Current Medicinal Chemistry - Volume 22, Issue 30, 2015

Chalcones constitute a group of phenolic compounds that command an increasing interest on cancer research. Natural chalcones are widespread through the plant kingdom. The most abundant and investigated chalcones are isoliquiritigenin, flavokawain and xanthohumol, which are present in the Fabaceae, Piperaceae, Cannabaceae, and Moraceae families. These chalcones have been shown to be promising lead antitumor-chemopreventive drugs by three different activities: antioxidants, cytotoxic and apoptosis inducers. In the recent years, SAR (structure-activity relationship) has contributed towards the improvement of anticancer properties of chalcones by substituting aryl rings and introducing heterocyclic moieties. This review summarizes the anticancer activities shown by natural chalcones and the SAR and describes how different chemical moiety modifications could lead them to be therapeutically useful in the treatment of cancer.

O-Prenyl secondary metabolites (3,3-dimethylallyl, geranyl-, farnesyl- and related biosynthetic derivatives) represent a class of rarely occurring natural products. In the last two decades such compounds have been found to exert promising and effective pharmacological activities, mainly in terms of anti-cancer properties. To date about 350 oxyprenylated secondary metabolites, the most part of which having a phenylpropanoid or a polyketide core, have been extracted from plants mainly belonging to the Rutaceae, Apiaceae, and Fabaceae families, and from fungi and bacteria. The aim of this comprehensive review is to make a survey of the in so far reported literature citations about O-prenyl secondary metabolites exhibiting in vitro and in vivo anti-cancer properties from phytochemical and pharmacological point of views.

Flavonoids are secondary metabolites abundantly present in commonly consumed fruits and vegetables. They possess diverse properties such as anti-inflammatory, anti-oxidant and anti-cancer. Epidemiologic studies suggest that an enrich flavonoids diet is linked to a decreased risk of breast cancer. These protective properties are due to the alteration of numerous signalling pathways involved in cancer-related phenomena such as inflammation and proliferation. Human clinical trials examining the effect of supplementation of some flavonoids on disease prevention have been conducted. There is no natural flavonoid that has been approved for the treatment of breast cancer. However, natural flavonoids served as lead compounds in the synthesis of cancer chemopreventive and/or therapeutic agents.

Cancer development is mostly due to a deregulation of cell death as cancer cells become resistant to apoptosis by increasing expression of anti-apoptotic proteins belonging to the Bcl-2 family. Mcl-1 is one anti-apoptotic protein, which is mainly responsible for cancer cell resistance as it is overexpressed by most cancer cell types. Many research projects aim to restore cancer cell death by using natural pharmacological scaffolds targeting anti-apoptotic proteins to inhibit their effect in cancer development. This review introduces natural compound inhibitors of the Bcl-2 protein family with a focus on Mcl-1.

During past two decades, plant-derived bioactive compounds have been reported as novel therapeutic agents for prevention and/or mitigation of different human diseases such as cancer, inflammation, cardiovascular and neurodegenerative diseases. Hesperidin is known as one of the most common and bioactive constituents of Citrus (C) species which possesses multiple health-promotion effects. A plethora of scientific literature reported that hesperidin possesses in-vitro and in-vivo anticancer activities. In addition, there are numerous scientific evidences regarding the molecular mechanisms of anticancer activities of hesperidin and its aglycone, hesperetin. However, in this case, the number of comprehensive reviews on molecular mechanisms underlying the anticancer effects of hesperidin is sparse. Therefore, in this work we present a critical review of the available literature regarding the molecular mechanisms of the anticancer effects of hesperidin and its aglycone, hesperetin.

