Antitumor complexes, review

Molecular-orbital calculations performed on platinum antitumor complexes and related species, and force-field calculations carried out on their adducts with nucleic acids are reviewed. The aim of the author is to point out the methodological difficulties encountered in these calculations, and to comment on the (sometimes problematic) results which they have yielded. 

The aim of the present contribution is to critically review computational work related to platinum antitumor drugs, published prior to 1998. After a section devoted to molecular-orbital calculations on platinum antitumor complexes and related compounds, we address force-field calculations on platinum adducts with DNA constituents that have been used (mainly in combination with NMR spectroscopy) to evaluate the structure of the adduct. A brief outlook concludes this chapter. 

McKeage, M.J., Maharaj, L. and Berners-Price, S.J. (2002) Mechanisms of cytotoxicity and antitumor activity of gold(I) phosphine complexes the possible role of mitochondria. Coordination Chemistry Reviews, 232, 127—135. 

The reader is referred to other reviews for detailed discussions of the electronic states and luminescence of nucleic acids and their constituents/0 fluorescence correlation spectroscopy/2) spectroscopy of dye/DNA complexes/0 and ethidium fluorescence assays/4,0 A brief review of early work on DNA dynamics as well as a review of tRNA kinetics and dynamics have also appeared. The diverse and voluminous literature on the use of fluorescence techniques to assay the binding of proteins and antitumor drugs to nucleic acids and on the use of fluorescent DNA/dye complexes in cytometry and cytochemistry lies entirely outside the scope of this chapter. 

Although there has heen a great deal of research concerning how platinum(II) complexes hind to biological molecules and the hkely mechanism of antitumor activity of these platinum-containing species, far less attention has heen paid to the properties of other metal complexes in this arena. Recent attention has fallen on cohalt(II)-Schiff hase complexes, as several have heen discovered to have promise as antiviral agents. A review of recent work has appeared elsewhere [64], so the topic will not he covered here however, in addition to focusing on recent developments, emphasis is placed on the introduction of the new head unit, 3,6-diformylpyridazine (13), into Schiff-hase macrocyclic electrochemistry. 

A final example of metabolic pathway engineering is based on polyketide and nonribosomal peptide biosynthesis. Polyketides and nonribosomal peptides are complex natural products with numerous chiral centers, which are of substantial economic benefit as pharmaceuticals. These natural products function as antibiotics [erythromycin A (65), vancomycin (66)], antifungals (rapamycin, amphotericin B), antiparasitics [avermectin Ala (67)], antitumor agents [epothiolone A (68), calicheamicin yj, and immunosuppressants [FK506 (69), cyclosporin A], Because this exponentially growing and intensely researched field has developed, the reader is directed to review articles for additional details.347-359 Also with the potential economic benefit to develop the next blockbuster pharmaceutical, a number of patents and patent applications have been published.360-366... 

In 1974, Dickson and Fraser reviewed the already substantial area of cobalt-alkyne complexes.1 Since then the number of examples and applications of this class of organometallic compounds, especially dinuclear complexes, has increased enormously. This review will present the chemistry of polynuclear cobalt-alkyne complexes, with emphasis on the more recent developments. Although there have been many exciting fundamental discoveries, this is a maturing area of research that is finding many important applications in organic synthesis,2 such as the use of [Co2(jU-alkyne)(CO)6] complexes in the synthesis of enediyne antitumor antibiotics.3-4... 

In order to fully understand the complex biochemical mechanisms by which the thymus and its hormones control the expression of immunity, it is first necessary to review briefly the organization of the thymus-dependent (T cell) immune system (Fig. I). The predominant cells of the peripheral lymphoid tissue (i.e., spleen, lymph nodes) includes both B and T lymphocytes. In the presence of foreign antigens, B lymphocytes differentiate into plasma cells, which in turn synthesize antibody thus, B cells make up the humoral arm of the immune system. In contrast, T lymphocytes are responsible for mediating all the classical cellular immune responses such as delayed type hypersensitivity skin responses, organ transplant rejections, and sensitized antitumor immunity as well as immunity toward various viral, fungal, and protozoal pathogens (Reinherz and Schlossman, 1980). 

Molecules containing sulfur or nitrogen donor atoms can serve as ligands to form stable complexes with the relatively kinetically inert Pt(II) center (for a review see Ref. 60). It is likely that cisplatin binds to many cellular components, the result of which is general toxicity, but coordination to the heterocyclic nitrogen atoms of DNA nucleobases is most likely responsible for its antitumor activity. 

Experimental antitumor agents such as streptonigrin, bisthiosemicarbazones, and perhaps monothiosemicarbazones must form iron or copper complexes to become biologically active as catalysts of oxidant damage to cells. In sum, metal-based catalysis of redox reactions in cells describes a major topic in cancer therapeutics. Nevertheless, it has remained underdeveloped as a theme for study and application. The sections below provide a coordinated review and perspective on the subject of redox-active, metal-dependent drugs in cancer chemotherapy. 

Continuing activity on platinum(II) antitumor drugs has resulted in several recent reviews/each of which cover mechanistic aspects. Other reviews include one on metal porphyrins, which features many reactions of 4- and 5-coordinate complexes, and substitution reactions at platinum(II) complexes with asymmetric olefin ligands have been discussed. ... 

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