Natural product inhibitors

Schering Plough has reported the discovery of the first non-hydroxamic acid containing natural product inhibitors of PDF. Sch 382582 (41) and Sch 382583 (42) were isolated from a fermentation broth of Streptomyces sp., and the proposed structures of these compoimds were derived from a combination of two-dimensional NMR studies (NOESY, HMBC and HMQC-TOCSY) and X-ray crystallography studies [116]. The proposed structure... 

Neckers L. (2006) Using natural product inhibitors to validate Hsp90 as a molecular target in cancer. Curr Top Med Chem 6 1163-1171. 

Natural Product Inhibitors and Activators of Histone Deacetylases... 

HDAC inhibitors have received tremendous attention with the recent FDA approval of Vorinostat (Zolinza) or suberoylanilide hydroxamic acid (SAHA) for the treatment of cutaneous T-cell lymphoma (CTCL). Multiple compounds have thus entered into clinical trials for a wide variety of diseases. Many of these compounds were inspired in some part from HDAC natural product inhibitors. In addition, one natural product Romidepsin has also gained FDA approval for treating cutaneous T-cell lymphoma. 

A further natural product inhibitor is mithramydn A, a structurally complex anticancer antibiotic. Mithramycin A is a member of a group of aureolic add-type polyketides that are produced by the soil bacterium Streptomyces argillaceus [94]. 

Gupta V, Ogawa AK, Du X et al (1997) A model for binding of structurally diverse natural product inhibitors of protein phosphatases PP1 and PP2A. J Med Chem 40 3199-3206... 

In contrast to the other members of the PDE family, PDE1 is unique in its ability to interact with calmodulin. As would be expected therefore, this interaction can also be the target of potential inhibitors. This appears to be so for some natural-product inhibitors of PDE1 isolated from ginseng root. The ginsenosides Rb, Rc, and Re are moderately active (5-15 pM) steroidal inhibitors of CaM PDE isolated... 

Few synthetic or natural Inhibitors of these enzymes have been elucidated. Some natural products such as curcurbitacin I and 0 can repress Induction of laccase by the pathogenic fungus of cucumber, Botrvtis cinerea (Si). It Is not known how this compound Is Involved In resistance or If these compounds are active Inhibitors that could reduce defense In plant species by causing PPO or PO Inhibition. Oxalates are natural product Inhibitors of chloroplastic PPO (SS) and... 

Compounds obtained from natural sources have always contributed to the development of small molecules for various targets in the history of medicinal chemistry. Recently, several small molecules derived from natural products have been shown to possess Icmt inhibitory activity [72,73]. This effort to discover other natural product inhibitors of Icmt utilized a HTS approach. Of the approximately 6 x 10 extracts screened, the extract from the order Verongida displayed Icmt inhibition. A bromotyrosine-derived chemotaxonomic marker characterizes marine sponges in this order. The extract from Pseudoceratina sp. contained a compound with a bromotyrosyl-spermine-bromotyrosyl sequence, named spermatinamine... 

Buchanan, M.S., et al (2007). Spermatinamine, the first natural product inhibitor of isoprenylcysteine carboxyl methyltransferase, a new cancer target. Bioorg Med Chem Lett 17 3. 

Natural Product Inhibitors to Study Biological Function... 

Diversity-Oriented Synthesis of Small Molecules Natural Product Inhibitors to Study Biological Function Nucleic Acid Synthesis, Key Reactions of Proteins Stmcture, Function and Stability Solution-Phase Synthesis of Biomolecules... 

Recently, Lazo and co-workers reported a combinatorial library of PTPIB inhibitors based on a pharmacophore derived from the structure-activity relationships for several natural product inhibitors of PSTPases such as oka-daic acid, microcystins and calyculin A [425, 426], The pharmacophore model involved a carboxylate, a non polar aromatic group and hydrogen-bond acceptors and donors and was used as a platform for functional group variation. Among the 18 library compounds generated by parallel solid-phase chemistry, a non-competitive inhibitor for PTPIB was identified (library 41, Kj=0.85 jiM) [425] and as well a serine/threonine phosphatase inhibitor (library 42, IC50 < 100 /iM) [426],... 

FARNESYL-PROTEIN TRANSFERASE A NEW PARADIGM FOR CANCER CHEMOTHERAPY, ADVANCES IN DISCOVERY AND DEVELOPMENT OF NATURAL PRODUCT INHIBITORS... 

Banyu Pharmaceutical Company reported that J-104134 (Figure 7) was a potent inhibitor of rat FPTase activity (IC50 = 5 nM). This compound, though structurally similar to many FPP competitive natural product inhibitors (vide infra), contain multiple free carboxyl groups but, surprisingly, unlike the natural product inhibitors, was active in cell-based assays (IC50 = 4.3 jiM) [63]. 

Natural Product Inhibitors Competitive with Ras-Peptide... 

There are only three examples of natural product inhibitors reported to date, which compete with the acceptor peptide for the binding to FPTase. These are listed in Table 4,... 

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