Cytostatics, synthesis

The unsaturated substituent in the carbene complex 1 often is aromatic or heteroaromatic, but can also be olefinic. The reaction conditions of the Dotz procedure are mild various functional groups are tolerated. Yields are often high. The use of chromium hexacarbonyl is disadvantageous, since this compound is considered to be carcinogenic however to date it cannot be replaced by a less toxic compound. Of particular interest is the benzo-anellation procedure for the synthesis of anthra-cyclinones, which are potentially cytostatic agents. ... 

By synthesis of compounds with a very large number and a strength of type I units (whereby the type I units must be more numerous and stronger than those of the cytostatic compound to be inhibited). 

Schott H, Schwendener RA. Synthesis of liposomal phospholipid-(N" -palmitoyl-l-P-D-arabinofuranosylcytosine)-conjugates and evaluation of their cytostatic activity against L1210 murine leukemia. Liebigs Annalen Chemie 1996 365. 

The coenzyme tetrahydrofolate (THF) is the main agent by which Ci fragments are transferred in the metabolism. THF can bind this type of group in various oxidation states and pass it on (see p. 108). In addition, there is activated methyl, in the form of S-adenosyl methionine (SAM). SAM is involved in many methylation reactions—e. g., in creatine synthesis (see p. 336), the conversion of norepinephrine into epinephrine (see p. 352), the inactivation of norepinephrine by methylation of a phenolic OH group (see p. 316), and in the formation of the active form of the cytostatic drug 6-mercaptopurine (see p. 402). 

Most cytostatic agents directly or indirectly inhibit DNA replication in the S phase of the cell cycle (see p. 394). The first group (A) lead to chemical changes in cellular DNA that impede transcription and replication. A second group of cytostatic agents (B) inhibit the synthesis of DNA precursors. 

Dihydrofolate reductase acts as an auxiliary enzyme for thymidylate synthase. It is involved in the regeneration of the coenzyme N, N -methylene-THF, initially reducing DHF to THF with NADPH as the reductant (see p. 418). The folic acid analogue methotrexate, a frequently used cytostatic agent, is an extremely effective competitive inhibitor of dihydrofolate reductase. It leads to the depletion of N, N -methylene-THF in the cells and thus to cessation of DNA synthesis. 

Many cytostatics inhibit nucleic acid synthesis or functions such as replication or transcription. There... 

In Fig. 1 various targets of some important cytostatic agents are depicted. Their main mechanisms of action can be briefly summarized as follows. Pentostatin blocks purine nucleotides by inhibiting adenosine deaminase. 6-Mercaptopurine and 6-thioguanine inhibit purine ring biosynthesis and they inhibit nucleotide interconversions. Methotrexate by inhibiting dihydrofolate reduction blocks thymidine monophosphate and purine synthesis. 5-Fluorouracil also blocks thymidine monophosphate synthesis. Dactinomycin, daunorubicin, doxorubicin and mitoxantrone intercalate with DNA and inhibit RNA synthesis. L-asparaginase deaminates... 

Figure 5). We have postulated that the decrease in protein synthesis occurs via an independent mechanism and that this action of NO may be important in its cytostatic properties or in the regulation of certain cellular functions. 

Margarete studied pharmacy at the Faculty of Natural Sciences, University of Vienna, from 1995 to 2001. In her master thesis she engaged in the synthesis of cytostatic drugs. After graduation, she underwent professional training to be pharmacist. In addition to working at a pharmacy, she studies at the Vienna University of Economics and Business Administration. 

Mechanism of Action Selectively inhibits inosine monophosphate dehydrogenase in the de novo pathway of purine synthesis, producing potent cytostatic effects on T and B lymphocytes... 

A microwave-assisted Fischer indole synthesis under solvent-free conditions with Montmorillonite K10 clay modified with zinc chloride was employed in a key step of the synthesis of analogues of the cytostatic natural product, Sempervirine (Scheme 3.6)8. A dedicated laboratory microwave synthesizer was utilised. 

Lipinska, T., General route to the total synthesis of sempervirine analogues containing modified E rings, potential cytostatics, Tetrahedron Lett., 2002, 43,9565-9567. 

Pyrrolizines have been studied for theoretical reasons. They are intermediates in synthesis and are important natural products. Synthetic studies of the cytostatic mitomycins have aroused further interest.1-6... 

Meegan et al. reported the synthesis of a number of [3-lactams and these were evaluated in a series of in vitro assays, which determined their antiproliferative activity in MCF-7 and MDA-MB-231 breast cancer cell lines and also their affinity for the oestrogen receptor (Fig. 6). The cytotoxicity of the [3-lactams was determined in the LDH assay to establish that the antiproliferative effects observed were due to cytostasis rather than cellular necrosis. Most of the compounds demons-treated low cytotoxicity, indicating that their action is cytostatic rather than cytotoxic. Cytotoxicity values considerably below that obtained for tamoxifen (13.4%, 10 pM) were observed with a most potent compound (3%, 10 pM in MCF-7 cell... 

The successful synthesis of optically active 7 then led to the first synthesis of verrucarin A (8), a macrotrilactone with significant cytostatic activity. The synthesis involved esterification of the primary alcohol of verrucarol (the tricyclic fragment) with the acetate of 7 (DCC, 4-pyrrolinopyridine) and then with a protected derivative of (E, Z)-muconic acid. After deprotection (Bu4NF), lactonization was effected by the Mitsunobu procedure (7,405-406). 

Zollinger M, Mayer P, Lindel T (2006) Total Synthesis of the Cytostatic Marine Natural Product Dibromophakellstatin via Three-Component Imidazolidinone Anellation. J Org Chem 71 9431... 

J. Thiem and M. Gerken, Synthesis of the E-D-C trisaccharide unit of aureolic acid cytostatics, J. Org. Chem., 50 (1985) 954-958 and references therein. 

Synthesis and Cytostatic Activity of Substituted 6-Phenylpurine Bases and Nucleosides Application of the Suzuki—Miyaura Cross-Coupling Reactions of 6-Chloropurine Derivatives with Phenylboronic Acids... 

A laboratory synthesis for vanillin is based on this procedure. 2-Hydroxytetrahydro-furan, an intermediate for cytostatics, was produced from the corresponding carboxylic acid by electrochemical oxidation 253 ... 

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