Cytotoxic Barrigenol-like Triterpenoids from an Extract of <i>Cyrilla racemiflora</i> Housed in a Repository

Two new [(+)-cyrillins A (<b>1</b>) and B (<b>2</b>)] and four known barrigenol-like triterpenoids (<b>3</b>–<b>6</b>), along with betulinic acid and (+)-3β-<i>O</i>-<i>trans</i>-feruloylbetulinic acid, were isolated from a sample-restricted CH₂Cl₂-soluble extract of the bark of <i>Cyrilla racemiflora</i>, collected in Dominica. The structures of the new compounds were elucidated by interpretation of their spectroscopic data, and the absolute configuration of the cyclic 1,2-diol unit of (+)-cyrillin A (<b>1</b>) was ascertained by analysis of the electronic circular dichroism (ECD) spectrum induced with [Mo₂(OAc)₄]. In the case of (+)-cyrillin B (<b>2</b>), which was found to contain a diangeloylated glucose residue, the structure proposed was supported by analysis of its MS² and MS³ spectra. All compounds isolated were evaluated for their cytotoxicity against HT-29 human colon cancer cells, and the known compound, (+)-barringtogenol B (<b>3</b>), was found to be the most potent, exhibiting an IC₅₀ value of 1.7 μM. This compound also showed inhibitory activity toward the CCD-112CoN human normal colon cell line, with an IC₅₀ value of 5.9 μM, indicating a lack of cytotoxic selectivity

Constituents of an Extract of <i>Cryptocarya rubra</i> Housed in a Repository with Cytotoxic and Glucose Transport Inhibitory Effects

A new alkylated chalcone (<b>1</b>), a new 1,16-hexadecanediol diester (<b>2</b>), and eight known compounds were isolated from a dichloromethane-soluble repository extract of the leaves and twigs of <i>Cryptocarya rubra</i> collected in Hawaii. The structures of the new compounds were determined by interpretation of their spectroscopic data, and the absolute configurations of the two known cryptocaryanone-type flavonoid dimers, (+)-bicaryanone A (<b>3</b>) and (+)-chalcocaryanone C (<b>4</b>), were ascertained by analysis of their electronic circular dichroism and NOESY NMR spectra. All compounds isolated were evaluated against HT-29 human colon cancer cells, and, of these, (+)-cryptocaryone (<b>5</b>) was found to be potently cytotoxic toward this cancer cell line, with an IC₅₀ value of 0.32 μM. This compound also exhibited glucose transport inhibitory activity when tested in a glucose uptake assay

Antiproliferative Constituents of the Roots of Ethiopian <i>Podocarpus falcatus</i> and Structure Revision of 2α-Hydroxynagilactone F and Nagilactone I

Bioassay-guided fractionation using the human colorectal adenocarcinoma (HT-29) cell line of the methanol extract of dried roots of <i>Podocarpus falcatus</i> led to the isolation of two new type C nagilactones, 16-hydroxynagilactone F (<b>1</b>) and 2β,16-dihydroxynagilactone F (<b>2</b>), and the new totarane-type bisditerpenoid 7β-hydroxymacrophyllic acid (<b>4</b>), along with the seven known compounds 2β-hydroxynagilactone F (<b>3</b>), macrophyllic acid (<b>5</b>), nagilactone D (<b>6</b>), 15-hydroxynagilactone D (<b>7</b>), nagilactone I (<b>8</b>), inumakiol D (<b>9</b>), and ponasterone A (<b>10</b>). The structures of the new compounds were determined by 1D and 2D NMR, HRESIMS, UV, and IR and by comparison with the reported spectroscopic data of their congeners. The orientation of the C-2 hydroxy group of <b>3</b> and <b>8</b> was revised to be β based on evidence from detailed analysis of 1D and 2D NMR data and single-crystal X-ray diffraction studies. Among the isolated compounds, the nagilactones, including the new dilactones 16-hydroxynagilactone F (<b>1</b>) and 2β,16-dihydroxynagilactone F (<b>2</b>), were the most active (IC₅₀ 0.3–5.1 μM range) against the HT-29 cell line, whereas the bisditerpenoids (<b>4</b> and <b>5</b>) and the other known compounds <b>9</b> and <b>10</b> were inactive. The presence of the bioactive nagilactones in <i>P. falcatus</i> supports its traditional use

Merocyclophanes A and B, Antiproliferative Cyclophanes from the Cultured Terrestrial Cyanobacterium Nostoc sp.

