, three triterpenoids, three sesquiterpenoids, three phytosterols, two phenolic compounds, one ferulic acid derivative, linoleic acid and two chlorophyll derivatives. The chemical structures of the isolated compounds were determined using NMR spectroscopy, mass spectrometry, and infrared and specific rotation experiments. DP4+ calculations were used to determine the absolute configuration of compound CM-6 whereas TDDFT-ECD simulation experiments were used to determine absolute configurations for compounds CM-1, CM-2, CM-5, CM-17, CH-19 and CH-21. Thirty-eight diterpenoids are described in this study for the first time, including eleven ent-abietane and one ent-pimarane diterpenoids from C. mubango, nine ent-kauranes, three ent-clerodanes and five ent-isopimaranes from C. haumanianus, and eight ent-clerodanes and one ent-trachylobane from C. dictyophlebodes. Thirty diterpenoids were submitted to the Development Therapeutics Program (DTP) of the National Cancer Institute (NCI) in the United States of America for the NCI 60 anticancer cell line screening programme. Compounds CM-17, CH-11, CH-12, CH-13 and CH-15 showed selective antiproliferative effects against three of the NCI 60 cancer cell lines. Compounds CH-11, CH-12, CH-13 and CH-15 were found to show 100% lethality against colon (HCT-116), melanoma (M14) and renal (786-0) cancer cell lines whereas CM-17 gave 99%, 89% and 82% cell lethality against melanoma (MALME-3M), renal (UO-31) and ovarian cancer (IGROV1) cell lines respectively at a concentration of 10-5 M

Ent-abietane and ent-pimarane diterpenoids from Croton mubango (Euphorbiaceae)

Twelve ent-abietane and two ent-pimarane diterpenoids were isolated from the leaves of Croton mubango Müll. Arg. (Euphorbiaceae) collected in the Democratic Republic of the Congo. 2β-Hydroxy-ent-abieta-7,13-dien-3-one, 15-hydroxy-ent-abieta-7,13-dien-3-one, 13α,15-dihydroxy-ent-abieta-8(14)-en-3-one, 2β,9,13-trihydroxy-ent-abieta-7-en-3-one, 2β,7β-dihydroxy-ent-abieta-8,11,13-trien-3-one, 15-hydroxy-ent-abieta-8,11,13-trien-3-one and ent-pimara-8(14),15-dien-3-one and the ent-forms of the previously reported normal series diterpenoids, ent-abieta-8,11,13-trien-3-one, 7β-hydroxy-ent-abieta-8,11,13-trien-3-one, 3α-hydroxy-ent-abieta-8,11,13-triene, 15-hydroxy-ent-abieta-8,11,13-triene and 6β-hydroxy-ent-abieta-8,11,13-triene are reported here for the first time. Structures were established using HRESIMS, FTIR, NMR, DP4+ probability calculations and by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. Ent-pimara-8(14), 15-dien-3-one, showed antiproliferative activity against melanoma (MALME-3M), renal (UO-31) and ovarian cancer cell lines (IGROV1) at a concentration of 10−5 M in the NCI 60 screen

Cytotoxic diterpenoids from the leaves and stem bark of Croton haumanianus (Euphorbiaceae)

The leaf extract of Croton haumanianus J. Léonard (Euphorbiaceae) yielded twenty-six compounds, including eight previously reported ent-kauranes and an ent-labdane and eight undescribed ent-kauranes, ent-16R-kauran-17-al, ent-3β-hydroxy-16R-kauran-17-al, ent-16S,17-epoxykauran-19-ol, ent-16S,17-epoxykauran-3β-ol, ent-17-palmityloxykaurane-3β,16β-diol, ent-17-palmityloxykauran-16β-ol, ent-3α,18-cyclokaurane-16β,17-diol and 19-nor-16α,17-dihydroxy-ent-kaur-4(18)-ene and three undescribed ent-clerodanes, dimethyl ent-15,16-epoxy-6β-hydroxy-1,3,13(16),14-clerodatetraen-20,12S-olide-18,19-dioate (saniolide A), dimethyl ent-15,16-epoxy-6β-hydroxy-1,3,13(16),14-clerodatetraen-20,12R-olide-18,19-dioate (12-epi-saniolide A), methyl ent-15,16-epoxy-1,3,13(16),14-clerodatetraen-18,6R:20,12S-diolide-19-oate (saniolide B) . The stem bark extract yielded the ent-clerodane crotocorylifuran, and five undescribed ent-isopimaranesent-isopimara-8(14),15-dien-18-al, ent-18-hydroxyisopimara-8(14),15-dien-7-one, ent-isopimara-7,15-dien-18-oic acid, ent-isopimara-7,15-dien-18-ol and ent-isopimara-8,15-dien-7-oxo-18-oic acid. Three compounds, ent-kaurane-3β,16β,17-triol, ent-17-palmityloxykaurane-3β,16β-diol and ent-17-palmityloxykauran-16β-ol, showed selective activity against three of the NCI 60 cancer cell lines, the colon (HCT-116), the melanoma (M14) and the renal (786-0) cancer cell lines at a concentration of 10-5 M

Ent-clerodane and ent-trachylobane diterpenoids from Croton dictyophlebodes.

