Cytostatic activities

German investigators (Brock et al) worked on the creation of alkylating pro-drugs that have cytostatic activity after specific biotransformation in the tumor tissue. Cyclophosphamide (CTX) has well pronounced antitumor activity with the broadest spectrum. It is metabolized to the cytotoxic phosphoamide mustard. In normal tissues with high enzyme level cyclophosphamide is converted to its inactive metabolites (Fig. 2). These differences in biotransformation can explain the relative selectivity of cyclophosphamide towards... 

An example of a separation primarily based on polar interactions using silica gel as the stationary phase is shown in figure 10. The macro-cyclic tricothecane derivatives are secondary metabolites of the soil fungi Myrothecium Verrucaia. They exhibit antibiotic, antifungal and cytostatic activity and, consequently, their analysis is of interest to the pharmaceutical industry. The column used was 25 cm long, 4.6 mm in diameter and packed with silica gel particles 5 p in diameter which should give approximately 25,000 theoretical plates if operated at the optimum velocity. The flow rate was 1.5 ml/min, and as the retention time of the last peak was about 40 minutes, the retention volume of the last peak would be about 60 ml. 

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. 

Cytostatically active esters of 1- or 2-ethyleneimino-2-hydroxy-3-butene, which are difficult to obtain by conventional methods because of the sensitivity of the unsaturated... 

In the course of an investigation of cytostatically active derivatives of l-ethylenimino-2-hydroxybuten-(3), also called Tetramine, the following carbamate was prepared [214]... 

Ciemerych MA, Kubiak JZ 1998 Cytostatic activity develops during Meiosis I in oocytes of LT/Sv mice. Dev Biol 200 198-211... 

Dominguez, M. F., Macias, R. I., Izco-Basurko, I., de La Fuente, A., Pascual, M. J., Criado, J. M., Monte, M. J., Yajeya, J., Marin, J. J., Low in vivo toxicity of a novel cisplatin-ursodeoxycholic derivative (Bamet-UD2) with enhanced cytostatic activity versus liver tumors, J. Pharmacol. Exp. Ther. 2001, 297, 1106-1112. 

Vincendeau, P. et al., Nitric oxide-mediated cytostatic activity on Trypanosoma brucei gambiense and Trypanosoma brucei brucei, Exp. Parasitol., 75, 353, 1992. 

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]. 

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. 

Acquired resistance to alkylating agents is a common event. Such resistance against the cytostatic activity can occur through at least three mechanisms. Increased thiol production can inactivate the agents. Also a decreased cell permeability to the drug can play a role. Increased capacity for DNA repair can mitigate cytotoxic activity. 

Besides these important procedures, research to discover new, original, pharmaceutical substances was also started. The first important success came in 1954 as the fruit of research in the field of cytostatics. It was Vargha s idea to combine cytostatically active groups with carbohydrates in the hope that, by using sugars as carriers, the high toxicity of the active groups would be decreased. This... 

The results obtained by Vargha and his coworkers in the field of cytostatics was followed with lively interest by several research groups abroad, and it was through these studies that the Research Institute for Pharmaceutical Chemistry became internationally known. Because of this appreciation of his work, Vargha was invited to the Xth International Cancer Congress (Houston, 1970) to attend a panel concerned with cytostatically active carbohydrate derivatives. 

In 1987, Hibbs published a landmark paper in the nitric oxide field (Hibbs et al., 1987a), by demonstrating that the L-arginine that is required for CAM cytostatic activity is metabolized to L-citrulline (similar to L-arginine but less one nitrogen atom from the guanidinium group) and nitrite plus nitrate. In addition,... 

Aminoacids occur in plants and animals, both in the free state and as the basic units of proteins and other metabolites. Aminoacid derivatives have been reported in marine environment, such as from marine sponges of the genus Jaspis sp. [371,372], from Suberea creba, a Coral Sea marine sponge [373], and the marine ascidian Leptoclinides dubius [374], Some of these compounds have been shown to possess interesting biological properties, e g., cytostatic activity exhibited by axinastatin-4, an aminoacid derivative isolated from a marine sponge [375],... 

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). 

Although the first survey listed 45 natural chlorinated sesquiterpene lactones, several such compounds were omitted in that coverage (1) and are described here. The novel sesquiterpene lactone chlorochrymorin (239) was isolated from Chrysanthemum morfolium (499), and the chlorohydrin graminichlorin (240) is found in Liatris graminifolia (500). The antibacterial AA-57 (241), which is related to pentalenolactone, is produced by a Streptomyces sp. (501). The plant Eupatorium chinense var. simplicifolium has yielded eupachifolin D (242) (502) (side-chain double bond stereochemistry revised (518)), and the new guaianolide andalucin (243) was characterized from Artemisia lanata (503). The previously known chlorohyssopifolins (1) have been studied for cytostatic activity, and the presence of one and even two chlorine atoms amplifies this activity (504). 

Gonzalez AG, Darias V, Alonso G, Estevez E (1980) The Cytostatic Activity of the Chlorohyssopifolins, Chlorinated Sesquiterpene Lactones from Centaurea. Planta Med 40 179... 

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