Cytotoxicity analogs

Schally AV, Halmos G, Rekasi Z, Arencibia JM (2001) The actions of LH-RH agonists, antagonists, and cytotoxic analogs on the LH-RH receptors on the pituitary and timiors. In Devroey P (ed) Infertility and reproductive medicine clinics of North America. Saunders, Philadelphia, pp 12, 17-44... 

Nagy, A., Schally, A. V., Armatis, P, et al. Cytotoxic analogs of luteinizing hormone-releasing hormone containing doxorubicin or 2-pyrrolinodoxorubicin, a derivative 500-1000 times more potent. Proc. Natl. Acad. Sci. USA 94 652-656, 1996. 

Szepeshazi K, Schally AV, Nagy A et al. (2003) Preclinical evaluation of therapeutic effects of targeted cytotoxic analogs of somatostatin and bombesin on human gastric carcinomas. Cancer 98 1401-1410... 

Decitabine (5-aza-deoxycytosine) is an analog of the nucleoside 2 -deoxycytidine. It is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and by inhibition of the enzyme DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation or apoptosis. DNA hypomethylation is achieved at concentrations below those required to significantly inhibit DNA synthesis, which may promote restoration of function to genes associated with control of cellular differentiation and proliferation. Cytotoxicity in rapidly dividing cells may also result from covalent adducts between DNA methyltransferase and decitabine. 

In contrast to this view, but in analogy with the behavior of several antitumor metal complexes, some authors proposed that the DNA is the probable target for cytotoxic activity of organotin(IV) compounds. In this section we survey and compare the most important literature data published to date on this subject. 

Sun L., Fuselier J.A., Murphy W.A., Coy D.H. Antisense peptide nucleic acids conjugated to somatostatin analogs and targeted at the n-myc oncogene display enhanced cytotoxity to human neuroblastoma 1M.R.32 cells expressing somatostatin receptors. Peptides 2002 23 1557-1565. 

The cytotoxic activities of the 2, 2 -difluoro analog (775) of 737 against Chinese hamster ovary and tumor cells, in comparison with those of 1- -d-arabinofuranosylcytosine ara-C, a drug for leukemia), have been studied 775 is transported the faster through membrane into cells, more effectively phosphorylated by the deoxycytidine kinase (to the 5 -mono-phosphate) and, after conversion into the 5 -triphosphate, more highly accumulated in the cells, with longer duration time, than is ara-C, but nevertheless 775 is incorporated into the DNA to a lesser extent than is ara-C. These characteristics of 775 were discussed. 

The 2 -chloro and 2 -bromo congeners of either 748 (FIAC) or 758 (FMAU) are more cytotoxic than FIAC and FMAU, suggesting that these chloro and bromo nucleosides, in contrast to the 2 -fluoro compounds, are comparatively better substrates for deoxycytidine kinase of human lymphocytes than the substrates for viral-specific thymidine kinase. The disposition of the 2 -fluoro group may also be important from the biological viewpoint. It should be noted that the structural difference between RNA and DNA is at the 2 -position. The ribo type of analog (738) of FIAC is 10 times less effective in suppression of HSV replication than is FIAC. Thus Fox, and Watanabe and coworkers concluded that the 2 - up fluorine disposition and the species of the substituent at C-5 are the two important factors influencing antiviral activity. Nevertheless, the mechanism of action of 2 -deoxy-2 -fluorocytidine (737) on certain herpes viruses, including HSV-1... 

Alkylation reactions by the iminium methide species are well known in the mitomycin and mitosene literature 4,49,51-53 and are largely responsible for the cytotoxicity/antitumor activity of these compounds. As illustrated in Scheme 7.8, the electron-rich hydroquinone intermediate can also be attacked by the iminium ion resulting in either head-to-head or head-to-tail coupling. The head-to-head coupling illustrated in Scheme 7.8 is followed by a loss of formaldehyde to afford the coupled hydroquinone species that oxidizes to the head-to-head dimer upon aerobic workup. Analogous dimerization processes have been documented in the indole literature, 54-56 while the head-to-tail mechanism is unreported. In order to... 

Fludarabine is an analog of the purine adenine. It interferes with DNA polymerase to cause chain termination and inhibits transcription by its incorporation into RNA. Fludarabine is dephosphorylated rapidly and converted to 2-fluoro-Ara-AMP (2-FLAA), which enters the cells and is phosphorylated to 2-fluoro-Ara-ATP, which is cytotoxic. Fludarabine is converted rapidly to 2-FLAA. The pharmacokinetics of 2-FLAA... 

MRP4 is an ubiquitously expressed transporter with highest expression in the prostate where it can be localized to the basolateral membrane of tubuloacinar cells [149]. Schuetz and colleagues [150] demonstrated that high copy number and overexpression of MRP4 in a human T-lymphoid cell line was associated with cytotoxic resistance and increased cell efflux of an acyclic nucleoside phosphonate drug PMEA. Furthermore, these cells were more resistant to nucleoside analog... 

Soon afterwards [123] the bromo- (105) and iodo- (106) analogs of chlorovulone I (100) were also isolated from C. viridis in exceptionally low yield (ca. 0.01% of lipid extract). Their structures were established principally by spectroscopic means in comparison with chlorovulone I. Both of the new compounds possess the same olefin geometries as found in clavulone I and chlorovulone I. R Stereochemistry at Cl 2 was established in 105 by comparisons of CD spectra with those of chlorovulone I (100). These new halogenated clavulones showed levels of antiproliferative activity and cytotoxicity comparable to those of chlorovulone I (100). 

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