Current Medicinal Chemistry - Volume 18, Issue 25, 2011

Discovery of a new drug is a long, arduous, and expensive process due to the challenges underlying the understanding of disease pathogenesis, and the design of interventions that target the disease process while sparing normal cells or processes. A promising new molecule identified in drug discovery has to go through complex and laborious testing involving expertise from various disciplines, and has to meet the current standards of scientific rigor, before it becomes available for the treatment of patients. Thus, designing or finding such a molecule which selectively modulates the disease process is not an easy task. Natural products have long been recognized as a thriving source for innovation in drug discovery due to the high chemical diversity, biochemical specificity, and other molecular properties that make them favorable as ‘lead’ structures for discovery of drugs, and which also differentiates them from libraries of synthetic and combinatorial compounds. The articles selected in this issue give us a glimpse of the richness of natural products and complimentary strength of medicinal chemistry in discovery of drugs. The introductory article is an extensive review on Prunus, which is a genus of trees and shrubs, with around 500 species spread throughout the northern temperate regions of the globe. Prunus are considered valuable as food and ornamental plants, while extracts from the tree have been used to alleviate some of the discomfort caused by inflammation in patients suffering from benign prostatic hyperplasia. A detailed account of the extensive work done on Puruns i.e. the chemical constituents of Genus Prunus and their medicinal properties, has been nicely described by Prof. Parmar et al. Dr. Sharma's team has delved into the chemistry of chromones, discussing the current status, their natural occurrence and biological activities. Podophyllotoxin (PPT) is a non-alkaloid toxin lignan extracted from the roots and rhizomes of Podophyllum species. Podophyllotoxin displays a range of activities such as a cathartic, purgative, antiviral, vesicant, and antihelminthic agent and also presents potentially exciting leads as an anti-tumor agent. Dr. Kumar and colleagues discuss the chemistry and anti-cancer activity of the aza-analogs of PPT, as potential alternative scaffolds of Podophyllotoxins. Prof. Fruzi and colleagues provide a unique perspective on the antioxidant therapy, analyzing the limitations of the past, the current status and its future prospects. Prof. Rawat et al. have reviewed the utility of Trioxane and Tetraoxane moieties, which are commonly found in compounds from plants such as Artemisia arnica. Such compounds have shown promising anti-malarial, anti-cancer, and antibacterial activity. The medicinal potential of these moieties has been presented in this article. The concluding article is a review on Coumarins- an old class of naturally occurring benzopyrene derivatives which have served as valuable leads for further design and synthesis of more active analogs. Dr. Kostova and colleagues discuss the antioxidant application of these natural compounds. I am grateful to all authors for their contribution of extensive reviews on their respective areas of expertise. I hope the readers will find this issue highly informative.

Prunus is a genus of trees and shrubs, including the plums, cherries, peaches, apricots and almonds. Nearly five hundred seventy chemical compounds have so far been isolated from several Prunus species. This comprehensive review summarizes the isolation of chemical compounds reported during the period 1908 to June 2010. As per scrutiny of literature, we did not find any review on the chemistry or biology of genus Prunus or on the biological activities of its constituents. Extensive work has been done at the Department of Chemistry, University of Delhi by several groups on the isolation, identification, biological activity evaluation and synthesis of a large number of novel compounds from different Prunus species during the the last six decades (1940-2000), primarly by Seshadri, Nagarajan and Parmar et al. on P. domestica, P. cerasus, P. cerasoides, P. puddum and P. communis. This comprehensive review will benefit a large number of researchers in the fields of chemistry, botany, drug industries and pharmacology.

The chemistry of chromones is very well known. This system is widely used in organic chemistry as an intermediate compound for the synthesis of numerous hetrocycles. On the other hand, chromones were extensively studied as bioactive compounds. They possess remarkable biological activities, such as antimicrobial, antiviral, anticancer, anti-inflammatory, antioxidant, etc. This comprehensive review describes the current status and knowledge of natural occurrence, and biological activities of chromones. Recent advances made over the last decade i.e. January 1999 to December 2009 are critically discussed and we have covered about 176 references and more than 350 compounds reported during this period.

