In search of novel antitumor therapies. The natural product indirubin (1) is one of the class of indigo dyes, insoluble in aqueous systems, employed by mankind since the Bronze Age for textile coloring. In 1999 indirubin was reported to be a modest inhibitor of the enzyme CDK2, a key target in the ongoing search for novel antitumor therapies. With the guidance of X-ray structures, indirubin was transformed to yield novel, soluble, almost colorless, highly potent CDK2 inhibitors that strongly inhibit the growth of the MCF7 tumor cell line in vitro.

Genistein is a major isoflavonoid in dietary soybean, commonly consumed in Asia. Genistein exerts inhibitory effects on the proliferation of various cancer cells and plays an important role in cancer prevention. However, the molecular and cellular mechanisms of genistein on human ovarian cancer cells are still little known. We show that exposure of human ovarian cancer HO-8910 cells to genistein induces DNA damage, and triggers G2/M phase arrest and apoptosis. Furthermore, we also found that checkpoint proteins ATM and ATR are phosphorylated and activated in the cells treated with genistein. It is also shown that genistein increases the phosphorylation and activation of Chk1 and Chk2, which results in the phosphorylation and inactivation of phosphatases Cdc25C and Cdc25A, and thereby the phosphorylation and inactivation of Cdc2 which arrests cells in G2/M phase. Moreover, genistein enhances the phosphorylation and activation of p53, while decreases the ratio of Bcl-2/Bax and Bcl-xL/Bax and the level of phosphorylated Akt, which result in cells undergoing apoptosis. These results demonstrate that genistein-activated ATM-Chk2-Cdc25 and ATR-Chk1-Cdc25 DNA damage checkpoint pathways can arrest ovarian cancer cells in G2/M phase, and induce apoptosis while the cellular DNA damage is too serious to be repaired. Thus, the antiproliferative, DNA damage-inducing and pro-apoptotic activities of genistein are probably responsible for its genotoxic effects on human ovarian cancer HO-8910 cells.

Aiming towards spiroketal-modified artificial cephalostatin molecules, two orthogonal approaches were investigated. First, the introduction of 17-O-functionality into hecogenin derivatives with a closed spiroketal moiety was accomplished by different remote-oxidation procedures. These allowed the synthesis of tetradecacyclic artificial cephalostatin molecules with improved tumor-inhibiting properties. Second, a novel reduction-oxidation pathway for spiroketal opening in sapogenins was discovered, which should provide the basis for a broad access towards spiroketal-modified building blocks for cephalostatins.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A seven-step cascade reaction-in which selective mesylation, epoxide formation, epoxide lysis, cyclization, reiterative oxidation, and nitrogen-oxygen exchange occur sequentially-facilitates the construction of the maleic anhydride moiety of CP molecules 1 and 2 (>93% yield per step). Unstable intermediates of this reaction sequence were detected, providing evidence for the proposed mechanism and resulting in the discovery of a new chemical entity.

New insight into the mild and regioselective formation of silyl enol ethers, a new way to synthesize β-ketal ketones by a novel variation of the Mukaiyama Aldol reaction, and a number of unprecedented cascade reactions that furnish novel polycyclic, highly oxygenated compounds from simple starting materials are some of the key results from these studies (see scheme). In addition, the first detailed proposed mechanism for the biosynthesis of trichodimerol is presented. Trichodimerol is important because of its potential medical use against septic shock.

With the objective of preparing higher oxygenated cephalostatin analogues and probing the importance of the Delta(14, 15)-double bond for biological activity we investigated the syn-dihydroxylation of homoallylic alcohol 3. Whilst this reaction took place with the expected P-diastereoselectivity using RuCl3/NaIO4 to provide glycol 10, we noticed that under more forcing conditions an oxidative cleavage occurred to yield the unusual bisketal 12. This interesting transformation was applied to bissteroidal pyrazines to afford the highly oxygenated cephalostatin analogues 24-26. Preliminary test results with these compounds indicated, however, a lack of cytostatic activity.

The synthesis of the cephalostatin-analogous bis-steroidal pyrazines 6, 27a/b and 41 by the transformation of the C-2-symmetrical diketone 6 as a central precursor, as well as the direct preparation of several non-symmetrical bis-steroidal pyrazines by coupling of enamino ketones (5, 40) with vinyl azides (17a/b) is reported. Furthermore, an improved procedure for preparation of the diketone 6 described earlier is presented.

We were successful in optimizing the synthesis of the homoallylic alcohol 6 from hecogenine acetate 2 as an important precursor for our approach to cephalostain analogues by doubling the yields. On this way we discovered that formation of homoallylic alcohol 6 proceeds via a diastereoselective intramolecular Lewis acid catalysed ene reaction directly from lumihecogenine acetate 3. Finally we were able to elucidate the structure of the already described but not clearly identified oxa-dimer 7.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.