The stem bark and root bark extracts of Croton dictyophlebodes (Euphorbiaceae) yielded seven undescribed ent-clerodanes: 15,16-epoxy-17,12(S)-olide-ent-cleroda-1,3,13(16),14-tetraen-18-oic acid methyl ester (crotodictyo A), 3β,4β:15,16-diepoxy-ent-cleroda-13(16),14-dien-20-al (crotodictyo B), 3β,4β:15,16-diepoxy-ent-cleroda-13(16),14-dien-19,20-dioic acid (crotodictyo C), 3β,4β:15,16-diepoxy-ent-cleroda-13(16),14-dien-20,19-olide (crotodictyo D), 3β,4β:15,16-diepoxy-20,12(R)-olide ent-cleroda-13(16),14-dien-19-oic acid methyl ester (crotodictyo E), 15,16-epoxy-ent-cleroda-3,13(16),14-trien-12-oxo-18-oic acid (crotodictyo F) and 15,16-epoxy-ent-cleroda-1,3,13(16),14-tetraen-12-oxo-18-oic acid (crotodictyo G), in addition to 15,16-epoxy- ent-cleroda-3,13(16),14-trien-12-oxo-18-oic acid methyl ester (crotodictyo H), reported previously as a synthetic derivative, and acetyl aleuritolic acid. The root extract yielded two ent-trachylobanes, ent-trachylobane-18,19-diol, the undescribed ent-trachylobane-2α,19-diol, along with ent-kaur-16-en-19-oic acid and 2-methoxybenzyl benzoate. Compounds were evaluated against the NCI 60 panel of human tumour cell lines at a single dose of 10−5 M, but showed no significant activity

Ecdysteroids from the Stem Bark of Vitex doniana Sweet (Lamiaceae; ex. Verbenaceae): A Geographically Variable African Medicinal Species.

Vitex doniana Sweet is an African medicinal species that is prescribed as an aqueous bark extract to be applied topically or orally to achieve anti-infective outcomes. In select regions it is also taken orally as an antimalarial agent. The aim of the current study was to explore the biological properties of V. doniana and isolated compounds in the context of pathogenic bacteria and the protozoan parasite Plasmodium falciparum. Three compounds were isolated and assigned by nuclear magnetic resonance spectroscopy as ecdysteroids: (1) 20-hydroxyecdysone, (2) turkesterone, and (3) ajugasterone C. Interestingly, two of these compounds had not previously been identified in V. doniana, providing evidence of chemical variability between regions. The bark extract and three ecdysteroids were screened for activity against a panel of pathogenic bacteria associated with skin, stomach and urinary tract infections, and the protozoan parasite P. falciparum. The crude extract of the bark inhibited all bacterial strains with MIC values of 125–250 μg.mL−1. The three isolated compounds demonstrated less activity with MIC values of 500–1000 μg.mL−1. Furthermore, no activity was observed against P. falciparum at the screening concentration of 4.8 μg.mL−1. Nevertheless, we present a hypothesis for the possible mechanism for symptomatic relief of malarial fever, which may involve reduction of prostaglandin E(1) & E(2) activity in the hypothalamus via modulation of the monoaminergic system. While further studies are required to identify all antimicrobial agents within this plant species and to determine the cytotoxicity of each of these compounds, these data suggest that the traditional application of this species as an antiseptic is valid

Effect of Elevated Temperature on the Compressive Strength and Durability Properties of Crumb Rubber Engineered Cementitious Composite

