Natural products as aromatase inhibitors

With the clinical success of several synthetic aromatase inhibitors (AIs) in the treatment of postmenopausal estrogen receptor-positive breast cancer, researchers have also been investigating the potential of natural products as AIs. Natural products from terrestrial and marine organisms provide a chemically diverse array of compounds not always available through current synthetic chemistry techniques. Natural products that have been used traditionally for nutritional or medicinal purposes (e.g., botanical dietary supplements) may also afford AIs with reduced side effects. A thorough review of the literature regarding natural product extracts and secondary metabolites of plant, microbial, and marine origin that have been shown to exhibit aromatase inhibitory activity is presented herein.     

Natural products as drug leads

The clinical efficacy of natural products has been demonstrated for centuries. However, by using the active principles in such extracts as leads for conventional medicinal chemistry programmes it is possible to develop compounds with an improved therapeutic profile. Using an acrylic acid lead, with antidiabetic properties, it has been shown that the attachment of a thiazolidinedione group provides a more effective antidiabetic agent that does not produce weight gain in animals. In contrast, cyclic analogues of the acrylic acid retain the anti-inflammatory activity of the lead, but do not display antidiabetic activity.     

Natural products as angiogenesis modulators

Cancer remains one of the major causes of death worldwide. Anti-angiogenic therapy is one of the new approaches to anticancer therapy. Out of 22 angiogenesis inhibitors currently under clinical trials there are 11 natural products or were modeled on a natural product parent. This review shows the potential of natural products for the discovery of new anti-angiogenic leads.     

Natural products as leads for tuberculosis drug development

New therapeutics are urgently needed to combat the immense disease burden of tuberculosis and related mycobacterial diseases worldwide. Natural products continue to provide leads for the development of novel drugs to treat the rapidly growing numbers of patients with multi- and extensively-drug resistant tuberculosis. This review presents natural products and synthesized analogues with anti-mycobacterial activity published between 2006 through 2009. Structure activity relationships, synthetic analogues and newly reported activities of known compounds reported during this period are also included.     

Natural products as promising drug candidates for the treatment of hepatitis B and C

Hepatitis B virus （HBV） or hepatitis C virus （HCV） infections are a major threat worldwide. Combination therapy of interferon-α and ribavirin is currently the treatment of choice for HCV-infected patients. However, this regimen is only effective in approximately 50% of patients and provokes severe side-effects. Numerous natural alternatives for treating HCV have been suggested. Deoxynojirimycin and its derivatives are iminosugars which exert anti-HCV activity by inhibiting α-glucosidases. A non-immunosuppressive derivate of cyclosporine A, NIM811, exerts anti-HCV activity by binding to cyclophilin. Other natural products with promising anti-HCV activity are 2-arylbenzofuran derivatives, Mellein, and pseudoguaianolides. For HBV treatment, several drugs are available, specifically targeting the virus polymerase （lamivudine, entecavir, telbivudine, and adefovir dipivoxil）. The efficacy of these drugs is hampered by the development of resistance due to point mutations in the HBV polymerase. Due to drug resistance and adverse side-effects, the search for novel drugs is mandatory. Wogonin, ellagic acid, artemisinin and artesunate, chrysophanol 8-O-β-D-glucoside, saikosaponin C, and protostane triterpenes are active against HBV. Natural products need to be investigated in more detail to explore their potential as novel adjuncts to established HBV or HCV therapy.     

Natural products as inhibitors of carcinogenesis

Background: Although carcinogenesis and cancer have been studied intensively for > 50 years, the rates of cancer incidence and mortality remain high. The most successful approach for reducing these rates has been primary prevention. For individuals at a high risk of developing cancer owing to certain genetic, environmental and occupational factors, cancer chemoprevention is a logical approach. Objective: This review discusses natural products as inhibitors of carcinogenesis. Conclusion: Natural product chemopreventive agents are inherently biologically active and have been demonstrated to prevent and reverse the carcinogenic process in a pleiotropic manner. Derivatives of compounds discovered by screening natural products for chemopreventive agents have shown efficacy in clinical trials. Despite the obstacles that must be overcome before chemopreventive drugs become an integral component of standard medical practice for cancer prophylaxis, there is vast potential for significant improvement in cancer morbidity and mortality through the use of natural product chemopreventive drugs.     

