189014-05-9Relevant academic research and scientific papers
Synthetic approaches to the microtubule-Sabilizing sponge alkaloid ceratamine A and desbromo analogues
Nodwell, Matt,Pereira, Alban,Riffell, Jenna L.,Zimmerman, Carla,Patrick, Brian O.,Roberge, Michel,Andersen, Raymond J.
body text, p. 995 - 1006 (2009/07/18)
Two synthetic approaches to the microtubule-stabilizing ceratamine alkaloids are described. The first approach involved attempts to graft an aminoimidazole moiety onto an azepine ring to form partially hydrogenated versions of the unprecedented aromatic imidazo[4,5-d]azepine core of the ceratamines. This route ultimately failed because it was not possible to aromatize the partially hydrogenated ceratamine intermediates. A second approach started with tribromoimidazole that was sequentially metalated and functionalized to efficiently generate a key imidazole intermediate containing vinyl bromide and amide functionalities. An intramolecular Buchwald vinyl amidation reaction converted this key intermediate into a bicyclic imidazo[4,5-d]azepine that was at the same oxidation state as the aromatic core of the ceratamines. The 2-amino functionality present on the imidazole ring of the ceratamines was installed using a Buchwald/Hartwig amination reaction on a 2-chloroimidazole precursor. Deprotection and aromatization resulted in the first synthesis of desbromoceratamine A (55) and desmethyldesbromoceratamine A (60). An unanticipated addition of atmospheric oxygen was encountered during deprotection of the imidazole ring in the last step of the synthesis leading to C-11 oxygenated ceratamine analogues as byproducts. Evaluation of the synthetic ceratamines in a TG3 cell-based assay for mitotic arrest revealed that the C-14 and C-16 bromine substituents in ceratamine A (1) play a major role in the antimitotic potency of the natural product. The synthetic route to ceratamine analogues has provided sufficient quantities of desbromoceratamine A (55) for testing in mouse models of cancer.
Synthesis of antimitotic analogs of the microtubule stabilizing sponge alkaloid ceratamine A
Nodwell, Matt,Riffell, Jenna L.,Roberge, Michel,Andersen, Raymond J.
body text, p. 1051 - 1054 (2009/04/06)
Antimitotic analogs of the microtubule stabilizing sponge alkaloid ceratamine A (1) have been synthesized starting from tribromoimidazole. A key step In the synthesis Is the formation of the azepine ring via an intramolecular Buchwald coupling between a vinyl bromide and a N-methyl amide. This represents the first synthesis of a fully unsaturated imidazo[4,5,d]azepine. NMR data obtained for the synthetic ceratamine analogs has provided support for the structure assigned to the natural product.
Total synthesis of ageladine A, an angiogenesis inhibitor from the marine sponge Agelas nakamurai
Meketa, Matthew L.,Weinreb, Steven M.
, p. 1443 - 1446 (2007/10/03)
A 12-step total synthesis of the tricyclic heteroaromatic marine metabolite ageladine A has been achieved using a 6π-azaelectrocyclization and a Suzuki-Miyaura coupling of N-Boc-pyrrole-2-boronic acid with a chloropyridine as key steps.
Synthesis of didemnolines A-D, N9-substituted β-carboline alkaloids from the marine ascidian Didemnum sp.
Schumacher, Robert W.,Davidson, Bradley S.
, p. 935 - 942 (2007/10/03)
Didemnolines A-D (1-4) were synthesized and their structures were confirmed through comparisons of data for the synthetic material with those obtained for natural 1-4. The synthesis of didemnolines A (1) and C (3) involved the coupling of 1-[(benzyloxy)methyl]-4-chloromethyl-5- (thiomethyl)imidazole (6) with 7-bromo-β-carboline (5), while didemnolines B (2) and D (4) were formed through the analogous coupling of 6 with norharmon (7). Intermediate 6 was efficiently prepared from 1-[(benzyloxy)methyl]- 2,4,5-tribromoimidazole using a sequential one-pot halogen-metal exchange reaction and 7-Br-β-carboline was synthesized using a new approach.
2,3-,4-,5-,6-,7-,8-,9- and/or 10-substituted dibenzoxazepine compounds, pharmaceutical compositions and methods of use
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, (2008/06/13)
The present invention provides substituted dibenzoxazepine compounds of Formula I: STR1 wherein X is oxygen, sulfur STR2 A is --CH2 -- or STR3 E and F may be --CH, oxygen, nitrogen or sulfur, and may not be the same; G is oxygen, nitrogen or sulfur; with the proviso that when G is oxygen or sulfur, one of E or F is nitrogen, which are useful as analgesic agents for the treatment of pain, and as prostaglandin-E2 antagonists for the treatment of prostaglandin-E2 mediated diseases, pharmaceutical compositions comprising a therapeutically-effective amount of a compound of Formula I in combination with a pharmaceutically-acceptable carrier, a method for eliminating or ameliorating pain in an animal, and a method for treating prostaglandin-E2 mediated diseases in an animal, comprising administering a therapeutically-effective amount of a compound of Formula I to the animal.
