Cytostatic compounds

Restricted access phases are another approach to exploiting the differences in characteristics of analytes. Large analytes are excluded from an internal surface on which an adsorptive stationary phase is present. A herbicide analysis for Metsulfuron methyl, Bentazone, Bromoxynil, methylchlorophenoxy acid, and Mecoprop in the presence of humic acid was performed on restricted access reversed phase media.52 The cytostatic compound epirubicin and its metabolites were separated from plasma using a Pinkerton GFF II column.53 Gradient separations of polymers on reversed phase and on normal phase represent an alternative to gel permeation chromatography. Polyesters of noncrystalline materials were separated on a variety of such phases.54... 

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). 

T. Kiffmeyer, H. J. Goetze, M. Jursch and U. Lueders, Trace enrichment, chromatographic separation, and biodegradation of cytostatic compounds in surface water. Fresenius Journal of Analytical Chemistry, 1998,361(2), 185-191. 

Tomlinson, E., Burger, J., and Schoonderwoerd, E. Human serum albumin microspheres for intraarterial drug targeting of cytostatic compounds, pharmaceutical aspects and release characteristics, in Microspheres and Drug Therapy. Pharmaceutical, Immunological and Medical Aspects, ed. S. Davies et al. New York Elsevier Science Publishers, 1984, pp. 217-227. 

Fuchs has used this reaction type for the construction of an 11-membered ring in the course of model studies for the [ll]cytochalasin synthesis. These cytostatic compounds, e.g. cytochalasin C (109), are metabolites of microorganisms. Reductive fragmentation of the benzenesulfonates (110 Scheme 37) produces the dienols (111). In contrast, both the sulfonates (112) on treatment with LDA afford the tricyclic ketones (113), the products of internal alkylation. Less than 1% of (111) is formed. In conclusion, the author points out that the enolate conformation (Scheme 37, in parentheses) appears to be all important in determining the reaction products of the four diastereoisomers (110) and (112). Whenever the enolate can easily assume a folded conformation, the tricyclic cyclobutane (113) will result. Models of the enolates of (110), where the intraannular fragmentation successfully occurs, show that the folded conformations are more strained than are the extended conformations. 

Scheme 1.1 Two (of many conceivable) retrosynthetic schemes for callystatin A, a cytostatic compound of limited natural supply...

The powerful cytostatic compound paclit-axel (Taxol ) is a diterpene with an V-benzoyl... 

Pyrolyses of Nl- or N3-substituted derivatives of compounds 4 and 5 have continued to find use as routes to azacarbazoles, although the yields are often indifferent and there are no recent examples. The photochemical reactions are dealt with in Section IV.G. Pyrolysis media are paraffin (P) or PPA, and examples of products are compounds 247 (P, cytostatic) (83MI2), 248 (P) (84MI1), and 249 (from a 1-substituted derivative) (86MI2). Indications of diradical intermediates are provided by the thermolysis of compound 250 (P) (83MI2) where one product is a dimer. 

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. ... 

Dacarbazine is the most active compound used for treating metastatic melanoma. It is also combined with anthracyclines and other cytostatics in the treatment of different sarcomas and Hodgkin s disease. Dacarbazine may cause severe nausea and vomiting. Myelosuppres-sion results in leukopenia and thrombocytopenia. Alopecia and transient abnormalities in renal and hepatic function also occur. 

Several dihydropyridazinones of type (78, R1 = cycloamino R2 = H, cycloamino R3 = H, Ph) characterized by a cycloaminomethyl substituent at C-5 have been reported to exhibit cytostatic activity [284, 285], In addition, compounds having a pyridazinone or pyridazinedione moiety linked to the purine system by a sulphur atom (79) have been prepared as potential cytostatic agents [286]. 

For labelled S-phase fraction, both compounds and all treatments of cell number was reduced, comparing to control, as expected to Topi mechanism of action. Cytostatic effects were found for unlabeled cells as show in normalized curves (Figure 8) with a progressive cytotoxicity at a longer time (48-72h) starting to 100 nM for edotecarin and 300 nM for SN-38. Cytotoxic effects... 

In 1984, Giibble et al. reported for the first time a novel l,10-bis-(6-methyl-5H-benzo[fc]carbazol-ll-yl)decane (469) which has potential bifunctional nucleic acid intercalating properties (406). To function as anti-tumor active drugs, one of the most important cytostatic mechanisms of action of coplanar annelated polycyclic compounds is their intercalation with DNA (405). Ten years later, Kucklander et al. studied a series of 5H-benzo[ 7]carbazole quinone derivatives for their cytotoxic activity against colon and lung cancer cells, and found that the heteroannelated 5H-benzo[ 7]carbazole quinone derivative 470 was the most active among the various analogs (407) (Scheme 4.2). 

To screen for bone marrow toxicity early in drug discovery, assays must be able to evaluate hundreds of compounds, be inexpensive, report results within two weeks (in order to impact chemistry cycle times) and be able to detect toxicity irrespective of cytotoxic or cytostatic mechanisms. Only cell line-based assays can meet all of these various criteria. 

---