The amount of research activity concerning alpha-methylene-gamma-butyrolactones and alpha-alkylidene-gamma-butyrolactones has increased dramatically in recent years. This Review summarizes the structural types, biological activities, and biosynthesis of these compounds, concentrating on publications from the past 10 years. Traditional approaches to alpha-methylene-gamma-butyrolactones and alpha-alkylidene-gamma-butyrolactones are then reviewed together with novel approaches, including those from our own research group, reported more recently.

The Renaissance of α‐Methylene‐γ‐butyrolactones: New Synthetic Approaches

Jin-Ming Gao,*,† Sheng-Xiang Yang,‡ and Jian-Chun Qin †Shaanxi Engineering Center of Bioresource Chemistry & Sustainable Utilization, Department of Chemistry and Chemical Engineering, College of Science, Northwest A&F University, 3 Taicheng Road, Yangling 712100, Shaanxi, China ‡College of Science, Zhejiang A&F University, Lin’an, Hangzhou 311300, Zhejiang, China College of Plant Sciences, Jilin University, Changchun, Jilin 130062, China

Azaphilones: Chemistry and Biology

Cancer cells produce high levels of reactive oxygen species (ROS) that lead to a state of increased basal oxidative stress. Since this state of oxidative stress makes cancer cells vulnerable to agents that further augment ROS levels, the use of pro-oxidant agents is emerging as an exciting strategy to selectively target tumor cells. Natural products have provided a significant contribution to the development of several drugs currently used in cancer chemotherapy. Although many natural products are known to affect the redox state of the cell, most studies on these compounds have focused on their antioxidant activity instead of on their pro-oxidant properties. This article provides an overview of natural products with pro-oxidant and anticancer activities, with special focus on plant secondary metabolites, and discusses their possible use as cancer chemotherapeutic agents.

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Pro-Oxidant Natural Products as Anticancer Agents

Terpenoids represent a large and diverse class of naturally occurring compounds found in a variety of fruits, vegetables and medicinal plants. Structurally some of the terpenoids are similar to human hormones. A diet rich in terpenoids is inversely related with the risk of chronic diseases including cancers. Breast and prostate cancers are hormone-related diseases and the second leading cause of female and male cancer mortality. Diterpenoid paclitaxel, and its semi-synthetic analogue docetaxel, have entered clinical use against established breast and prostate cancers. Here we reviewed potential molecular targets and biological properties of natural terpenoids, including monoterpenoids, diterpenoids, triterpenoids and tetraterpenoids, and their applications in treatment of human breast and prostate cancers. These terpenoids are able to inhibit tumor cell proliferation and induce tumor cell death by inhibiting multiple cancer-specific targets including the proteasome, NF-kappaB, and antiapoptotic protein Bcl-2. The efficacy of these terpenoids against breast or prostate cancer cells, as demonstrated in pre-clinical studies support clinical application of these naturally occurring terpenoids in treatment of hormone-related human cancers.

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Targeting apoptosis pathway with natural terpenoids: implications for treatment of breast and prostate cancer.

Naturally occurring aristolochic acid analogues and their toxicities

In this study, we investigate the anticancer effect of isoobtusilactone A (IOA), a constituent isolated from the leaves of Cinnamomum kotoense, on human non-small cell lung cancer (NSCLC) A549 cells. IOA was found to induce the arrest of G2-M phase, induce apoptosis, increase sub-G1, and inhibit the growth of these cells. Further investigation revealed that IOA's blockade of the cell cycle was associated with increased levels of p21/WAF1, p27 (kip1), and p53. In addition, IOA triggered the mitochondrial apoptotic pathway, as indicated by an increase in Bax/Bcl-2 ratios, resulting in a loss of mitochondrial membrane potential, release of cytochrome c, activation of caspase-9 and caspase-3, and cleavage of PARP. We also found the generation of reactive oxygen species (ROS) to be a critical mediator in IOA-induced inhibition of A549 cell growth. In antioxidant and NO inhibitor studies, we found that by pretreating A549 cells with either N-acetylcystenine (NAC), catalase, mannitol, dexamethasone, trolox, or L-NAME we could significantly decrease IOA production of ROS. Moreover, using NAC to block ROS, we could significantly suppress IOA-induced antiproliferation, antimigration, and anti-invasion. Finally, we found that IOA inhibited the migration and invasion of A549 cell migration and invasion. Taken together, these results suggest that IOA has anticancer effects on A549 cells.

