Multidrug-resistant cancer cell susceptibility to cytotoxic quassinoids, and cancer chemopreventive effects of quassinoids and canthin alkaloids

Twenty-three quassinoids (1-23), which were isolated previously from Simaroubaceous plants, were evaluated for cytotoxicity against three multidrug-resistant cancer cell lines, KB-VIN, KB-7d, and KB-CPT. Nine compounds (2-7 and 9-11) showed significant cytotoxicity in all three cell lines. Compounds 1, 12-14, 17, and 20 demonstrated significant activity against the KB-7d and KB-CPT cell lines, and compounds 18, 19, and 23 revealed notable activity only against KB-7d cells. Structure-activity relationships were drawn based on these data. In addition, six quassinoid derivatives (24-29) and four canthin alkaloids (30-33), which were isolated from Brucea antidysenterica, were examined for their inhibitory effects on 12-O-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus early antigen (EBV-EA) activation as cancer chemopreventive agents. All of these compounds demonstrated significant inhibitory effects against EBV-EA activation.     

Trigoxyphins H and I: two new daphnane diterpenoids from Trigonostemon xyphophylloides

Two new daphnane diterpenoids (1 and 2), together with four known analogues (3-6) were isolated from Trigonostemon xyphophylloides. Their structures were elucidated by spectroscopic analysis. Compounds 1 and 2 were evaluated for in vitro cytotoxic activities against the SPCA-1 (human lung cancer) and BEL-7402 (human hepatocellular carcinoma) cancer cell lines. Trigoxyphin I (2) showed modest cytotoxicity against two tumor cell lines.     

Cespitulactones A and B, new diterpenoids from Cespitularia taeniata

Two new diterpenoids, designated cespitulactones A (1) and B (2), were isolated from a sample of the soft coral Cespitularia taeniata collected in Taiwan. Compound 1 possesses a novel structure with a bond cleavage between C-10 and C-11, and having a 14-membered lactone ring junction between C-10 and C-12. Their structures were elucidated on the basis of extensive spectroscopic analysis and chemical derivatization. The isolated compounds were also evaluated for cytotoxicity toward human cancer cell lines.     

Azaphilone pigments from a yellow mutant of the fungus Monascus kaoliang

Azaphilone pigments, monascusones A (1) and B (2), together with two known azaphilones, monascin (3) and FK17-P2b2 (4), were isolated from the CH2Cl2 extract of a yellow mutant of the fungus M. kaoliang grown on rice. Structures of the isolated compounds were elucidated by analyses of spectroscopic data. Monascusone A (1), the major metabolite of M. kaoliang, showed no antimalarial (against Plasmodium falciparum), antitubercular (against Mycobacterium tuberculosis H37Ra), and antifungal (toward Candida albicans) activities. Compound 1 exhibited no cytotoxicity against BC (breast cancer) and KB (human epidermoid carcinoma of cavity) cell lines.     

Novel antibacterial diterpenoids from Larix chinensis Beissn

Two novel labdane-type diterpenoids, butanedioic acid mono[(13S)-13-hydroxylabda-8(17),14-dien-19-yl] ester (1) and butanedioic acid bis[(13S)-13-hydroxylabda-8(17),14-dien-19-yl] ester (2), along with the eleven known diterpenoids 3-13 and three other known compounds, were isolated from the bark of Larix chinensis. Their structures were elucidated both spectroscopically and chemically. The major diterpenoids 1-9, 11, and 13, as well as the very abundant phenolic compound 16, were subjected to antibacterial and cytotoxic bioassays. Compounds 7 and 9 showed remarkable in vitro inhibition of Staphylococcus aureus and S. epidermidis (MIC = 37-73 microM).     

Abietane diterpenes from the cones of Cedrus atlantica

Five new abietanes, three of them isolated as the corresponding acetate derivatives, i.e., 9alpha,13alpha-epidioxiabiet-8(14)-en-18-ol, 7alpha,18-diacetoxy, 9beta,13beta-epidioxiabiet-8(14)-ene, 7alpha,18-diacetoxyabiet-8(14)-en-13beta-ol, 7alpha,18-diacetoxy-13beta-methoxyabiet-8(14)-ene, and 13beta-hydroxyabiet-8(14)-en-7-one, were isolated from the neutral part of the hexane extract of the cones of Cedrus atlantica collected in Middle Atlas, Morocco. The structures of these compounds were established by spectroscopic techniques, including 2D NMR spectra, and in the case of 1, by chemical correlation. The cytotoxicity of these abietane diterpenoids was tested against five cell lines.     

