Current Pharmaceutical Design - Volume 21, Issue 38, 2015

The endogenous steroid 2-methoxyestradiol (2-ME) is a metabolite of 17β-estradiol and its biosynthesis is well established. Moreover, 2-ME is also biosynthesized from estrone. For several years, 2-ME was perceived as an inactive metabolite devoid of any interesting biological activities. Since the late 1980s, a number of biological and pharmacological studies have revealed that 2-ME possesses interesting anti-cancer effects without any undesirable estrogen activity. In particular, the anti-vascular effects and anti-angiogenic activities that 2-ME exhibit, are of great interest and importance, in view of the development of new anti-cancer drugs based on 2-ME. Several clinical trial development programs have been initiated using the steroid 2-ME. In addition, based on the many pharmacological activities reported for 2-ME, but also due to the general interest in total and semi-synthesis of endogenous steroids, several research groups working with organic synthesis have prepared this steroid. Herein, the anti-cancer effects, the results from the clinical trial development programs and the synthetic studies towards 2-ME, are reviewed.

The xenicanes are a large class of mostly bicyclic marine diterpenoids featuring a cyclononane ring as a common structural denominator. After a brief introduction into the characteristic structural features of xenicanes and some biogenetic considerations, the major focus of this review will be on the various biological activities that have been reported for xenicanes and on efforts towards the total synthesis of these structures. Several xenicanes have been shown to be potent antiproliferative agents in vitro, but activities have also been reported in relation to inflammatory processes. However, so far, data on the possible in vivo activity of xenicanes are lacking. The major challenge in the total synthesis of xenicanes is the construction of the nine-membered ring. Different strategies have been pursued to establish this crucial substructure, including Grob fragmentation, ring-closing olefin metathesis, or Suzuki cross coupling as the enabling transformations.

Flavonolignans are plant natural products, composed of a flavonoid moiety and a lignan (phenylpropanoid) part. Current literature focuses on flavonolignans formed from taxifolin and coniferyl alcohol as e.g. silybin and its congeners from fruit extract from the purple variety of the milk thistle (Silybum marianum) denoted as “silymarin”. This review describes chemistry and biological activity of so far neglected “non-taxifolin” based flavonolignans, derived from apigenin, luteolin, tricin, chrysoeriol, naringenin and eriodictyol, as the flavonoid part. Up-to-date knowledge on hydnocarpin, hydnocarpin-D, pseudotsuganol, hydnowightin, neohydnocarpin, palstatin, salcolins A and B, anastatins A and B, sinaiticin, silyamandin and silandrin is summarized in the present paper. Most of non-taxifolin derived flavonolignans have been shown to exhibit in vitro and/or in vivo anti-hepatotoxic, anti-oxidant, free radical scavenging, anti-inflammatory, anti-proliferative, anti-cancer, chemotherapy potentiating, anti-melanogenic, anti-bacterial, vasorelaxing, anti-platelet aggregation and/or hypotriglyceridemic activity, often stronger than silybin. Many of these compounds inhibited Staphylococcus aureus multidrug resistance pump NorA and sensitized multidrug resistant cancer cell lines showing a potential as adjuvants. Non-taxifolin derived flavonolignans are a relatively unexplored group of compounds with interesting biological activity and great application potential. Their detailed study could provide a new insight into the biomimetic synthesis in order to obtain new compounds with greater activity and identify new lead structures for the biomedicinal research.

Thapsigargin was originally isolated from the roots of the Mediterranean umbelliferous plant Thapsia garganica in order to characterize the skin irritant principle. Characteristic chemical properties and semi-syntheses are reviewed. The biological activity was related to the subnanomolar affinity for the sarco/endoplasmic reticulum calcium ATPase. Prolonged inhibition of the pump afforded collapse of the calcium homeostasis and eventually apoptosis. Structure-activity relationships enabled design of an equipotent analogue containing a linker. Conjugation of the analogue containing the linker with peptides, which only are substrates for either prostate specific antigen (PSA) or prostate specific membrane antigen (PSMA) enabled design of prodrugs targeting a number of cancer diseases including prostate cancer (G115) and hepatocellular carcinoma (G202). Prodrug G202 has under the name of mipsagargin in phase II clinical trials shown promising properties against hepatocellular carcinoma.

Corynantheine alkaloids with a tetracyclic indole[2,3-a]-quinolizidine motif are an important issue in academia and in the life science industries due to their broad bioactivity profile. In particular, the main biological effects described for indoloquinolizidines include analgesic, anti-inflammatory, antihypertensive, and antiarrhythmic activities, as well as inhibition of multiple ion channels, affinity for opioid receptors, and activity against Leishmania. For that reason, in the last decades, numerous efforts have been invested in the development of novel synthetic strategies to obtain the indole[2,3-a]-quinolizidine system. This review focuses on the synthetic methodologies developed to target the most important alkaloids of this family, and highlights the potential use of these alkaloids or analogs to treat several diseases, ranging from cancer to neurodegenerative disorders.