Natural products as anti-invasive and anti-metastatic agents

Invasion and metastasis, the hallmark of malignant tumor, is the main reason for the clinical death of most cancer patients. Tumor invasion and metastasis are complex, multi-step biochemical processes, which involve cell detachment, invasion, migration, intravasation and circulation, implantation, angiogenesis and proliferation. Therefore, how to prevent tumor metastasis has been the biggest challenge in cancer chemotherapy. In recent years, many natural products have been found to have anti-invasive and anti-metastatic activities. In this paper, these natural compounds are classified as polyphenols, terpenoids, alkaloids, steroids and saponins, saccharides, macrolides, amides and others, their anti-invasive and anti-metastatic activities as well as their biological targets are reviewed.     

Natural products as a source of protein kinase activators and inhibitors

Many of the protein kinase activators and inhibitors presently under investigation are natural products or are derivatives of natural products. Since over 500 kinases are encoded by the human genome, the task is to discover modulatory compounds which have high specificity for a single enzyme. Many different low molecular weight compounds have been studied for activity. These come from various sources, such as plants, marine organisms, microorganisms and cyanobacteria. The search for specific inhibitors is mainly performed in cell-based assays.     

Natural products as potential anticonvulsants: Caffeoylquinic acids

Current anticonvulsant therapies are generally directed at symptomatic treatment by suppressing excitability within the brain. Consequently, they have adverse effects such as cognitive impairment, dependence, and abuse. The need for more effective and less toxic anticonvulsants has generated renewed interest in natural products for the treatment of convulsions. Caffeoylquinic acids (CQs) are naturally occurring phenolic acids that are distributed widely in plants. There has been increasing interest in the biological activities of CQs in diseases of the central nervous system. In this issue, Nugroho et al. give evidence for the anticonvulsive effect of a CQ-rich extract from Aster glehni Franchet et Sckmidt. They optimized the extract solvent conditions, resulting in high levels of CQs and peroxynitrite-scavenging activity. Then, they investigated the sedative and anticonvulsive effects in pentobarbital- and pentylenetetrazole-induced models in mice. The CQ-rich extract significantly inhibited tonic convulsions as assessed by onset time, tonic extent, and mortality. They suggested that the CQ-rich extract from A. glehni has potential for treating convulsions. This report provides preclinical data which may be used for the development of anticonvulsants from natural products.     

Natural and synthetic products used for the treatment of smoke inhalation: a patent review

Introduction: Inhalation injury is the leading cause of death in burn patients and is usually caused by the uninhibited absorption of smoke, which has an extremely toxic effect on the respiratory system. The physiopathology of inhalation injury covers multiple factors and the injured respiratory system may present deterioration in a few hours.

Areas covered: In this present review, we analyzed patents based on both natural and synthetic products developed for the treatment of smoke inhalation. We found 14 patents in Espacenet, 25 in WIPO and none in the USPTO data search.

Expert opinion: Several previous reports on treatments used for smoke inhalation are discussed. Although there are a number of research based products for this injury, there has been no review of the patents dealing with treatments for smoke inhalation. The development of novel natural or synthetic products are discussed in detail in the review.     

Natural products of plant origin as anticancer agents

Natural products have been used as effective remedies for the treatment of various ailments. Numerous plant products in the form of decoction, tincture, tablets and capsules have been clinically used for the treatment of different kinds of cancer. This review covers some of the important plants with clinically proven anticancer activity, including Catharanthus roseus, Podophyllum peltatum, Taxus brevifolia, Camptothecin acuminata, Cephalotaxus harringtonia, Viscum album, Onchrosia elliptica, Annona bullata, Asmina triloba and Rhizoma zedoariae. Synthetic analogues in some cases have also been prepared to improve the efficacy and decrease the side effects of parent compounds. The modes of action of clinically used drugs are also delineated.     