The cell extract of a cultured terrestrial Nostoc sp. (UIC 10062), obtained from a sample collected at Grand Mere State park in Michigan, displayed antiproliferative activity against the HT-29 human colon cancer cell line. Bioactivity-guided fractionation of the cell extract, combined with LC-MS analysis, led to the isolation of two new cyclophanes, named merocyclophanes A and B (1 and 2). The planar structures were determined by various spectroscopic techniques including HRESIMS, and 1D and 2D NMR experiments. The stereoconfiguration was assigned on the basis of X-ray crystallographic and CD analyses. The structures of merocyclophanes A and B (1 and 2) revealed a new natural [7.7]paracyclophane skeleton characterized by α-branched methyls at C-1/14. Merocyclophanes A and B (1 and 2) displayed antiproliferative activity against the HT-29 human colon cancer cell line with IC50 values of 3.3 and 1.7 μM, respectively

Bioactive Constituents of <i>Indigofera spicata</i>

Four new flavanones, designated as (+)-5″-deacetylpurpurin (<b>1</b>), (+)-5-methoxypurpurin (<b>2</b>), (2<i>S</i>)-2,3-dihydrotephroglabrin (<b>3</b>), and (2<i>S</i>)-2,3-dihydrotephroapollin C (<b>4</b>), together with two known flavanones (<b>5</b> and <b>6</b>), three known rotenoids (<b>7</b>–<b>9</b>), and one known chalcone (<b>10</b>) were isolated from a chloroform-soluble partition of a methanol extract from the combined flowers, fruits, leaves, and twigs of <i>Indigofera spicata</i>, collected in Vietnam. The compounds were obtained by bioactivity-guided isolation using the HT-29 human colon cancer, 697 human acute lymphoblastic leukemia, and Raji human Burkitt’s lymphoma cell lines. The structures of <b>1</b>–<b>4</b> were established by extensive 1D- and 2D-NMR experiments, and the absolute configurations were determined by the measurement of specific rotations and CD spectra. The cytotoxic activities of the isolated compounds were tested against the HT-29, 697, Raji, and CCD-112CoN human normal colon cells. Also, the quinone reductase induction activities of the isolates were determined using the Hepa 1c1c7 murine hepatoma cell line. In addition, <i>cis</i>-(6aβ,12aβ)-hydroxyrotenone (<b>7</b>) was evaluated in an in vivo hollow fiber bioassay using HT-29, MCF-7 human breast cancer, and MDA-MB-435 human melanoma cells

Caeruleanone A, a Rotenoid with a New Arrangement of the D‑Ring from the Fruits of <i>Millettia caerulea</i>

Caeruleanone A (<b>1</b>), a novel rotenoid with an unprecedented arrangement of the D-ring, was isolated with another two new analogues, caeruleanones B (<b>2</b>) and C (<b>3</b>), together with 11 known rotenoids from the fruits of <i>Millettia caerulea</i>. The structures of the new compounds were determined by spectroscopic data analysis, with that of <b>1</b> being confirmed by single-crystal X-ray diffraction. Compounds <b>2</b> and <b>3</b> displayed potent mitochondrial transmembrane potential inhibitory and quinone reductase induction activities

Alkaloids from <i>Microcos paniculata</i> with Cytotoxic and Nicotinic Receptor Antagonistic Activities

<i>Microcos paniculata</i> is a large shrub or small tree that grows in several countries in South and Southeast Asia. In the present study, three new piperidine alkaloids, microgrewiapines A–C (<b>1</b>–<b>3</b>), as well as three known compounds, inclusive of microcosamine A (<b>4</b>), 7′-(3′,4′-dihydroxyphenyl)-<i>N</i>-[4-methoxyphenyl)­ethyl]­propenamide (<b>5</b>), and liriodenine (<b>6</b>), were isolated from cytotoxic fractions of the separate chloroform-soluble extracts of the stem bark, branches, and leaves of <i>M. paniculata</i>. Compounds <b>1</b>–<b>6</b> and <b>1a</b> (microgrewiapine A 3-acetate) showed a range of cytotoxicity values against the HT-29 human colon cancer cell line. When evaluated for their effects on human α3β4 or α4β2 nicotinic acetylcholine receptors (nAChRs), several of these compounds were shown to be active as nAChR antagonists. As a result of this study, microgrewiapine A (<b>1</b>) was found to be a selective cytotoxic agent for colon cancer cells over normal colon cells and to exhibit nicotinic receptor antagonistic activity for both the hα3β4 and hα4β2 receptor subtypes