Cytotoxic ent-kaurane diterpenoids from Isodon sinuolata

Five (1–5) ent-kaurane diterpenoids and 17 other known ones, were isolated from the leaves and stems of Isodon sinuolata. Their structures were determined on the basis of spectroscopic methods including 1D and 2D NMR spectroscopic analysis. All compounds were evaluated for cytotoxicity against a small panel of cell lines. Some compounds exhibited significant cytotoxicity.     

Two cyathane-type diterpenoids from the liquid culture of Strobilurus tenacellus

The structures of two new cyathane-type diterpenoids isolated from a liquid culture of Strobilurus tenacellus have been elucidated. The chemical structures of the new compounds 1 and 2 were identified as (12S)-11alpha,14alpha-epoxy-13alpha,14beta,15-trihydroxycyath-3-ene and (12R)-11alpha,14alpha-epoxy-13alpha,14beta,15-trihydroxycyath-3-ene, respectively, by spectral methods, including HR-EI-MS, and 1D- and 2D-NMR techniques. Compounds 1 and 2 show antimicrobial activity against Pseudomonas aeruginosa. In addition, both compounds were also tested for activity against human cancer cells, and 2 showed growth inhibitory activity against YMB and COLO 201 cells.     

Cytotoxic labdane diterpenoids from Croton oblongifolius

Three labdane diterpenoids, 2-acetoxy-3-hydroxy-labda-8(17),12(E)-14-triene, 3-acetoxy-2-hydroxy-labda-8(17),12(E)-14-triene, and 2,3-dihydroxy-labda-8(17),12(E),14-triene were isolated from stem bark of Croton oblongifolius. Their structures were established by spectroscopic data, and each was also tested for cytotoxicity against various human tumor cell lines. The latter compound showed non-specific, moderate, cytotoxicities against all the cell lines; whereas the first two compounds were less active.     

Synthesis and structure-activity relationships of taxuyunnanine C derivatives as multidrug resistance modulator in MDR cancer cells

A series of new generation taxoids bearing a bulky group on different positions such as C-2, C-5, C-7, C-9, C-10 or C-14 were obtained by chemical modifications and biotransformation of taxuyunnanine C (1) and its analogs, 4, 5, and 10. Compounds 3, 5, 6, 8, and 9a showed significant activity toward calcein accumulation in MDR 2780AD cells. The most effective compound 9a with a cinnamoyloxy group at C-14 and a hydroxyl group at C-10 was actually efficient for the cellular accumulation of the anticancer agent, vincristine, in MDR 2780AD cells. The enhancing effects of 6 and 9a for taxol, adriamycin, and vincristine were at the same levels as those of verapamil toward MDR 2780AD cells. Thus, compounds 6 and 9a can modulate the multidrug resistance of cancer cells. The cytotoxicity (IC(50)) of the compounds was examined against human normal cell line, WI-38, and cancer model cell lines, VA-13 and HepG2. Since compounds 6 and 8 had no cytotoxicity, they were expected to be lead compounds of MDR cancer reversal agents. On the contrary, compounds 3, 5, and 9a showed cell growth inhibitory activity toward VA-13 and/or HepG2 as well as accumulation activity of calcein and/or vincristine in MDR 2780AD and they were expected to be lead compounds of new-type anticancer agents.     

Five new quassinoids and cytotoxic constituents from the roots of Eurycoma longifolia

Eurycoma longifolia has been widely used for various traditional medicinal purposes in South-East Asia. In this study, five new quassinoids, eurylactone E (1), eurylactone F (2), eurylactone G (3), eurycomalide D (4), and eurycomalide E (5), along with ten known quassinoids (6–15) were isolated from the roots of E. longifolia. Their structures were determined by extensive spectroscopic methods, including 1D and 2D NMR, and MS spectra data. Among the isolated compounds, 13β-methyl,21-dihydroeurycomanone (6) has been reported as a synthetic derivative. However, it was isolated from the natural product for the first time in this study. The cytotoxic activities of fifteen compounds were evaluated against human lung cancer cell line, A549 and human cervical cancer cell line, HeLa.     

