BSP :: Current Medicinal Chemistry Home Page

Contents

The Search of DNA-Intercalators as Antitumoral Drugs: What it Worked and What did not Work Pp. 127-151
R. Martinez and L. Chacon-Garcia
[Abstract] [Full text article]

Phytoecdysteroids – From Isolation to Their Effects on Humans Pp. 153-172
Maria Bathori and Zita Pongracz
[Abstract] [Full text article]

Biologically Active Quassinoids and Their Chemistry: Potential Leads for Drug Design Pp. 173-190
Z. Guo, S. Vangapandu, R.W. Sindelar, L.A. Walker and R.D. Sindelar
[Abstract] [Full text article]

Novel Chemical Strategies for Thymidylate Synthase Inhibition Pp. 191-202
W.H. Gmeiner
[Abstract] [Full text article]

Gastric Mucosal Protection: From Prostaglandins to Gene-Therapy Pp. 203-215
K. Gyires
[Abstract] [Full text article]

Targeting C5a: Recent Advances in Drug Discovery Pp. 217-236
M. Allegretti, A. Moriconi, A.R. Beccari, R. Di Bitondo, C. Bizzarri, R. Bertini and F. Colotta
[Abstract] [Full text article]

Chemistry and Biological Activities of Caffeic Acid Derivatives from Salvia miltiorrhiza Pp. 237-246
Ren-Wang Jiang, Kit-Man Lau, Po-Ming Hon, Thomas C. W. Mak, Kam-Sang Woo and Kwok-Pui Fung
[Abstract] [Full text article]

Abstracts

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The Search of DNA-Intercalators as Antitumoral Drugs: What it Worked and What did not Work
R. Martinez and L. Chacon-Garcia
[Full text article]

The discovery of new compounds with antitumoral activity has become one of the most important goals in medicinal chemistry. One interesting group of chemotherapeutic agents used in cancer therapy comprises molecules that interact with DNA. Research in this area has revealed a range of DNA recognizing molecules that act as antitumoral agents, including groove binders, alkylating and intercalator compounds. DNA intercalators (molecules that intercalate between DNA base pairs) have attracted particular attention due to their antitumoral activity. For example, a number of acridine and anthracycline derivatives are excellent DNA intercalators that are now on the market as chemotherapeutic agents. Commercially available acridine and anthracycline derivatives have been widely studied from a variety of viewpoints, such as physicochemical properties, structural requirements, synthesis and biological activity. However, the clinical application of these and other compounds of the same class has encountered problems such as multidrug resistance (MRD), and secondary and/or collateral effects. These shortcomings have motivated the search for new compounds to be used either in place of, or in conjunction with, the existing compounds. Unfortunately, the results of this search have not met expectations. The vast majority of candidate intercalator compounds tested for use as anticancer agents have shown little or no biological activity. Research in this area has not been without benefits, however, for it has produced much information on the synthesis and antitumoral properties of hundreds of compounds, which have been tested on diverse tumoral cell lines. This review considers the structural and biological considerations relevant to the use of DNA intercalators and bis-intercalators as antitumoral agents, with an emphasis on the relationship between structure and activity, produced in last decade.

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Phytoecdysteroids – From Isolation to Their Effects on Humans
Maria Bathori and Zita Pongracz
[Full text article]

An overview is given on both well-known and recently discovered phytoecdyteroids including a sophisticated isolation scheme and notable physiological and pharmacological effects of ecdysteroids on vertebrates. The isolation of pure ecdysteroids has been improved by the use of low-pressure reversed-phase chromatography. An optimized combination of preliminary purification and chromatographic separations results in pure ecdysteroids. Structural elucidation has been done using spectroscopic methods, however, the final proof of the steric structure is rendered using x-ray crystallography.

Ecdysteroid containing preparations show a boom and both OTC products and numerous preparation techniques can be found using the Internet. This paper will give a review on the kaleidoscope of pharmacological effects attributed to the ecdysteroids, such as:

• An increase of protein synthesis (for body-building, AIDS, patients with neoplasm disease, etc.), and other body functions;

• Antidepressant effect;

• Shielding the body from stress, and improve the physical and sexual performance;

• Prevention from infections and certain diseases.

A list of recent offers of ecdysteroid-containing products will also be given.

The perspective use of ecdysteroids is promising in genetics. Steroid regulation of programmed cell death during development and differentiation has recently come to the limelight. Murine model of human diseases and its influencing with ecdysteroids are detailed.

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Biologically Active Quassinoids and Their Chemistry: Potential Leads for Drug Design
Z. Guo, S. Vangapandu, R.W. Sindelar, L.A. Walker and R.D. Sindelar
[Full text article]

Quassinoids are highly oxygenated triterpenes, which were isolated as bitter principles from the plants of Simaroubaceae family. Their synthesis has attracted much attention because of the wide spectrum of their biological properties. The most prevalent quassinoids have C-20 picrasane skeleton, some known as bruceolides as they were isolated from the genus Brucea, which showed marked antileukemic and antimalarial activities.