This paper reports the findings of the effect of elevated temperature on the compressive strength and durability properties of crumb rubber engineered cementitious composite (CR-ECC). The CR-ECC has been tested for its compressive strength and chemical resistance test against acid and sulphate attack. Different proportions of crumb rubber (CR) in partial replacement to the fine aggregate and polyvinyl alcohol (PVA) fiber have been utilized from 0 to 5% and 0 to 2%. The experiments were designed based on a central composite design (CCD) technique of response surface methodology (RSM). After 28 days curing, the samples were preconditioned and exposed to high temperatures of 100 °C, 200 °C, 300 °C, 400 °C, 500 °C, 600 °C, 700 °C, 800 °C, 900 °C, and 1000 °C for one hour. Although the residual compressive strength of CR-ECC was negatively affected by elevated temperature, no explosive spalling was noticed for all mixes, even at 1000 °C. Results indicated that CR-ECC experiences slight weight gain and a reduction in strength when exposed to the acidic environment. Due to the reduced permeability, CR-ECC experienced less effect when in sulphate environment. The response models were generated and validated by analysis of variance (ANOVA). The difference between adjusted R-squared and predicted R-squared values for each model was less than 0.2, and they possess at least a 95% level of confidence

Diterpenoids from the stem bark of Croton megalocarpoides Friis & M. G. Gilbert

Five previously undescribed compounds, megalocarpoidolide I (1), megalocarpoidolide J (3), 12-epi-crotonzambefuran A (4), megalocarpoidolide K (5), 1-trans-p-hydroxycoumaroyl–geranylgerani-1-ol (6) were isolated from the stem bark of Croton megalocarpoides Friis & M. G. Gilbert. The known ent-trachyloban-18-ol, megalocarpoidolide B, megalocarpoidolide C (2), megalocarpoidolide H, crotocorylifuran, 7,8-dehydrocrotocorylifuran, 1,2-dehydrocrotocorylifuran-2-one, acetyl aleuritolic acid, lupeol, N-trans-p-coumaroyl-3′,4′-dihydroxyphenylethylamine, dodecyl trans-ferulate and lignoceryl trans-ferulate were also isolated. The structures of the compounds were determined using NMR, IR spectroscopy and HRMS. The structure of compound 1 was determined using Logic for Structural Determination (LSD). Compounds 1, 2 and 3 that were selected for screening based on their ability to add diversity to the NCI small molecule compound collection, were evaluated against the NCI60 panel of human tumour cell lines at 10μM level but found to be inactive

Chemical Composition and Synergistic Antimicrobial Effects of a Vegetatively Propagated Cameroonian Lemon, Citrus x limon (L.) Osbeck

Nsangou MF, Happi EN, Fannang SV, et al. Chemical Composition and Synergistic Antimicrobial Effects of a Vegetatively Propagated Cameroonian Lemon, Citrus x limon (L.) Osbeck. ACS Food Science & Technology. 2021.This study analyzed the antimicrobial effects of compounds present in the roots and leaves of Citrus x limon (L.) Osbeck to help understand how this plant (1) ecologically modulates microbial defense in the rhizosphere and (2) protects against food-borne bacterial pathogens. Antimicrobial effects of C. limon collected from a farm in Foumban in Cameroon are reported against Salmonella typhi, Salmonella typhimurium, Salmonella enteritidis, Escherichia coli, Shigella flexineri, and Saccharomyces cerevisiae. The study modeled synergistic antifungal effects of an essential oil from the roots of C. limon or E-caryophyllene when combined with the isolated compounds against S. cerevisiae. Twenty-four compounds were identified from the methanol extracts of the roots and leaves: 10 prenylated coumarins (1–10), six methoxylated flavones (11–16), two limonoids (18 and 19), a phenylalanine derivative (20), lupeol, stigmasterol, sitosterol, and sitosterol-3-O-β-d-glucoside. Major compound 16, atalantoflavone, was esterified using lauric acid to yield the undescribed 5,4′-dilaureate atalantoflavone (16a). The essential oil from the roots contained methyl esters of hexadecanoic acid (39%) and 9-octadecenoic acid (9.3%) and sesquiterpenes β-bisabolene (10.1%) and α-santalene (8.0%). The antimicrobial effects of the root extract, leaf extract, compounds 1, 2, 4, 7–9, 11, 12, 14, 16, 16a, and 18 were evaluated against S. typhi, S. typhimurium, S. enteritidis, E. coli, S. flexineri, and S. cerevisiae. Compounds 11, 16, and 18 from the root extract of C. x limon showed significant antimicrobial effects with a minimum inhibitory concentration (MIC) of 62.5 μg/mL against S. flexineri, whereas compounds 5, 7, 11, and 18 showed significant antimicrobial effects with a MIC of 62.5 μg/mL against S. typhi. The essential oil from the roots synergized compounds 11–14 against S. cerevisiae. A synergistic MIC of 7.8 μg/mL was registered by combining 12 and E-caryophyllene