Mini Reviews in Medicinal Chemistry - Volume 11, Issue 10, 2011

For centuries people have been highly dependent on plants as sources of proteins, fats, carbohydrates, vitamins, and minerals. Moreover plants accumulate a large spectrum of metabolites (over 100,000 compounds), some of which are used as medicines for treating a variety of illnesses and maladies. Currently more than a quarter of all prescribed medicines in the industrialized countries are derived either directly or indirectly from plants. It was recently estimated that over 60% of anticancer drugs and 75% of drugs for infectious diseases currently used originated from natural sources, and that annual sales of such drugs exceed several billion US dollars [1, 2]. Mass production of plant-derived molecules via classical approaches leads to several difficulties, resulting mainly from seasonal, geographical, soil features, and etc. Moreover the isolation of these compounds (often less than 1%) from huge plant biomass is time- and labor- consuming. Furthermore, the production of some bioactive molecules at commercial scales could create serious ecological problems. For example, for the production of 1 kg paclitaxel (the active ingredient of Taxol®) over three thousand 100-year-old yew trees should be killed. These continuously increasing demands for therapeutic molecules, produced by ever greener processes, along with dramatic reductions in natural diversity, are driving efforts to find alternative ways to produce high value plant-derived metabolites. Plant biotechnology offers an attractive alternative for the supply of high-value molecules. Plant cell, tissue and organ cultures are an enormous source of metabolites that have considerable advantages over standard crops, since they can be mass produced totally independently of geographical and climatic factors, in sterile and eco-friendly conditions. Furthermore, the up-scaling in bioreactors allows the mass production of desired compounds at commercial scales. The over century progress in the field of plant biotechnology resulted in the commercial production of several important metabolites, such as Taxol®, berberine, shikonin, ginseng biomass and tuberose's polysaccharides by different companies [1, 2]. This hot topic issue has been prepared to highlight the current developments for the production of anticancer, antiinflammatory and antioxidative molecules by artificially cultivated plant cell, tissue and organs. The issue consists of 4 excellent reviews, which were peer-reviewed by a number of outstanding scientists. The subject is introduced by Korkina et al. [3], highlighting the recent advances in the field of anti-inflammatory plant phenylpropanoids. Erdogan Orhan et al. [4] discuss on the progress of finding new and potent cholinesterase inhibitors. Potentially new drugs from plant origin for the treatment of cancer are covered by Ionkova [5]. Finally de Costa et al. [6] summarize the recent progress in the field of plant saponins with immunoadjuvant and anti-inflammatory activity....

Plant-derived phenylpropanoids (PPPs) compose the largest group of secondary metabolites produced by higher plants, mainly, for the protection against biotic or abiotic stresses such as infections, wounding, UV irradiation, exposure to ozone, pollutants, and herbivores. PPPs are parent molecules for biosynthesis of numerous structurally and functionally diverse plant polyphenols (simple phenolic acids and esters, glycosylated derivatives of primary PPPs, flavonoids, isoflavonoids, stilbenes, coumarins, curcuminoids, lignans, etc.), which play multiple essential roles in plant physiology. During the last few decades, extensive research has been dedicated to natural and biotechnologically produced PPPs for medicinal use as antioxidants, UV screens, anticancer, antiviral, anti-inflammatory, wound healing, and antibacterial agents. In the present review, the metabolic pathways of phenylpropanoid biosynthesis in plants and their re-construction in biotechnologically engineered systems are described. Chemical physical peculiarities of PPPs defining their antioxidant, metal chelating, and UV-protecting effects as a molecular basis for their anti-inflammatory properties are discussed as well. We focused also on the discovery of PPPs-based anti-inflammatory agents since distinct PPPs were found to modulate molecular pathways underlying inflammatory responses in human cells triggered by different pro-inflammatory stimuli in vitro and to inhibit inflammation in various tissues in vivo. The problem of low bioavailability, fast metabolism, and potential toxicity/sensitization as limiting factors for the development of PPPs-based anti-inflammatory drugs is also highlighted.

Cholinesterase enzyme family consisting of acetylcholinesterase (AChE) and butrylcholinesterase (BChE) is important in pathogenesis of Alzheimer's disease (AD), explained by “cholinergic hypothesis”. Accordingly, deficiency of the neuromediator called “acetylcholine” excessive amount of BChE has been well-described in the brains of AD patients. Consequently, cholinesterase inhibition has become one of the most-prescribed treatment strategies for AD. In fact, cholinesterase inhibitors have been also reported for their effectiveness in some other diseases including glaucoma, myasthenia gravies, as well as Down syndrome, lately. They play a role in the action of mechanism of insecticidal drugs such as carbamate derivatives as well as nerve gases such as malathion and parathion. All these utilizations can make them a multi-targeted drug class putting a special emphasis on AD therapy in the first place. Several inhibitors of cholinesterases with synthetic and natural origins are available in drug market; however, the reasons including side effects, relatively low bioavailability, etc. limit their uses in medicine and there is still a great demand to discover new cholinesterase inhibitors. Galanthamine, an alkaloid derivative isolated from snowdrop (Galanthus nivalis L.), is the latest anticholinesterase drug used against AD. Huperzine A, isolated from Huperzia serrata (Thunb.) Trev. is the most-promising drug candidate with potent anticholinesterase effect and it is a licensed anti-AD drug in China. In this review, a short introduction will be given on known cholinesterase inhibitors and, then, galanthamine and huperzine A will be covered in regard with their cholinesterase inhibitory potentials and mass productions by organic synthesis and in vitro culture techniques.