Phytocannabinoids (pCBs) are lipid-soluble phytochemicals present in the plant, Cannabis sativa L. and non-cannabis plants which have a long history in recreation and traditional medicine. The plant and the constituents isolated were central in the discovery of the endocannabinoid system (ECS), the most new target for drug discovery. The ECS includes two G-protein-coupled receptors; the cannabinoid receptors-1 and -2 (CB1 and CB2) for marijuana's psychoactive principle Δ9-tetrahydrocannabinol (Δ9-THC), their endogenous small lipid ligands; namely anandamide (AEA) and 2-arachidonoylglycerol (2-AG), also known as endocannabinoids and the enzymes for endocannabinoid biosynthesis and degradation such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The ECS has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during pathological conditions including cancer. Targeting the CB1 receptors becomes a concern because of adverse psychotropic reactions. Hence, targeting the CB2 receptors or the endocannabinoid metabolizing enzymes by pCBs obtained from plants lacking psychotropic adverse reactions has garnered interest in drug discovery. These pCBs derived from plants appear safe and effective with a wider access and availability. In the recent years, several pCBs derived other than non-cannabinoid plants have been reported to bind to and functionally interact with cannabinoid receptors and appear promising candidate for drug development including cancer therapeutics. Several of them also targets the endocannabinoid metabolizing enzymes that control endocannabinoid levels. In this article, we summarize and critically discuss the updates and future prospects of the pCBs as novel and promising candidates for cancer therapeutics.

Terpenes have received a great deal of attention in the scientific literature due to complex, synthetically challenging structures and diverse biological activities associated with this class of natural products. Based on the number of C5 isoprene units they are generated from, terpenes are classified as hemi- (C5), mono- (C10), sesqui- (C15), di- (C20), sester- (C25), tri (C30), and tetraterpenes (C40). Among these, sesterterpenes and their derivatives known as sesterterpenoids, are ubiquitous secondary metabolites in fungi, marine organisms, and plants. Their structural diversity encompasses carbotricyclic ophiobolanes, polycyclic anthracenones, polycyclic furan-2-ones, polycyclic hydroquinones, among many other carbon skeletons. Furthermore, many of them possess promising biological activities including cytotoxicity and the associated potential as anticancer agents. This review discusses the natural sources that produce sesterterpenoids, provides sesterterpenoid names and their chemical structures, biological properties with the focus on anticancer activities and literature references associated with these metabolites. A critical summary of the potential of various sesterterpenoids as anticancer agents concludes the review.

Mangrove associated endophytes are treasure chests for bioprospecting especially in light of the need for new anticancer leads that are necessary to overcome drug resistance of cancer cells. This review highlights the potent anti-tumour compound phomoxanthone A (PXA), which represents a tetrahydroxanthone atropisomer derived from the mangrove-associated fungus Phomopsis longicolla. PXA displayed strong anti-tumour activity when tested against a panel of solid (including cisplatin resistant) tumour cell lines or of blood cancer cell lines with IC50 values in the submicromolar range whereas it was up to 100 folds less active against peripheral blood mononuclear cells (PBMC) from healthy donors. The anti-tumour activity of PXA was demonstrated to be due to an induction of caspase 3 dependent apoptosis. At the same time PXA was shown to activate immune cells such as murine T-lymphocytes, NK cells and macrophages which might help in fighting resistance during cancer chemotherapy. Structure activity studies that involved several naturally occurring as well as semisynthetic derivatives of PXA indicated the position of the biaryl linkage and the acetyl substituents as structural features that are important for the activity of this natural product.

Cholesterol-5,6-epoxide hydrolase (ChEH) in mammals is a heterooligomeric complex of two cholesterogenic enzymes that control mammalian developmental programs. Following the identification of this complex, it was hypothesized that a new metabolic pathway existed that centered on 5,6-epoxy cholesterols (5,6-EC). Conjugation products of 5,6-EC with biogenic amines known to interact with ChEH subunits were synthesized. According to their structures, these steroidal alkaloids showed the specific potency to induce cell differentiation at low doses, suggesting their possible existence as metabolites. One of these compounds, named dendrogenin A (DDA), was recently discovered in mammalian tissues. It was shown that DDA arises from the stereoselective enzymatic conjugation of 5,6α-epoxy-cholesterol with histamine by an as-yet-unidentified enzyme. DDA was detected in normal tissues from several organs but not in cancer cells and its level was decreased in breast tumors from patients, evidencing a deregulation of DDA metabolism during carcinogenesis. DDA was also able to control the growth of tumor cells implanted in mice and improve animal survival. In addition, DDA efficiently restored hearing in a preclinical model of deafness. These biological properties of DDA, as well as its decreased levels in tumors, suggest a physiological function in maintaining cell integrity and differentiation. DDA is the first steroidal alkaloid found to date in mammals. Its discovery reveals the existence of a new metabolic pathway in mammals at the crossroads of cholesterol and histamine metabolism that leads to the production of a metabolic tumor suppressor and neuroprotective agent.