Podophyllotoxin (1) has been known to possess anti-tumor activity and is still considered an important lead for research and development of antineoplastic agents. Derivatives of podophyllotoxin, namely etoposide (2), etopophos (3) and teniposide (4) have been developed and are currently used in clinic for the treatment of a variety of malignancies. These agents are also used in combination therapies with other drugs. Due to the drug resistance developed by cancer cells as well as side effects associated with the use of these agents in clinic, the search for new effective anticancer analogues of podophyllotoxin remains an intense area of research. The structural complexity of podophyllotoxin, arising from the presence of four stereogenic carbons in ring C has restricted most of the structural activity relationship (SAR) studied by derivatization of the parent natural product rather than by de novo multi-step chemical synthesis. These issues provide strong impetus to a search for analogues of 1 with simplified structures, which can be accessible via short synthetic sequences from simple starting materials. Even if such initial compounds might have diminished cytotoxic potencies compared with the parent cyclolignan, the ease of preparation of carefully designed libraries of analogues would lead to more informative SAR studies and expeditious structure optimization. In this regard, during the last two decades considerable efforts have been made to synthesize aza- analogs of podophyllotoxin, i. e. aza-podophyllotoxins, with hetero atoms at different positions of the podophyllotoxin skeleton, while keeping the basic podophyllotoxin structure. Recently, there have been significant efforts towards the convenient synthesis of aza-analogs of 1. The use of multicomponent reactions (MCRs) and the synergies of ultrasound and microwave irradiations have increased the synthetic speed and variety of azapodophyllotoxins which are and will be available to be tested against a diverse population of carcinomas and other diseases. It has been reported that several aza-podophyllotoxins retain a great fraction of the cytotoxicity associated with the parent lignan. This review focuses on the strategies towards synthesis of various aza-podophyllotoxin analogues and their biological activities.

Reactive oxygen species (ROS) are widely believed to cause or aggravate several human pathologies such as neurodegenerative diseases, cancer, stroke and many other ailments. Antioxidants are assumed to counteract the harmful effects of ROS and therefore prevent or treat oxidative stress-related diseases. In this report, recent human studies exploring the efficiency of antioxidants in prevention and treatment of various diseases are reviewed. Few antioxidants including edaravone (for ischemic stroke in Japan), Nacetylcysteine (for acetaminophen toxicity), alfa-lipoic acid (for diabetic neuropathy) and some flavonoids (polyphenolic compounds present in dietary plants), such as micronized purified flavonoid fraction (diosmin and hesperidin) and oxerutins (for chronic venous insufficiency) as well as baicalein and catechins (for osteoarthritis) have found accepted clinical use. However, despite much enthusiasm in the 1980s and 1990s, many well-known agents such as antioxidant vitamins and also more recently developed compounds such as nitrones have not successfully passed the scrutiny of clinical trials for prevention and treatment of various diseases. This has given rise to a pessimistic view of antioxidant therapy, however, the evidence from human epidemiological studies about the beneficial effects of dietary antioxidants and preclinical in vitro and animal data are compelling. We have probably wasted too much time on agents like antioxidant vitamins instead of focusing on more disease specific, target-directed, highly bioavailable antioxidants. We here discuss possible reasons for the lack of success in some clinical trials and seek to provide some suggestions to be considered if antioxidant therapy is to succeed as an effective therapeutic strategy.

Trioxane based compounds such as artemisinin and its synthetic and semi-synthetic analogues constitute promising class of antimalarial agents. The pharmaceutical development of artemisinin was started in 1971 after the isolation from Chinese medicinal plant Artemisia annua and this compound has drawn much attention from medical chemist and pharmacologist worldwide. Researchers from across the globe have independently and collaboratively conducted various studies on the artemisinin system in an attempt to identify lead molecules for malaria chemotherapy. This systematic study led to the discovery of artemether, arteether, dihydroartemisinin, and sodium artesunate which are being used as antimalarial drug for the treatment of Plasmodium falciparum related infections. These studies also revealed that the trioxane bridge is essential for the antimalarial activity of this class of compounds. Another class of structurally simple peroxides that emerged from these studies was the 1,2,4,5-tetraoxanes. Some of the tetraoxane based compounds have shown promising antimalarial potential, and much of work has been done on this type of compound in recent years. Apart from their antimalarial activity, these classes of compounds have also shown promising anticancer and antibacterial activity. To this end, an attempt has been made to describe the medicinal potential of trioxane and tetraoxane-based compounds. Literature from 1999 has been critically reviewed and an attempt has been made to discuss structure activity relationship study among the series of trioxane and tetraoxane based compounds.

Coumarins, a well-known class of naturally occurring compounds, display a remarkable array of biochemical and pharmacological actions, some of which suggest that certain members of this group of compounds may significantly affect the function of various mammalian cellular systems. The development of coumarins as antioxidant agents has attracted much attention in recent years. Coumarins afford an opportunity for the discovery of new antioxidants with truly novel mechanisms of action. This review updates and expands the 2006 review by the same author. The review considers and incorporates the most recently published literature on coumarins as related to their antioxidant properties. A lot of coumarins have been identified from natural sources, especially green plants. These natural compounds have served as valuable leads for further design and synthesis of more active analogues. Beyond doubt, a deep understanding of the mechanisms of existing synthetic and natural coumarins will build the basis for the rational design.