Natural tyrosine kinase inhibitor

SPINOZZI F, PAGLIACCI M C, MIGLIORATI G, MORACA R, GRIGANI F, RICCARDI C, NICOLETTI I (1994) The natural tyrosine kinase inhibitor genistein produces cell cycle arrest and apoptosis in Jurkat T-leukemia cells. LeukRes. 18 431-9. 

One of the first reported solid-phase syntheses of a nonoligomeric natural product was that of lavendustin A.31 This compound is a potent tyrosine kinase inhibitor. Fortunately, the structure of this material is highly amenable to synthesis and elaboration on a solid phase. In fact, the synthesis was reported by a researcher working alone on this project (Green).31... 

Stahl, P, Kissau, L., Mazitschek, R., Giannis, A., Waldmann, H. Natural Product derived receptor tyrosine kinase inhibitors identification of IGFIR, tie-2, and VEGFR-3 inhibitors. Angew. Chem. Int Ed. 2002,41,1174-1178. 

Success stories of natural products as drug leads continue to be reported. For example, the recent discoveries of natural product-based tyrosine kinase inhibitors or antagonists of the cancertriggering Tcf-beta-catenin interactions illustrate this point. The latter case study is particularly impressive because active compounds could be identified by screening a small natural product library of 7(X)0 compounds. Screening of much larger synthetic libraries failed to produce any antagonists. ... 

Kissau, L. et ah, Development of natural product-derived receptor tyrosine kinase inhibitors based on conservation of protein domain fold, J. Med. Chem., 46, 2917, 2003. 

This protocol is particularly useful in the synthesis of the class of polychlorinated marine natural product known as chlorosulfolipids, which are believed to be responsible for seafood poisoning. ° With this protocol, Vanderwal et al. succeeded in the enantioselective total synthesis of maUiamensilipin A 11, a protein tyrosine kinase inhibitor isolated from alga Poterioochromonas malhamen-sis The enantioselective synthesis of (+)-danicalipin A 14, another chlorosulfolipid isolated from the alga Ochro-monas danica by Umezawa et al. also used this strategy as a key step (Scheme 42.5). 

An oxime derivative of indirubin (a natural bis-indole alkaloid used in traditional Chinese medicine to treat chronic myelocytic leukemia), indirubin-3 -monoxime (37), was found to be a potent inhibitor of cyclin-dependent kinases (CDKs), and of the proliferation of myeloid leukemia cells via inhibition of a tyrosine kinase . The 3D structure of the complex of 37 with CDK revealed that the oxime function is intact, and that it occupies the ATP-ribose site of the CDK-ATP structure. While the specific role of the oxime group in the biological activity of 37 is not clear, it was proposed that its reactivity may be utilized for further drug design... 

Figure 5 (a) Chaetomellic acid A is a novel dicarboxylate-containing natural product that is thought to mimic farnesyl pyrophosphate and thus to inhibit the enzyme FTPase. This compound can exist in either the dicarboxylate or anhydride form, (b) As peptides that contain aromatic oxamic acids are good inhibitors of tyrosine kinase p56 SH2 domains, it is believed that the oxamic acid moiety may mimic the phosphate group, (c) A symmetric 3,5-disubstituted benzoate analog of S3P (substrate) and EPSP (product) inhibits EPSPS. 

---