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Novel Chemical Strategies for Thymidylate Synthase Inhibition
W.H. Gmeiner
[Full text article]

Thymidylate synthase (TS) is a well-validated target for cancer chemotherapy. TS was established as the principal target of the widely used anticancer drug 5-fluorouracil (5FU). The 5FU metabolite FdUMP forms a covalent complex with TS that is stabilized by 5-formyl tetrahydrofolate (leucovorin; LV). Numerous chemical strategies have been employed to develop novel TS inhibitors that are superior to 5FU/LV. 5FU is non-ideal as a TS-inhibitory drug because it is only inefficiently converted to FdUMP, while the remainder of the administered dose is converted to toxic metabolites. My laboratory has explored the utility of FdUMP[N] compounds (oligodeoxynucleotides comprised of FdUMP nucleotides) as FdUMP pro-drugs. FdUMP[N] compounds result in potent TS-inhibition, and display many advantages relative to 5FU/LV. A number of other chemical strategies have also been employed to develop pro-drugs, or metabolic precursors of FdUMP, and several of these strategies will be reviewed. In addition to chemical strategies to develop FdUMP prodrugs, a number of chemical strategies have been devised to develop molecules that resemble the reduced folate co-factor required for TS catalysis. The synthesis of antifolates that have TS-inhibitory activity, such as Raltitrexed, has resulted in compounds that are effective and specific TS-inhibitors and, in some cases, have clinical potential. Chemical strategies that target TS mRNA for destruction are also being explored as potential chemotherapeutics. These diverse chemical approaches to control TS activity in tumor cells for the treatment of cancer will be reviewed.

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Gastric Mucosal Protection: From Prostaglandins to Gene-Therapy
K. Gyires
[Full text article]

The maintenance of gastric mucosal function and integrity highly depends on the status of microcirculation. Vasoactive agents - prostaglandins, nitric oxide and sensory neuropeptides (e.g. calcitonin gene-related peptide) - play a crucial role in mucosal defensive processes.

Beside the local release of vasoactive mediators the central nervous system is also involved in regulation of gastric functions. Cerebral lesions, stimulation of different brain areas can result in gastric mucosal injury. Noxious challenge of gastric mucosa alters the sodium currents in gastric sensory neurons and induces cfos mRNA expression in nucleus tractus solitarii and area postrema. Vagal nerve has long been established to play a permissive role in the development of gastric lesions. However, several lines of evidences suggest its physiological relevance in the enhancement of gastric mucosal resistance. It was concluded that gastroprotection can be induced by low level of central vagal stimulation and the consequent release of prostaglandins, nitric oxide, and calcitonin gene-related peptide.

Prostaglandins, nitric oxide and sensory neuropeptides play a role also in ulcer healing by stimulating the formation of growth factors, the epithelial proliferation and angiogenesis. Both systemic and local administration of growth factors accelerated the ulcer healing. Local, single injection of plasmid-DNA encoding vascular endothelial growth factor (VEGF) was shown to stimulate the ulcer healing in the rat. The transient, local expression of VEGF in ulcerated tissue might be a new therapeutic strategy in the treatment of gastric ulcer disease.

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Targeting C5a: Recent Advances in Drug Discovery
M. Allegretti, A. Moriconi, A.R. Beccari, R. Di Bitondo, C. Bizzarri, R. Bertini and F. Colotta
[Full text article]

Activation of complement via the innate and adaptive immune system is vital to the body’s defences in fighting infections. Unregulated complement activation is likely to play a crucial role in the pathogenesis of several diseases including psoriasis, adult (acute) respiratory distress syndrome (ARDS), bullous pemphigoid (BP), rheumatoid arthritis (RA) and ischemia-reperfusion (I/R) injury. The 74 amino acid peptide C5a is released after complement activation at sites of inflammation and is a potent chemoattractant for neutrophils, basophils, eosinophils, leukocytes, monocytes and macrophages. Recombinant proteins and humanized anti-C5 antibodies have been recently developed for blocking specific proteins of the complement system bringing renewed attention towards complement inhibition. Pharmacological studies have been highlighting the complement fragment C5a as an interesting target for the management of complement mediated diseases. Specific inhibition of C5a biological activity could gain therapeutic benefit without affecting the protective immune response. In the last few years several peptide and non-peptide antagonists of C5a have been discovered and tested in relevant pharmacological models; the availability of orally active compounds is rapidly helping to delineate the precise role of C5a in immunoinflammatory disorders. Moreover, mutagenesis data for the C5a/C5a receptor (C5aR) couple make C5aR a valuable model for mechanistic studies of peptidergic G-protein coupled receptors (GPCRs). The aim of this review is to outline the recent advances in C5a inhibition, especially highlighting the value of a multidisciplinary integrated approach in drug discovery.

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Chemistry and Biological Activities of Caffeic Acid Derivatives from Salvia miltiorrhiza
Ren-Wang Jiang, Kit-Man Lau, Po-Ming Hon, Thomas C. W. Mak, Kam-Sang Woo and Kwok-Pui Fung
[Full text article]

Caffeic acid (3,4-dihydroxycinnamic acid), one of the most common phenolic acids, frequently occurs in fruits, grains and dietary supplements for human consumption as simple esters with quinic acid or saccharides, and are also found in traditional Chinese herbs.

Caffeic acid derivatives occur as major water-soluble components of Salvia miltiorrhiza, including caffeic acid monomers and a wide variety of oligomers. This review provides up-to-date coverage of this class of phenolic acids in regard to structural classification, natural resources, chemical and biosyntheses, analytical methods and biological activities including antioxidant, anti-ischemia reperfusion, anti-thrombosis, antihypertension, anti-fibrosis, antivirus and antitumor properties. Special attention is paid to both structural classification and biological activities. The structural diversity and the pronounced biological activities encountered in the caffeic acid derivatives of S. miltiorrhiza indicate that this class of compounds is worthy of further studies that may lead to new drug discovery.