Six new cassane diterpenoids from the seeds of Caesalpinia sappan

Six new cassane diterpenoids (1–6) and 15 known compounds were isolated and identified from the seeds of Caesalpinia sappan. The structures of the new compounds were determined based on the spectroscopic methods, including 1D and 2D NMR techniques. Compound 1 is a rare cassane diterpenoid featuring a nitrogen containing bridge between C-19 and C-20. Compounds 1 and 2 exhibited moderate cytotoxicity against HCT116, AGS, and HepG2 cell lines with IC₅₀ values ranging from 6.36 to 27.86 μM.     

Two New Sesquiterpene Derivatives from the Tunisian Endemic Ferula tunetana Pom.

A new sesquiterpene ester, tunetanin A ( 1 ), a new sesquiterpene coumarin, tunetacoumarin A ( 2 ), together with eight known compounds, i.e., coladin ( 3 ), coladonin ( 4 ), isosmarcandin ( 5 ), 13‐hydroxyfeselol ( 6 ), umbelliprenin ( 7 ) propiophenone ( 8 ), β‐sitosterol ( 9 ), and stigmasterol ( 10 ), were isolated from the roots of Ferula tunetana. Their structures were elucidated on the basis of extensive spectroscopic methods, including 1D‐ and 2D‐NMR experiments and MS analysis, as well as by comparison with published data. The cytotoxicity of compounds 1 – 7 towards two human colon cancer cell lines, HT‐29 and HCT 116, was evaluated. Compounds 3, 4 , and 6 showed weak cytotoxic activities.     

Cytotoxicity and immunomodulating characteristics of labdane diterpenes from Marrubium cylleneum and Marrubium velutinum

From the aerial parts of Marrubium cylleneum, one labdane nor-diterpene has been isolated together with two labdane diterpenes, hitherto not known as natural products. The structures of the isolated compounds were established by means of NMR [(1)H-(1)H-COSY, (1)H-(13)C-HSQC, HMQC-TOCSY, HMBC, NOESY] and MS spectral analyses. Several diterpenoids from M. cylleneum and M. velutinum were tested for their cytotoxic effect against various cancer cell lines and their immunomodulating potential in human peripheral blood mononuclear cells in standard in vitro assays. Our results show a differential cytotoxicity of some compounds as well as their ability to improve selected lymphocyte functions.     

Diterpenoids from Pinus massoniana resin and their cytotoxicity against A431 and A549 cells

Five diterpenoids and 14 known diterpenoids were isolated from the petroleum ether extract of Pinus massoniana resin. Their structures were elucidated by spectroscopic data interpretation. The cytotoxic activities of these compounds were evaluated using the MTT method. The results showed that three of the less polar diterpenoids had strong cytotoxicity against A431 and A549 cancer cells, whereas those of high polarity had none.     

Anti-tumor promoting diterpenes from the stem bark of Thuja standishii (Cupressaceae).

Three new labdane-type diterpenoids, labda-8(17),13-dien-15,12R-olid-19-oic acid (1), 12S-hydroxylabda-8(17),13(16),14-trien-19-oic acid (2) and 13-ethoxylabda-8(17),11,14-trien-19-oic acid (3), along with known diterpenoids, trans-communic acid (4), totarol (5), 12-methoxyabieta-8,11,13-trien-11-ol (6), and 7 alpha,8 alpha-epoxy-6 alpha-hydroxyabieta-9(11),13-dien-12-one (7) were isolated from the stem bark of Thuja standishii. The structures of 1--3 were established by spectroscopic methods and chemical conversion. These compounds together with standishinal (8), 12-hydroxy-6,7-seco-abieta-8,11,13-trien-6,7-dial (9) and 6 alpha-hydroxysugiol (10) were tested for their inhibitory effects on Epstein--Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), as a test for potential cancer chemopreventive agents. Compound 10 showed strong inhibitory effect on EBV-EA induction (100% inhibition at 1000 mol ratio/TPA), and compounds 2 and 6 showed moderate inhibitory effects on EBV-EA induction. In addition, 15-oxolabda-8(17),11Z,13E-trien-19-oic acid (11) was found to exhibit the anti-tumor promoting activity in two-stage mouse skin carcinogenesis test using 7,12-dimethylbenz[a]anthracene and TPA.     

