Isolating Candidates

The combination of a root hair specific EST approach and expression analysis was an effective strategy for isolating candidate polyketide synthases potentially involved in sorgoleone biosynthesis. As a result of these efforts, two novel type III polyketide synthases have been identified that preferentially use long chain acyl Co-A s and are potentially involved in sorgoleone biosynthesis. These candidate polyketide synthases can form pentadecatriene resorcinol, an intermediate in sorgoleone biosynthesis. Furthermore, these efforts may aid in the identification of other polyketide synthases responsible for the biosynthesis of phenolic lipids in other plant species. 

The majority of promising drug candidates emerging from marine natural products research to date are potential cancer treatments. Six anti-cancer compounds that are either marine natural products or synthetic analogs of marine natural products have made it to clinical trials. The first of these compounds to enter clinical trials was didemnin B (43), one of a family of cyclic depsipetides isolated from the Caribbean tunicate Trididemnum solidum Didemnin B was advanced to Phase II clinical trials for treatment of small cell lung cancer, myeloma, prostate cancer, and melanoma. Unfortunately, no favorable responses were found so the compound has been withdrawn. Crude extracts of another Caribbean tunicate, Ecteinascidia turbinata, showed extremely... 

Wlieii thiomethoxymethyl hexachloroaiitimoiiate was treated with pyridine, a methylthio derivative 28 was isolated in low yield in addition to the expected chlorinated sulfides (71T4209). Several A, A -haloalkyl-bis-4,4 -pyridiniumethenes 29 have been reported in a Japanese patent (80JAP75479). Tliese compounds are promising candidates for the construction of electrochromic display devices (Scheme 7). 

In the next step, the best candidate from the series 2-oxo-4-(9-phenanthryl)-dihy-dropyrimidine 22 was prepared and isolated in enantiomerically pure form, then attached to a macroporous polymer support. To attach the isolated selector to the amino functionalized macroporous polymethacrylate support, a suitable reactive handle had to be introduced into the dihydropyrimidine. We chose to functionalize the methyl group at the C6 carbon atom by a simple bromination to afford (-)-22. Coupling of this compound to the amino functionalized support then gave the desired chiral stationary phase CSP 12 (Scheme 3-6) containing 0.20 mmol g of the selector. 

The second step introduces the side chain group by nucleophilic displacement of the bromide (as a resin-bound a-bromoacetamide) with an excess of primary amine. Because there is such diversity in reactivity among candidate amine submonomers, high concentrations of the amine are typically used ( l-2 M) in a polar aprotic solvent (e.g. DMSO, NMP or DMF). This 8 2 reaction is really a mono-alkylation of a primary amine, a reaction that is typically complicated by over-alkylation when amines are alkylated with halides in solution. However, since the reactive bromoacetamide is immobilized to the solid support, any over-alkyla-tion side-products would be the result of a cross-reaction with another immobilized oligomer (slow) in preference to reaction with an amine in solution at high concentration (fast). Thus, in the sub-monomer method, the solid phase serves not only to enable a rapid reaction work-up, but also to isolate reactive sites from... 

The ability of a dendritic shell to encapsulate a functional core moiety and to create a specific site-isolated microenvironment capable of affecting the molecular properties has been intensively explored in recent years [19]. A variety of experimental techniques have been employed to evidence the shielding of the core moiety and to ascertain the effect of the dendritic shell [19, 20]. Dendrimers with a fullerene core appear to be appealing candidates to evidence such effects resulting from the presence of the surrounding dendritic branches. Effectively, the lifetime of the first triplet excited state of fullerene derivatives... 

Until 1987, the (R)-PaHNL from almonds was the only HNL used as catalyst in the enantioselective preparation of cyanohydrins. Therefore, it was of great interest to get access to HNLs which catalyze the formation of (5 )-cyanohydrins. (5 )-SbHNL [EC 4.1.2.11], isolated from Sorghum bicolor, was the first HNL used for the preparation of (5 )-cyanohydrins. Since the substrate range of SbHNL is limited to aromatic and heteroaromatic aldehydes as substrates, other enzymes with (5 )-cyanoglycosides have been investigated as catalysts for the synthesis of (5 )-cyanohydrins. The (5 )-HNLs from cassava (Manihot esculenta, MeHNL) and from Hevea brasiliensis (HbHNL) proved to be highly promising candidates for the preparation of (5 )-cyanohydrins. Both MeHNL and HbHNL have been overexpressed successfully in Escherichia coli, Saccharomyces cerevisiae and Pichia pastoris. 

There are numerous examples of intramolecular Heck reactions,151 such as in Entries 10 to 14. Entry 11 is part of a synthesis of the antitumor agent camptothecin. The Heck reaction gives an 11 1 endocyclic-exocyclic mixture. Entries 12-14 are also steps in syntheses of biologically active substances. Entry 12 is part of a synthesis of maritidine, an alkaloid with cytotoxic properties the reaction in Entry 13 is on a route to galanthamine, a potential candidate for treatment of Alzheimer s disease and Entry 14 is a key step in the synthesis of a potent antitumor agent isolated from a marine organism. 

Deprotection of the pMB group from 20 proceeded smoothly in TFA to provide the drug candidate 2. The isolation conditions of a suitable crystal form of 2 for development were optimized later since we had to change the protective group of the nitrogen of 4 for the subsequent asymmetric addition reaction. 

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