Serena Fiorito

Lapachol and its congeners as anticancer agents: a review

Lapachol is a naturally occurring 1,4-naphthoquinone originally isolated by the Italian phytochemist E. Paterno from Tabebuia avellanedae (Bignoniaceae) in 1882 and subsequently found in several other genera belonging to the families of Leguminosae, Malvaceae, Plumbaginaceae, Lamiaceae, Arecaceae, Scrophulariaceae, Verbenaceae, Celastraceae, Avicenniaceae, Caesalpiniaceae, Rubiaceae, and Proteaceae. A wide range of pharmacological activities have been observed for lapachol and its semi-synthetic derivatives in the literature, such as antileishmanial, anticarcinomic, anti-inflammatory, antimalarial, antiseptic, antitumor, antiviral, bactericidal, fungicidal, insectifugal, pesticidal, schistosomicidal, termiticidal, and viricidal effects. The aim of this review is to discuss in detail the phytochemical properties and pharmacological effects of the title compound that have been reported thus far, highlighting its potential therapeutic benefits for the future.

Growth inhibitory activity for cancer cell lines of lapachol and its natural and semi-synthetic derivatives.

A series of 17 selected natural and semisynthetic 1,4-naphthoquinones were synthesized, and their growth inhibitory activity was evaluated in vitro. The compounds were tested on six human cancer cell lines using the MTT colorimetric assay. The data revealed that of the chemicals under study only lapachol, its acetate and 3-geranyllawsone displayed the highest activity, recording mean IC50 values ranging from 15 to 22 μM.

A newly synthesized compound, 4'-geranyloxyferulic acid-N(omega)-nitro-L-arginine methyl ester suppresses inflammation-associated colorectal carcinogenesis in male mice.

We previously reported the cancer chemopreventive activity of 4′‐geranyloxyferulic acid (GOFA, Miyamoto et al., Nutr Cancer 2008; 60:675‐84) and a β‐cyclodextrin inclusion compound of GOFA (Tanaka et al., Int J Cancer 2010; 126:830‐40) in colitis‐related colorectal carcinogenesis. In our study, the chemopreventive effects of a newly synthesized GOFA‐containing compound, GOFA–N(omega)‐nitro‐l‐arginine methyl ester (L‐NAME), which inhibits inducible nitric oxide (iNOS) and cyclooxygenase‐2 (COX) enzymes, were investigated using a colitis‐associated mouse colorectal carcinogenesis model with azoxymethane (AOM) and dextran sodium sulfate (DSS). The dietary administration of GOFA–L‐NAME after the AOM and DSS treatments significantly reduced the multiplicity of adenocarcinomas (inhibition rates: 100 ppm, 84%, p < 0.001; 500 ppm, 94%, p < 0.001) compared with the AOM + DSS group. Dietary GOFA–L‐NAME significantly decreased the proliferation (p < 0.001) and increased the apoptosis (p < 0.001) of colonic adenocarcinoma cells. A subsequent short‐term experiment revealed that dietary GOFA–L‐NAME decreased the mRNA expression of inflammatory enzymes, such as iNOS and COX‐2, and proinflammatory cytokines, such as tumor necrosis factor‐α, interleukin (IL)−1β, IL‐6 and macrophage inflammatory protein (MIP)−2 in the colonic mucosa of mice that received 1.5% DSS in their drinking water for 7 days. Our findings indicate that GOFA–L‐NAME is able to inhibit colitis‐associated colon carcinogenesis by modulating inflammation, proliferation, apoptosis and the expression of proinflammatory cytokines in mice.

Screening for novel plant sources of prenyloxyanthraquinones: Senna alexandrina Mill. and Aloe vera (L.) Burm. F.

As a continuation of our ongoing studies aimed to reveal the presence of oxyprenylated anthraquinones in plants claimed to have a laxative effect, in this article, we describe the extraction and HPLC separation of madagascin (3-isopentenyloxyemodin) and 3-geranyloxyemodine from dried leaves and fruits of Senna alexandrina Mill. (Leguminosae) and leaves and gel of Aloe vera (L.) Burm. F. (Xanthorrhoeaceae). Both compounds are described herein for the first time as components of extracts of the title plants.

Quantification of biologically active O-prenylated and unprenylated phenylpropanoids in dill (Anethum graveolens), anise (Pimpinella anisum), and wild celery (Angelica archangelica)

HIGHLIGHTSA method has been set up for the quantification of prenyloxyphenylpropanoids in Apiaceae plants.Prenyloxyphenylpropanoids have been disclosed in dill, anise, and wild celery for the first time.Widening of the phytochemical pool knowledge in dill, anise, and wild celery. ABSTRACT An analytical strategy based on different extraction methodologies and HPLC with spectrophotometric (UV–vis) detection has been developed to investigate the presence of and to quantitate biologically active selected unprenylated and O‐prenylated phenylpropanoids, namely umbelliferone, 4′‐geranyloxyferulic acid, 7‐isopentenyloxycoumarin, auraptene, and umbelliprenin in dill (Anethum graveolens L.), anise (Pimpinella anisum L.), and wild celery (Angelica archangelica L.). Absolute ethanol or 7:3 water/ethanol mixtures were seen to be the most powerful extraction solvents to perform “classic” maceration or ultrasound‐assisted one in terms of yields in secondary metabolites. For anethum and anise, umbelliprenine was found to be the most abundant prenyloxy secondary metabolite, while in wild celery 4′‐geranyloxyferulic acid recorded the highest concentration. Our experimental approach demonstrated to be efficient for the simultaneous identification and quantitation of the above mentioned prenyloxyphenylpropanoids in the title plant species, that is reported herein for the first time in the literature.

