Cytostatic properties

To assess the trapping of biological nucleophiles, the pyrido[l,2-a]indole cyclopropyl quinone methide was generated in the presence of 5 -dGMP. The reaction afforded a mixture of phosphate adducts that could not be separated by reverse-phase chromatography (Fig. 7.16). The 13C-NMR spectrum of the purified mixture shown in Fig. 7.16 reveals that the pyrido [1,2-a] indole was the major product with trace amounts of azepino[l,2-a] indole present. Since the stereoelec-tronic effect favors either product, steric effects must dictate nucleophilic attack at the least hindered cyclopropane carbon to afford the pyrido[l,2-a]indole product. Both adducts were stable with elimination and aromatization not observed. In fact, the pyrido [1,2-a] indole precursor (structure shown in Scheme 7.14) to the pyrido [l,2-a]indole cyclopropyl quinone methide possesses cytotoxic and cytostatic properties not observed with the pyrrolo [1,2-a] indole precursor.47... 

Table 7.3 shows the concentrations of 1-5 that result in 50% growth inhibition (GI50) of five human cancer cell lines. Inspection of these data reveals that cytostatic activity of 1 and 3-5 depends on the thermodynamic favorability of the quinone methide species compared to the corresponding keto form. The most cytostatic prekinamycins 1 and 5 are associated with the thermodynamically stable quinone methides. In contrast, the inactive prekinamycins 3 and 4 are associated with thermodynamically stable keto tautomers. The exception is prekinamycin 2, which is cytostatic and possesses a relatively stable keto tautomer 3 compared to its quinone methide. Although the AE value for quinone methide tautomerization can predict cytostatic properties, prekinamycin 2 shows that there must be other factors determining biological activity. 

A number of antibiotics possess pronounced cytostatic properties, and they are extremely effective in treating certain tumors. Included in this group are actinomycin, anthracyclins (daunorubicin and doxorubicin), bleomycin, and others. 

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. 

Scarcia V, Furlani A, Longato B, Corain B, Pilloni G (1988) Heteropolymetallic complexes of 1, l -bis(diphenylphosphino)ferrocene (dppf). IV. Solvolytic behavior and cytostatic properties towards the KB cell-line of dppf and 1, 2-bis(diphenylphosphino)ethane cis complexes of platinum(II) and palladium(II). Inorg Chim Acta 153 67-70... 

Heterocyclic analogues of anthraquinone are a family of potent antibiotics, many with antitumor and cytostatic properties. Diazaquinomycin A (118) is a thymidine synthetase inhibitor <88TL3545>. Low solubility of compound (118) has led to the development of more soluble active analogues, for example, (119) (92JPS815, 94EUP574195). 

Polypeptide pyrolysis is important in connection with protein pyrolysis, but some studies were done on particular peptides such as actinomycins, which have antibiotic and cytostatic properties. Several actinomycins are known, the formulas for some of them being represented by ... 

Conversely, cephalostatins 5 and 6 (5, 6), in which ring C of the left hand steroid unit is aromatized, exhibited reduced activity in the PS system (10 2-10 3 pgmL 1) suggesting the importance of C - D ring junction and possibly C-22 spiroketal structural integrity to the cytostatic properties of the cephalostatins [19]. 

The 1,3-dipolar character of the azido group has been previously exploited for [2 + 3]-cycloaddition reactions of glycosyl azides with compounds containing triple bonds. It is known that formation of 1,4-disubstituted 1,2,3-triazoles is favored over the 1,5-disubstituted ones. Motivated mainly by pharmacological considerations (in order to obtain compounds with cytostatic properties), syntheses of a great number of 1-A -glycosyl-1,2,3-triazole derivatives have been reported. " " "" ... 

Quinone antibiotics of the angucyclin/angucyclinone type from cultures of Nocardia and Streptomyces sp. Acid hydrolysis of S. A furnishes S, B as aglycone and D-rhodinose. S. C is 2-deoxy-S, A, S. D is the 5,6-di-hydro derivative of the aglycone S. B, S. E is the 5-methylthio derivative of S. A. All S. are yellow-red, optically active compounds with antibacterial activity, S. A is also active against AIDS viruses and S. E has cytostatic properties. 

Nebularine 9-P-D-ribofutanosylpurme [M, 2S223, m. 181-182°C, fajo -48.6° (c = 1, water)], a pitrine antibiotic (see Nucleoside antibiotics) synthesized by the mushroom Agaricus (Clitocybe) nebularis, and by Streptomyces spp. N. is selectively active against mycobacteria It has ntarked cytostatic properties, and in animals it is among the most poisonous of the pmine derivatives. 

Cicrcq E. Synthesis and cytostatic properties of daunorubicin derivatives, containing N-phenylthiouiea or N-ethylthiourea moieties in the 3 -position. J Antibiot i 991 44 192-199. 

During the normal catalytic turnover of ribonucleotide reductase a tyrosyl radical is formed. Its reaction with NO has been proposed as a factor in the cytostatic properties of NO, due to the suppression of DNA synthesis through the salvage pathway. [285]... 

Information is available concerning the cytostatic properties of 2-amino-1,3,4-thiadiazole and its acyl derivatives, and its 5-isopropyl and 5-butyl homologues. ... 

For this reason, novel molecules are being sought that do not operate exclusively via an apoptotic mechanism, but instead are able to induce cytostatic properties by other routes such as senescence [158]. 

Electric neutraUty of the compounds, postulated as an essential prerequisite for the achievement of cytostatic properties in the case of platinum complexes is obviously not a crucial condition for cyclopentadienyl metal complexes to exhibit antitumor properties. There exist, on the one hand, numerous neutral compounds such as the metallocene diaddo complexes I-XLIU and the decasubstituted main group IV metallocenes LVn-LIX exhibiting antiproliferative properties on the other hand, marked tumor-inhibitmg potendes were also found with the charged ferricenium salts XLIX-LVI as well as with the ionic cyclopentadienyl titanium complexes Xl.IVXLVlll wherein the titanium-containing unit may either form the cationic or the anionic moiety. Because of... 

Methylated xanthines have pharmacologic applications (theophylline = 1,3-di-methylxanthine, caffeine = 1,3,7-trimethylxanthine). Certain analogs of the purines (8-azaguanine, 6-mercaptopurine) have antibiotic and cytostatic properties they have been used as chemotherapeutic agents against tumors. 

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