Biological antileukemic activity

Biological Activity. The maytansinoids possess antitumor activity, particulady against P 388 lymphocytic leukemia, B 16 melanocarcinoma, and Lewis lung carcinoma. A number of semisynthetic esters of maytansinol have been prepared and exhibit good antileukemic activity (52,255). The maytansides lack antitumor activity, indicating that the ester at C-3 is a requirement for activity (50,52). The carbinolamide also appears to be necessary for... 

Bis(thiosemicarbazones) [89-97] and AT-heterocyclic thiosemicarbazones comprise two interesting series of experimental chemotherapeutic agents. 2-formylpyridine thiosemicarbazone, the first of the latter series to be examined for biological activity, showed mild antileukemic activity against 1-1210 tumor in mice [98]. However, it was found to be toxic at the therapeutic dose levels which led to synthesis of other aromatic and heterocyclic thiosemicarbazones as potential agents [80, 99, 100]. However, the only active anticancer compounds besides glyoxal bis(thiosemicarbazones) were the iV-heterocyclic thiosemicarbazones [101], 2 formyl-3-hydroxypyridine thiosemicarbazone [102] and... 

To evaluate the effects on biological activity of variations in structure of the ester moiety, several semisynthetic esters of maytansinol were prepared. The propionate (230), bromoacetate (231), crotonate (232), and trifluoroacetate (233) esters of maytansinol (229) were made by procedures involving either anhydride-pyridine (230-232) or anhydride-acid (233) treatment. Fig. (58). TTie esters 228, and 230-232 were found to show antileukemic activity comparable to those of the naturally occurring substituted alanyl esters. The trifluoroacetate ester 233 showed no antileukemic activity, possibly because of ready solvolysis in vivo to inactive maytansides. 

Interest in these naturally occurring and synthetic lactones, podolactones, and related podocarpic acid derivatives has been mainly due to the novel structures of these compounds and the various types of biological activity possessed by them. Octahydrophenanthrene lactones (II) and related podocarpic acid derivatives (III) have been reported to possess hormonal and anti-inflammatory properties (4). Other similar podolactones have been shown to inhibit the expansion and division of plant cells (IV) (5-10), to have antileukemic activity (V) (11), to have antibacterial activity (12), to have insect toxicity properties (13-15), and to exhibit antitumor activity (16-19). 

CigHisO, Mr 344.32, yellow prisms, mp. 203 °C, [a] +495° and -495° (CHCl,), respectively. A biologically highly active dibenzofuran derivative, occurring both as the (+)- and the (-)-forms in numerous lichens (especially in Usnea species) antibiotic, antileukemic, growth regulatory (in plants), and antifeedant (in insects) activities have been described. It is used as the free acid and as the sodium salt in pharmaceutical preparations. The biosynthesis presumably proceeds via phenolic oxidation. Other dibenzofuran derivatives from lichens are didymic acid, pannaric acid, pla-codiolic acid, and schizopeltic acid. 

Within the realm of natural products and bioactive compounds, the tri- or tetra-ort/w-substituted biaryl subunit is by far the most common form of atropisomerism. The Sj Ar reaction allows the formation of the backbone of important drugs with diverse biological activities such as (-)-steganone (1), a dibenzocyclooctadienyl lignan lactone exhibiting antileukemic activity [6] spirooxoindohnes... 

More than ten years have elapsed since the publication of a comprehensive review on the quassinoids, the bitter principles of the Simaroubaceae family (80). Interest in these terpenoids has increased enormously in recent years due in part to the finding of the American National Cancer Institute in the early 1970s that these compounds display marked antileukemic activity. Furthermore, a wide spectrum of other biological properties for the quassinoids has been discovered and studies on chemical modifications of inactive members to yield biologically active ones were undertaken. New structures have been established also and numerous synthetic approaches have been developed which include the total synthesis of the parent compound, quassin (p. 250) and also that of castelanolide (p. 253). 

The broad spectrum of biological properties, especially the antileukemic activity, of the quassinoids as well as their highly oxygenated carbon backbone coupled with the stereochemical features have stimulated a great deal of synthetic activity. A number of approaches towards their synthesis have been described, but success at total synthesis has so far been limited to only two published accounts (vide infra). 

Early work in the field has established the synthetic strategies and analytical tools for such class of libraries (for reviews see refs[111 112 456]). As listed in Table 13, the first generation of cyclic peptide libraries focused on biologically active sequences such as the cell adhesion RGD motif, the antileukemic heptapeptide stylostatin, or endothelin antagonists, but also on metal-binding sequence motifs and on the de novo discovery of bioactive cyclic peptides without sequence-biased motifs. Moreover, synthetic questions were addressed such as the sequence dependency of peptide cyclization reactions (see Table 13). 

From another Dysidea sponge species, Dysidea avara, the sesquiterpenes avarol, Fig. (9) and avarone, Fig. (10), which show a wide variety of biological activities, were first isolated. Both compounds are potent antileukemic agents in vitro and in vivo. They were determined to be neither direct mutagens nor premutagens, and they displayed antimutagenic activity... 

Theonelladins C 214 and D 215 and niphatesine C 216 are members of a rapidly growing dass of 3-substituted pyridine alkaloids that are known to display important biological activities (Scheme 12.30) [107]. For instance, theonelladins C and D have shown antileukemic and antineoplastic properties while niphatesine C is a known antileukemic agent. 

These reactions have been applied to synthetic studies on biologically active compounds such as l/ -methylcarbapenem (87), the antileukemic principle, pareitropone (88), and the potentially antiinflammatory marine alkaloid, halichlorine (89). 

Resveratrol [2], 3,4 ,5-trihydroxy-rra/ A-stilbene, is a phytoalexin found in grapes and other plants, that exhibits a variety of biological activities, including antileukemic, antibacterial, antifungal, anti antiplatelet aggregation, coronary vasodilator. Recently, it has been shown to induce apoptosis and decrease expression of Bcl-2 in the human leukaemia HL-60 cell line. 

Source Cephalotaxus fortunei. Molecular formula C29 H39 N O9. Molecular weight 545.62. Melting point 125-132 deg C. Biological activity Antileukemic. 

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