Malignant diseases are the second mortality cause within the human population. Despite the serious progress in establishing and introduction of novel specifically targeted drugs the therapy of these diseases remains severe medical and social problem. Some of the most effective cancer treatments to date are natural products or compounds derived from plant products. Isolation of anticancer pharmaceuticals from plants is difficult due to their extremely low concentrations. The industry currently lacks sufficient methods for producing all of the desired plant-derived pharmaceutical molecules. Some substances can only be isolated from extremely rare plants. Plant cell cultures are an attractive alternative source to whole plant for the production of high-value secondary metabolites. The biotechnological method offers a quick and efficient method for producing these high-value medical compounds in cultivated cells. Due to the pharmaceutical importance and the low content in the plants the present review focuses on discovery and alternative production systems for anticancer lignans - aryltetralin and arylnaphthalene lignans. The aim is to focus on recent progress of in vitro production of anticancer lignans, together with structure elucidation, the methods of increasing the levels of desired substances in plant cell and tissue cultures in general. Experience of different authors, working worldwide on plant biotechnology, has been discussed to show positive results in experiments.

Saponins can be classified as triterpenoid (C30) or steroidal (C27), based on their carbon nucleus (aglycone). Sugar residues are linked to the aglycone, conferring an amphiphilic nature on these molecules, which is relevant for their biological activities. Saponins include a large variety of molecules that find several applications in pharmacology. Saponins have been shown to display immunoadjuvant, anti-inflammatory, antiplatelet, hypocholesterolemic, antitumoral, anti- HIV, antibacterial, insecticide, fungicide and anti-leishmanial activities. Anti-inflammatory medicines are increasingly demanded to treat various forms of arthritis in aging and obese populations and to help reduce the doses and duration of conventional corticotherapy with less side effects and without immunosuppression. The vaccine market for both human and veterinary uses is close to US$ 15 billion, progressively inflated by the recurrent threat of global pandemics.This paper provides an overview of recent advances (main focus on the last five years) on plant saponins that show antiinflammatory and/or immunoadjuvant activities: source plants, isolation procedures, mechanism of action and biotechnological approaches towards sustainable production of bioactive saponins. Special attention is given to ginseng and Quillaja saponins. Strategies based on plant cultivation, cell and tissue culture, elicitation, and metabolic engineering for improved production of saponins are described. Future directions for research in the field and strategies to overcome bottlenecks are also discussed.

Cancer cell resistance to kinase inhibitors and targeted agents, acquisition of a multidrug-resistant (MDR) phenotype and/or intrinsic resistance to apoptosis prevent effective treatment in about 50% of solid cancers in adults, and the percentage is even higher in children. Glycyrrhetinic acid (GA) and some of its derivatives may offer hope in combating cancer types associated with poor prognoses. Some GA derivatives are indeed able to target both the proteasome and peroxisome proliferator-activated receptors (PPARs), two proteins that play major roles in cancer cell biology but are not related to MDR and/or apoptosis-related resistance phenotypes.

New antimicrobials able to counteract bacterial resistance are needed to maintain the control of infectious diseases. The last 40 years have seen the systematic tailoring and refinement of previously identified antibiotics, to produce a multitude of semi-synthetic derivatives that share their mechanism of action with the original molecules. The major limit of this approach is the emergence of multi- and cross-resistant bacterial strains, favoured by the selective pressure inherent to the targeting of specific enzymes. The most promising new strategies aim to the development of molecules that, targeting essential bacterial structures instead of specific enzymatic activities, achieve infection control without enforcing a selective pressure on bacteria. This review, based on the consultation of the up-to-date literature, deals with antimicrobial peptides and some antivirulence factors.

Podophyllotoxin, one of the well-known naturally occurring aryltetralin lignans, has been used as the leadcompound for the preparation of potent anticancer agents, such as etoposide, teniposide, and etopophos. In our previous review, we described the advances of podophyllotoxin derivatives from 2003 and 2007. In recent years, an increased number of interesting research work has been carried out on the podophyllotoxins. As a continuation, the present review summarizes and highlights the update advances of podophyllotoxin derivatives from 2008 and 2010 in regard to semisynthesis, biosynthesis, biological activities, mode of action and structure-biological activity relationship.

The ent-kaurane diterpenoids are widely distributed in China, some of which have high natural abundance in plants of Isodon, Pteris, Gnaphalium, Diplospora, Croton and some other species. These compounds exhibit significant anti-tumor, antibacterial and anti-inflammatory activities, which have attracted the attention of medicinal chemists. This review focuses on the recent advances in the research of derivatives, anti-tumor activity, mechanism of action, and structure- activity relationships of ent-kaurane diterpenoids. All of these will show the potential in the development of new antitumor agents in natural products.