By Daniel Best, Mickael Jean, Pierre Van De Weghe
Enediynes are average items with hugely lively cytotoxicity and antibacterial job, and therefore have major strength within the improvement of anti-cancer treatments. besides the fact that, they aren't available and will degrade swiftly in the course of isolation; one resolution is to provide them utilizing overall synthesis. Dynemicin A and uncialamycin are such enediynes, with related buildings, for which overall synthesis has been achieved. This booklet offers the isolation and instruction of those compounds and their analogues via a variety of synthesis options. information of the structural components necessary to their anti-cancer task are provided, with the target of explaining and optimizing their organic actions and strength improvement as drugs.
- Presents typical ènediynes with related constructions whose overall syntheses were accomplished
- Explores structural analogs of guidance for reasons of optimizing the anti-cancer activity
- Describes the entire syntheses of dynemicin A, the uncialamycine, in addition to analogs via emphasizing the synthesis concepts adopted
- Features stories of the organic actions and information to deliver out the structural components of those crucial compounds
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Additional resources for Dynemicin A, Uncialamycin and Analogues
Sample text
Following benzyl protection, acetal hydrolysis of 2-202 with a concomitant Friedel–Crafts cyclization provided a ~4:1 mixture of regioisomeric quinolinones, where the major isomer 2-203 had arisen from reaction at the less hindered position of the aromatic ring. Reduction of the amide gave dihydroquinoline 2-204, which was slurred with silica gel under air to promote oxidation to quinoline 2-205. 25), and catalytic hydrogenolysis provided 7-hydroxyquinoline 2-207. From here, investigations proceeded with two types of protecting groups: pivaloyl (Piv, compound 2-208), which shows lability under intracellular conditions, and o-nitro benzyl (o-NB, compound 2-209), which is photolabile and allows deprotection of delicate downstream intermediates under mild conditions.
17) was presumed to be a consequence of high epoxide lability, which then triggers Bergman cyclization and potentially cytotoxic activity. g. g. 2-108 and 2-126) can be regenerated by reduction in the cytosol of (often hypoxic) cancer cells [SHA 94b, DAN 96b]. Intermediate 2-96 was acetylated and desylilated to form the unstable enediyne 2-126, which is immediately oxidized with PhI(OAc)2 to allow purification and isolation of the stabilized quinone imine 2-127. 1) and led to significant reduction of tumor size in mice with better performance than the chemotherapy drug mitomycin C 2-143.
The synthesis was carried out in two phases: 1) a proof of principle demonstration of Bergman cyclization under acidic conditions with an analogue featuring a stable carbamate group and 2) introduction of a photocleavable group R to the analogues, allowing triggering of epoxide hydrolysis and cycloaromatization under mild conditions. 11. Wender’s dynemicin A 2-1 analogues. 2. 38 [WEN 91]. First the aldehyde function in the commercially available quinoline 2-253 was reduced, and Yamaguchi reaction with trimethylsilylacetylene in the presence of methyl chloroformate introduced the first alkyne unit of the enediyne 2-254.