Potent Cytotoxic Arylnaphthalene Lignan Lactones from <i>Phyllanthus poilanei</i>

Two new (<b>1</b> and <b>2</b>) and four known arylnaphthalene lignan lactones (<b>3</b>–<b>6</b>) were isolated from different plant parts of <i>Phyllanthus poilanei</i> collected in Vietnam, with two further known analogues (<b>7</b> and <b>8</b>) being prepared from phyllanthusmin C (<b>4</b>). The structures of the new compounds were determined by interpretation of their spectroscopic data and by chemical methods, and the structure of phyllanthusmin D (<b>1</b>) was confirmed by single-crystal X-ray diffraction analysis. Several of these arylnaphthalene lignan lactones were cytotoxic toward HT-29 human colon cancer cells, with compounds <b>1</b> and 7-<i>O</i>-[(2,3,4-tri-<i>O</i>-acetyl)-α-l-arabinopyranosyl)]­diphyllin (<b>7</b>) found to be the most potent, exhibiting IC₅₀ values of 170 and 110 nM, respectively. Compound <b>1</b> showed activity when tested in an in vivo hollow fiber assay using HT-29 cells implanted in immunodeficient NCr <i>nu</i>/<i>nu</i> mice. Mechanistic studies showed that this compound mediated its cytotoxic effects by inducing tumor cell apoptosis through activation of caspase-3, but it did not inhibit DNA topoisomerase IIα activity

Cytotoxic and non-cytotoxic cardiac glycosides isolated from the combined flowers, leaves, and twigs of Streblus asper

A new non-cytotoxic [(+)-17β-hydroxystrebloside (1)] and two known cytotoxic [(+)-3'-de-O-methylkamaloside (2) and (+)-strebloside (3)] cardiac glycosides were isolated and identified from the combined flowers, leaves, and twigs of Streblus asper collected in Vietnam, with the absolute configuration of 1 established from analysis of its ECD and NMR spectroscopic data and confirmed by computational ECD calculations. A new 14,21-epoxycardanolide (3a) was synthesized from 3 that was treated with base. A preliminary structure-activity relationship study indicated that the C-14 hydroxy group and the C-17 lactone unit and the established conformation are important for the mediation of the cytotoxicity of 3. Molecular docking profiles showed that the cytotoxic 3 and its non-cytotoxic analogue 1 bind differentially to Na+/K+-ATPase. Compound 3 docks deeply in the Na+/K+-ATPase pocket with a sole pose, and its C-10 formyl and C-5, C-14, and C-4' hydroxy groups may form hydrogen bonds with the side-chains of Glu111, Glu117, Thr797, and Arg880 of Na+/K+-ATPase, respectively. However, 1 fits the cation binding sites with at least three different poses, which all depotentiate the binding between 1 and Na+/K+-ATPase. Thus, 3 was found to inhibit Na+/K+-ATPase, but 1 did not. In addition, the cytotoxic and Na+/K+-ATPase inhibitory 3 did not affect glucose uptake in human lung cancer cells, against which it showed potent activity, indicating that this cardiac glycoside mediates its cytotoxicity by targeting Na+/K+-ATPase but not by interacting with glucose transporters

Cardiac Glycoside Constituents of <i>Streblus asper</i> with Potential Antineoplastic Activity

Three new (<b>1</b>–<b>3</b>) and two known (<b>4</b> and <b>5</b>) cytotoxic cardiac glycosides were isolated and characterized from a medicinal plant, <i>Streblus asper</i> Lour. (Moraceae), collected in Vietnam, with six new analogues and one known derivative (<b>5a</b>–<b>g</b>) synthesized from (+)-strebloside (<b>5</b>). A preliminary structure–activity relationship study indicated that the C-10 formyl and C-5 and C-14 hydroxy groups and C-3 sugar unit play important roles in the mediation of the cytotoxicity of (+)-strebloside (<b>5</b>) against HT-29 human colon cancer cells. When evaluated in NCr <i>nu</i>/<i>nu</i> mice implanted intraperitoneally with hollow fibers facilitated with either MDA-MB-231 human breast or OVCAR3 human ovarian cancer cells, (+)-strebloside (<b>5</b>) showed significant cell growth inhibitory activity in both cases, in the dose range 5–30 mg/kg