Anticancer compounds formation mechanisms

There are various pathways for free radical-mediated processes in microsomes. Microsomes can stimulate free radical oxidation of various substrates through the formation of superoxide and hydroxyl radicals (the latter in the presence of iron) or by the direct interaction of chain electron carriers with these compounds. One-electron reduction of numerous electron acceptors has been extensively studied in connection with the conversion of quinone drugs and xenobiotics in microsomes into reactive semiquinones, capable of inducing damaging effects in humans. (In 1980s, the microsomal reduction of anticancer anthracycline antibiotics and related compounds were studied in detail due to possible mechanism of their cardiotoxic activity and was discussed by us earlier [37], It has been shown that semiquinones of... 

Granting that precise mechanisms responsible for the characteristic anticancer activity and mammalian toxicity of vinblastine, vincristine, and related compounds have not been rigorously established, it nevertheless is important to describe representative biological and biochemical actions of the drugs that may have mechanistic pertinence. The susceptibility to mitotic spindle dissolution of cell lines with 100-fold differences in sensitivity to vinblastine has been investigated 14). There was an excellent correlation between drug concentrations required to produce inhibition of cell colony formation and those required to dissolve mitotic spindles. It is noteworthy that effects on the mitotic spindle of vinblastine occur very rapidly and can be detected within 30 sec. 

These reactions, and in particular the ease of formation of the N(7)-0(6) chelate, may be relevant to the mechanism of action of the anticancer transition metal compounds such as m-[PtCl2(NH3)2].230... 

Monastrol (Figure 10), the most representative Biginelli adduct in anticancer drug development, showed to be a cell permeable molecule whose mechanism of action on cancer cells involves the selective inhibition of kinesin Eg5 [63]. Kinesin Eg5 is a motor enzyme that is responsible for the formation and maintenance of mitotic spindles. The inhibition of this enzyme activity by monastrol leads to the loss of chromosome alignments and bipolar spindle formation. The resulting "monastral phenotype" inspired scientists to name this specific Biginelli compound as monastrol [63]. Fluorastrol (Figure 10), a monastrol-derived Eg5 inhibitor, showed to be more potent... 

Many of these reactions have attracted the attention of researchers due to the fact that these processes occur in the body during the application of anticancer drugs containing an enediyne block. Chapter 3 is devoted mainly to the analysis of papers related to the study of the cyclization mechanism. Chapter 4 includes additional material on cycloaddition with acetylenic units or those sourced from acetylenic compounds, leading to the formation of carbo- and heterocycles of different structures. The concluding Chapter 5 includes some recent results. 

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