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Anticancer activity of isoobtusilactone A from Cinnamomum kotoense: involvement of apoptosis, cell-cycle dysregulation, mitochondria regulation, and reactive oxygen species.

Three new butanolides, tenuifolide A (1), isotenuifolide A (2), and tenuifolide B (3), a new secobutanolide, secotenuifolide A (4), and one new sesquiterpenoid, tenuifolin (5), along with 16 known compounds were isolated from the stems of Cinnamomum tenuifolium. Their structures were determined by spectroscopic analyses. Compound 4 was found to induce apoptotic-related DNA damage, increase sub-G1 cells, and inhibit the growth of human prostate cancer cells, DU145. In addition, treatment with 4 significantly increased intracellular H2O2 and/or peroxide. The results show that 4 induced (a) noticeable reduction of mitochondrial transmembrane potential (DeltaPsim); (b) significant increase in the ratio of cytochrome c concentration (cytosol/mitochondria); and (c) subsequent activation of caspase-9/caspase-3. Antiproliferation caused by 4 was found to markedly decrease when pretreated with caspase-9/caspase-3 inhibitor. In ROS scavenging, antioxidant, NADPH oxidase, and NO inhibitor studies, pretreatment of DU145 cells with either DPI, dexamethasone, L-NAME, or mannitol decreased 4-induced intracellular DCF fluorescence of ROS. These results suggest that an increase of H2O2 and/or peroxide by 4 is the initial apoptotic event and 4 has anticancer effects on DU145 cells.

Cytotoxic compounds from the stems of Cinnamomum tenuifolium.

The genus Michelia (Magnoliaceae) consists of about 30 species. Michelia alba is an evergreen tree, especially distributed in Taiwan and China. Michelia species have been used by indigenous peoples for the treatment of cancer. For example, Michelia champaca has been used in India for the treatment of abdominal tumors and M. hypoleuca and M. officinalis for carcinomatous sores and leukemia, respectively, in China [1]. Previous phytochemical studies on this species isolated, from the roots and flowers of M. alba, ushinsunine, oxoushinsunine, salicifoline, michelalbine, limonene, benzyl acetate, linalool, nerol, hydroxycitronellal, benzaldehyde, benzyl benzoate, and methyl eugenol [2, 3]. To further understand the chemotaxonomy and to continue searching for novel agents from Magnoliaceous plants, the leaves of M. albawere chosen for the first time for phytochemical investigation. In this paper, we report the isolation of 21 pure substances. The compounds included four aporphines, (-)-anonaine ( 1) [4], (-)-norushinsunine ( 2) [5], (-)-ushinsunine ( 3) [5], and (-)-N-acetylanonaine ( 4) [6]; two oxoaporphines, liriodenine ( 5) [5] and oxoxylopine ( 6) [7]; three sesquiterpene lactones, michelenolide ( 7) [8], costunolide ( 8) [8], and 11,13-dehydrolanuginolide ( 9) [9]; one amide, N-trans-feruloyltyramine ( 10) [10]; one lignan, (+)-syringaresinol ( 11) [11]; three benzenoids, 4-hydroxybenzaldehyde ( 12) [12], 4-hydroxybenzoic acid ( 13) [12], and methylparaben ( 14) [12]; two steroids, β-sitosterol and stigmasterol [13]; three aliphatic compounds, palmitic acid [14], stearic acid [15], and linoleic acid [16]; and two chlorophylls, pheophorbide a [17] and aristophyll-C [18]. In addition to 3 and 5, all of these compounds were isolated for the first time from this source.

Chemical constituents from the leaves of Michelia alba

Two new butanolides, subamolide D (1) and subamolide E (2), and a new secobutanolide, secosubamolide A (3), along with 21 known compounds were isolated from the leaves of Cinnamomum subavenium. The structures of 1-3 were determined by spectroscopic analysis. Propidium iodide staining and cytometry analysis were used to evaluate the cell cycle progression of the treated SW480 cells and it was found that 1 and 2 caused DNA damage in a dose- and time-dependent manner.

Wen-Li Lo

Papers

Anticancer activity of isoobtusilactone A from Cinnamomum kotoense: involvement of apoptosis, cell-cycle dysregulation, mitochondria regulation, and reactive oxygen species.

Cytotoxic compounds from the stems of Cinnamomum tenuifolium.

Chemical constituents from the leaves of Michelia alba

Cytotoxic constituents from the leaves of Cinnamomum subavenium.

A novel cytotoxic monoterpenoid from the leaves of Cinnamomum subavenium.