Natural products used for diabetes

OBJECTIVE: To review the efficacy and safety of natural products commonly used for diabetes. DATA SOURCES: English and Spanish-language journals retrieved through a MEDLINE search of articles published between 1960 and December 2001 using these index terms: Opuntia, karela, gymnema, tecoma, alpha lipoic acid, thioctic acid, ginseng, panaxans, and diabetes. DATA SYNTHESIS: Natural products have long been used in traditional systems of medicine for diabetes. Products in common use include nopal (prickly pear cactus), fenu-greek, karela (bitter melon), gymnema, ginseng, tronadora, chromium, and alpha-lipoic acid. The popularity of these products varies among people of different ethnicities. Nopal is the most commonly used herbal hypoglycemic among persons of Mexican descent. Karela is more commonly used by persons from Asian countries. Some of these agents have gained universal appeal. For a select number of products, studies have revealed single or multiple mechanisms of action. For several of these, high soluble fiber content is a contributing factor. CONCLUSION: Based on the available evidence, several natural products in common use can lower blood glucose in patients with diabetes. Commonly used natural products often have a long history of traditional use, and pharmacists who have a stronger understanding of these products are better positioned to counsel patients on their appropriate use.     

Mast cells as a target of rheumatoid arthritis treatment

Rheumatoid arthritis (RA) is a chronic inflammatory disease and its exact cause and pathophysiological process remain unclear. Fibroblast-like synoviocytes, macrophages and T lymphocytes are considered to be the major contributors in the pathophysiological process of RA; however, an increasing number of papers have drawn attention to the potential role of mast cells (MCs) in the process. In an animal model of RA, we reported an increase in MC numbers in the arthritic region, which agreed with the observation in human RA. In addition, a good correlation between the number of MCs and the development of disease was observed. However, there has been little experimental or clinical evidence of the beneficial effects of the modification of MC activity on the pathogenesis of RA and this is the weak point of the hypothesis. We therefore studied the effects of a MC-stabilizing compound, cromoglicate lisetil (CL), which is an orally deliverable prodrug of cromolyn sodium, on the RA disease model. The MC-stabilizer had efficacy in a mouse model. The beneficial effects of CL in this animal model further suggested the contribution of MCs in the pathophysiological process of RA. Concerning the contributive mechanism of MC on the pathogenesis of RA, our results using a disease model suggested that activation of MC chymase and matrix metalloproteinases might be involved. MC is now considered to be one of the targets of RA treatment.     

天然产物在黑色素瘤防治中的研究进展

恶性黑色素瘤是一种高致死性的皮肤肿瘤,发病率在全世界范围内呈上升趋势。恶性黑色素瘤严重至危及生命的原因主要是其具有较强的侵袭转移能力。出现远处转移病灶的患者,即使采用最新的治疗,仍会出现复发现象,中位生存期仅有数月。目前关于黑色素瘤的防治手段主要包括手术切除、化学疗法、免疫治疗及靶向治疗。然而,这些治疗策略会导致耐药性和严重的不良反应。近年来,越来越多的研究发现天然产物具有良好的抗黑色素瘤活性,包括抑制肿瘤生长、诱导细胞凋亡、抑制血管生成和转移、消除肿瘤干细胞等。此外,许多研究报告了天然产物和传统抗黑色素瘤药物的联合作用增强了治疗效果。本文就天然产物对黑色素瘤的预防潜力、治疗效果进行简要总结讨论。     

Natural products as trypanocidal,antileishmanial and antimalarial drugs

Parasitic diseases caused by protozoa as Leishmania, Trypanosome or Plasmodium are responsible for more than three millions deaths annually throughout the developing countries. This review covers recent studies on plant-secondary metabolites isolated from medicinal plants and that have demonstrated moderate to high activity in in vitro and in vivo bioassays against these protozoa. The biological activity of the last promising antiparasitic leads are described.     

Intracellular signaling pathways as a target for the treatment of rheumatoid arthritis.

Recent advances in our understanding of cellular and molecular mechanisms of rheumatoid arthritis have highlighted a critical role for interleukin-1 and tumor necrosis factor alpha. The quest for chemically amenable targets has recently led to the identification and characterization of the intracellular signaling pathways associated with these inflammatory cytokines. In particular the mitogen-activated protein kinase pathway, the nuclear factor kappaB pathway and the cross-talk between these offer several potential therapeutic opportunities for rheumatoid arthritis.