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

Tyrosinase is known to be the first two and rate-limiting enzyme in the synthesis of melanin pigments responsible for colouring skin, hair and eyes. Tyrosinase inhibition is one major strategy used to treat hyperpigmentation. In human skin melanocytes, the cellular tyrosinase inhibition was examined by the conversion of l-tyrosine and oxidation of l-DOPA to dopaquinone. We evaluated the skin pigmentation inhibitor effects with both in vitro and in vivo systems to find skin-whitening agents without cytotoxic concerns. First, linderanolide B and subamolide A were isolated from the stems of Cinnamomum subavenium and exhibited mushroom tyrosinase inhibition. Then, these two herbal compounds were proved to have good pigmentation inhibitory abilities at low doses and demonstrated free cytotoxicities to normal human skin cells and zebrafish system. With molecular docking, in a virtual model of human tyrosinase, linderanolide B and subamolide A displayed meta(l) -coordinating interactions with Cu(2+) ions. The results obtained from biological assays showed that linderanolide B and subamolide A possessed anti-tyrosinase properties, which exhibited potential for application in medical cosmetology.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-0625.2010.01161.x

Identifying melanogenesis inhibitors from Cinnamomum subavenium with in vitro and in vivo screening systems by targeting the human tyrosinase.

Michelia alba extract attenuates UVB-induced expression of matrix metalloproteinases via MAP kinase pathway in human dermal fibroblasts.

(−)-N-Formylanonaine from Michelia alba as a human tyrosinase inhibitor and antioxidant

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.

Cytotoxic constituents from the leaves of Cinnamomum subavenium.

(52), 403 (11),377 (13), 321 (100)1) School of Medicine and Health Sciences, Fooyin University, Kaohsiung, Taiwan 831, ROC, e-mail:low463@gmailcom; 2) Bioresource Collection and Research Center (BCRC), Food Industry Research and DevelopmentInstitute (FIRDI), Hsinchu, Taiwan 300, ROC, e-mail: cmj0404@gmailcom Published in Khimiya Prirodnykh Soedinenii,No 4, pp 538–539, July–August, 2010 Original article submitted March 23, 2009

Soong-Yu Kuo

Papers

Chemical constituents from the leaves of Michelia alba

Cytotoxic constituents from the leaves of Cinnamomum subavenium.

Secondary metabolites from the stems of Artocarpus heterophyllus

Cytotoxic Constituents from the Leaves of Cinnamomum subavenium