Two novel neo-clerodane diterpenoids from Scutellaria barbata

Two novel neo-clerodane diterpenoids, barbatellarines A (1) and B (2), were isolated from the whole plants of Scutellaria barbata, along with the known compound scutebarbatine F (3). The chemical structures and relative stereochemistry of the isolated compounds were established by NMR (1D and 2D) and mass spectroscopic analyses. Compounds 2 and 3 were evaluated for in vitro cytotoxic activity against the HL-60 (human leukemia), MCF7 (human breast cancer), and LLC (Lewis lung carcinoma) cancer cell lines. Compound 2 exhibited weak cytotoxic activity against HL-60 cells, with an IC₅₀ value of 41.4 μΜ.     

Cytotoxic clerodane diterpenoids from Croton crassifolius

Hepatocellular carcinoma (HCC) is the most common type of liver cancer, and treatment options for HCC are limited. In addition, the discovery of new natural compounds with anti-hepatocarcinoma activity is attracting increasing attention. For this reason, phytochemical investigation of Croton crassifolius led to the isolation of 17 diterpenoids, including three new clerodane diterpenoids, named crassifolius A-C (1–3), along with 14 known ones (4–17). Their structures were established by 1D, 2D NMR, HR-ESI-MS, detailed calculated electronic circular dichroism (ECD) spectra and the assistance of quantum chemical predictions (QCP) of ¹³C NMR chemical shifts. The cytotoxicities of all these compounds against human liver cancer lines (HepG2 and Hep3B) were determined. Among them, compound 1 exhibited good cytotoxicity with IC₅₀ value of 17.91 μM against human liver tumor cells Hep3B. Following further studies of the anti-tumor mechanism of compound 1-induced cell growth inhibition, we found that compound 1 caused apoptotic cell death in Hep3B cells by detecting morphologic changes and Western blotting analysis.     

Novel diterpenoids with potent inhibitory activity against endothelium cell HMEC and cytotoxic activities from a well-known TCM plant Daphne genkwa

Twelve highly oxygenated novel daphnane-type diterpenoids genkwanines A-L (1-12), together with four known diterpenes (13-16), were isolated from the bud of Daphne genkwa, a well-known traditional Chinese medicine (TCM). The new structures were elucidated on the basis of spectral methods, especially 2D NMR spectra (HMQC, HMBC, NOESY). Inhibitory activity against endothelium cell HMEC proliferation and cytotoxic activities against two tumor cell lines were assessed for all the compounds 1-16, and found to be significant and structure related. A number of compounds showed very potent cytotoxic activities against two tumor cell lines at the IC50 levels of 0.15-8.40 microM, and most interestingly, five of the compounds 4, 8, 10, 13, and 14 exhibited strong activity to inhibit the endothelium cell HMEC at the IC50 levels of 2.90-15.0 microM.     

Cytotoxic macrocyclic diterpenoids from Jatropha multifida

Nine new macrocyclic diterpenoids (1–9), jatromultones A-I, along with eight known analogues (10–17) were isolated from the trunks of Jatropha multifida. The structures of the new compounds, including their absolute configurations, were elucidated by combination of spectroscopic analysis, single crystal X-ray diffraction, Rh₂(OCOCF₃)₄-induced CD method, and chemical correlations. All compounds were screened for the cytotoxicity against five cancer cell lines, including one drug-resistant cell line, and seven compounds exhibited significant activity with IC₅₀ values less than 10 μM. Compound 4 with IC₅₀ values ranging from 2.69 to 6.44 μM toward all cell lines was selected for further mechanistic study, which showed that 4 could arrest cell cycle at G2/M phase and induce apoptosis. The brief structure-activity relationships (SARs) of these macrocyclic diterpenoids were also discussed.