The development of modern technologies casts a new light on the natural products as an invaluable source of lead compounds that could guide drug discovery. Cancer stem cells are a subpopulation of cancer cells with a high clonogenic capacity and the ability to reform the parental tumours upon transplantation. They have been proposed to drive tumorigenesis and metastases. In this review, we present the ability of forty-nine different natural products to influence the biology of cancer stem cells.

major trend in fine chemicals and pharmaceuticals is the synthesis of molecules with increased complexity. This trend translates the aim of organic syntheses to conditions in which high degrees of chemo-, regioand stereoselectivity can be provided. In this context, the chemoselective hydrogenation of one functional group in the presence of other reactive groups is a frequently encountered problem in fine chemicals manufacture. This study provides a critical analysis including elegant examples of reactions in which high chemo- and diastereoselectivities were achieved in the hydrogenation of a C=O group in the presence of C=C double bond. A particular emphasis is addressed to the stereoselective C(15) synthesis from Cloprostenol - a PGF2α structural analogue.

The influenza virus represents a permanent global health threat because it circulates not only within but also between numerous host populations, thereby frequently causing unexpected outbreaks in animals and humans with a generally unpredictable course of disease and epidemiology. Conventional influenza therapy is directed against the viral neuraminidase protein, which promotes virus release from infected cells, and the viral ion channel M2, which facilitates viral uncoating. However, these drugs, albeit effective, have a major drawback: their targets are of a highly variable sequence. As a consequence, the virus can readily acquire resistance by mutating the drug targets. Indeed, most seasonal A/H1N1 viruses and the 2009 H1N1 virus are resistant to M2 inhibitors, and a significant proportion of the seasonal A/H1N1 viruses are resistant to the neuraminidase inhibitor oseltamivir. Development of new effective drugs for treatment of disease during the regular influenza seasons and the possible influenza pandemic represents an important goal. The results presented here point out natural products as a promising source of low toxic and widely accessible drug candidates for treatment of the influenza disease. Natural products combined with new therapeutic targets and drug repurposing techniques, which accelerate development of new drugs, serve as an important platform for development of new influenza therapeutics.

Resistance to chemotherapeautic drugs is one of the main obstacles to effective cancer treatment. Multidrug resistance (MDR) is defined as resistance to structurally and/or functionally unrelated drugs, and has been extensively investigated for the last three decades. There are two types of MDR: intrinsic and acquired. Tumor microenvironment selection pressure leads to the development of intrinsic MDR, while acquired resistance is a consequence of the administered chemotherapy. A central issue in chemotherapy failure is the existence of heterogeneous populations of cancer cells within one patient and patient-to-patient variability within each type of cancer. Numerous genes and pathways contribute to the development of MDR in cancer. Point mutations, gene amplification or other genetic or epigenetic changes all affect biological functions and may lead to the occurrence of MDR phenotype. Similar to the characteristics of cancerogenesis, the main features of MDR include abnormal tumor vasculature, regions of hypoxia, aerobic glycolysis, and a lower susceptibility to apoptosis. In order to achieve a lethal effect on cancer cells, drugs need to reach their intracellular target molecules. The overexpression of the efflux transporter P-glycoprotein (P-gp) in MDR cancer cells leads to decreased uptake of the drug and intracellular drug accumulation, minimising drug-target interactions. New agents being or inspired by natural products that sucessfully target these mechanisms are the main subject of this review. Two key approaches in combating MDR in cancer are discussed (i) finding agents that preserve citotoxicity toward MDR cancer cells; (ii) developing compounds that restore the cytotoxic activity of classic anticancer drugs.

Natural products, or their synthetic derivatives are a treasure trove to find potential candidates for novel drugs for human treatment. The selection of diamonds from the huge pile of worthless stone is a critical – and difficult - stage in the discovery pipeline. Of all the factors to be considered, perhaps the most important, is that the compound should have the desired effect on the tissue in vivo. Since it is not possible (or ethical) to test all compounds in vivo one must preselect using a surrogate assay system. While animal models have the advantage of being holistic and current 3D culture systems are reductionistic, they at least can be constructed from human cell types. In this review we will consider some of the evidence demonstrating that cells grown in 3D cultures have physiological performances that mimic functions seen in human tissues significantly better than cells grown using classical 2D culture systems. We will discuss advantages and disadvantages of these new culture technologies and highlight theoretical reasons for the differences. 3D cell culture technologies are more labour intensive than 2D culture systems and therefore their introduction is a trade-off between the value of obtaining data that is more relevant to the human condition against their through-put. It is already clear that future in vitro 3D systems will become more complex, using multiple cell types to more faithfully represent a particular tissue or even organ system. And one thing is sure – the diamonds are not easy to find!