Phytochemistry and pharmacognosy of the genus Acronychia

The genus Acronychia (Rutaceae) comprise 44 species, most of which are represented by shrubs and small trees, distributed in a wide geographical area of South-Eastern Asia comprising China, India, Malaysia, Indonesia, Australia, and the islands of the western Pacific Ocean. Most of the species of the genus Acronychia have been used for centuries as natural remedies in the ethnomedical traditions of indigenous populations as anti-microbial, anti-fungal, anti-spasmodic, stomachic, anti-pyretic, and anti-haemorragic agent. Moreover fruits and aerial parts are used as food in salads and condiments, while the essential oil obtained from flowers and leaves has been employed in cosmetics production. Phytochemicals isolated from Acronychia spp. include acetophenones, quinoline and acridone alkaloids, flavonoids, cinnamic acids, lignans, coumarins, steroids, and triterpenes. The reported biological activities of the above mentioned natural compounds refer to anti-plasmodial, anti-cancer, anti-oxidant, anti-inflammatory, anti-fungal, and neuroprotective effects. The aim of this review is to examine in detail from a phytochemical and pharmacologically point of view what is reported in the current literature about the properties of phytopreparations or individual active principles obtained from plants belonging to the Acronychia genus.

Auraptene and Other Prenyloxyphenylpropanoids Suppress Microglial Activation and Dopaminergic Neuronal Cell Death in a Lipopolysaccharide-Induced Model of Parkinson’s Disease

In patients with Parkinson’s disease (PD), hyperactivated inflammation in the brain, particularly microglial hyperactivation in the substantia nigra (SN), is reported to be one of the triggers for the delayed loss of dopaminergic neurons and sequential motor functional impairments. We previously reported that (1) auraptene (AUR), a natural prenyloxycoumain, suppressed inflammatory responses including the hyperactivation of microglia in the ischemic brain and inflamed brain, thereby inhibiting neuronal cell death; (2) 7-isopentenyloxycoumarin (7-IP), another natural prenyloxycoumain, exerted anti-inflammatory and neuroprotective effects against excitotoxicity; and (3) 4′-geranyloxyferulic acid (GOFA), a natural prenyloxycinnamic acid, also exerted anti-inflammatory effects. In the present study, using an intranigral lipopolysaccharide (LPS)-induced PD-like mouse model, we investigated whether AUR, 7-IP, and GOFA suppress microglial activation and protect against dopaminergic neuronal cell death in the SN. We successfully showed that these prenyloxyphenylpropanoids exhibited these prospective abilities, suggesting the potential of these compounds as neuroprotective agents for patients with PD.

Recent developments in the pharmacology of prenylated xanthones

Prenylated xanthones are secondary metabolites that are particularly common in plants belonging to the Clusiaceae family. Such compounds have been the focus intensive research because of their potential as biologically active agents. Here, we survey data published over the past decade relating to the properties of prenylated xanthones to provide a more detailed view of the potential of these naturally occurring compounds as therapeutic agents.

4′-Geranyloxyferulic acid: an overview of its potentialities as an anti-cancer and anti-inflammatory agent

Abstract3-(4′-Geranyloxy-3′-methoxyphenyl)-2-trans propenoic acid (4′-geranyloxyferulic acid, GOFA) 1 is an oxyprenylated ferulic acid derivative that has been extracted for the first time in 1966 from the root and bark extracts of Acronychia baueri Schott (Fam. Rutaceae). In the last decade the pharmacological properties of the title compound began to be characterized, revealing its valuable potentialities as an anti-inflammatory and anti-tumor agent. In this context the aim of this review article is to report the insofar described biological effects of 4′-geranyloxyferulic acid. Data collected during the recent years indicates that 1 is an effective dietary feeding colon cancer chemopreventive agent in vivo. When administered to animals, in which colon adenoma and adenocarcinoma have been induced by the administration of azoxymethane in the diet, as a large bowel delivered prodrug linked to dipeptides, or as an inclusion complex in cyclodextrins, or coupled to known anti-inflammatory agents like L-NAME, a protective effect on colon cancer growth and development have been recorded. Recent studies on the natural occurrence of 4′-geranyloxyferulic acid, showed the presence of this oxyprenylated secondary metabolite in widely consumed edible fruits and vegetables like citrus fruits and their phytopreparations.

Synthesis and anti-cancer activity of naturally occurring 2,5-diketopiperazines

Three naturally occurring oxyprenylated diketopiperazines were synthesized and preliminarily tested as growth inhibitory agents in vitro against various cancer cell lines. The compounds were tested on six human cancer cell lines with different sensitivity to proapoptotic stimuli using the MTT colorimetric assay. The data revealed that of the chemicals under study only deoxymicelianamide (11) displayed the highest activity, recording mean IC50 growth inhibitory values ranging from 2 to 23 μM. A comparative study with the non-geranylated saturated derivative of (11) revealed the importance of the presence of the geranyloxy side chain and the exocyclic 2,5-DPK double bond moiety for the observed activity.