885274-50-0Relevant articles and documents
Chemoenzymatic synthesis, structural study and biological activity of novel indolizidine and quinolizidine iminocyclitols
Gómez, Livia,Garrabou, Xavier,Joglar, Jesús,Bujons, Jordi,Parella, Teodor,Vilaplana, Cristina,Cardona, Pere Joan,Clapés, Pere
, p. 6309 - 6321 (2012/09/05)
The synthesis, conformational study and inhibitory properties of diverse indolizidine and quinolizidine iminocyclitols are described. The compounds were chemo-enzymatically synthesized by two-step aldol addition and reductive amination reactions. The aldol addition of dihydroxyacetone phosphate (DHAP) to N-Cbz-piperidine carbaldehyde derivatives catalyzed by l-rhamnulose 1-phosphate aldolase from Escherichia coli provides the key intermediates. The stereochemical outcome of both aldol addition and reductive amination depended upon the structure of the starting material and intermediates. The combination of both reactions furnished five indolizidine and six quinolizidine type iminocyclitols. A structural analysis by NMR and in silico density functional theory (DFT) calculations allowed us to determine the population of stereoisomers with the trans or cis ring fusion, as a consequence of the inversion of configuration of the bridgehead nitrogen. The trans fusion was by far the most stable, but for certain stereochemical configurations of the 3-hydroxymethyl and hydroxyl substituents both trans and cis fusion stereoisomers coexisted in different proportions. Some of the polyhydroxylated indolizidines and quinolizidines were shown to be moderate to good inhibitors against α-l-rhamnosidase from Penicillium decumbens. Indolizidines were found to be moderate inhibitors of the rat intestinal sucrase and of the exoglucosidase amyloglucosidase from Aspergillus niger. In spite of their activity against α-l-rhamnosidase, all the compounds were ineffective to inhibit the growth of the Mycobacterium tuberculosis, the causative agent of tuberculosis. The Royal Society of Chemistry 2012.
Synthesis of new analogues of the tetraponerines
Rouchaud, Anne,Braekman, Jean-Claude
experimental part, p. 2666 - 2674 (2009/10/01)
To evaluate the influences of the tetraponerine alkyl chains and tricyclic ring systems on their cytotoxic activities, we have prepared a series of alkyl derivatives (3a, 3b and 4a-f) of the non-natural tricyclic skeletons d.ecahyd.ro-2H,6fi-dipyrido[1.,2-a:1.2'-c]pyrimidine (3, 6-6-6 skeleton) and. dodecahydro-2W-l,8a-diazaphenanthrene (4, iso-6-6-6 skeleton). In this study, two ways to synthesise the 6-6-6 analogues have been developed and compared. One is based, on the condensation of a-tripiperideme with diethyl malonate (DBM) in. water at pH11. This yielded, oxo ester 11, precursor of the amino nitrile 8, but only in moderate yield. In the second pathway, the key intermediate 8 was more efficiently synthesised by starting from. 2-(2-piperidyl)ethanol. Treatment of 8 with alkyl Grignard reagents led to the 6-6-6 analogues 3a and 3b. When the one-pot reaction between a-tripiperideine and DEM was performed in water at pH 8, the lactam 12, precursor of the iso-6-6-6 skeleton, was obtained, in a yield of 76 %. The same lactam was also obtained in a yield of 86 % by treatment of tetrahydroanabasine 14 with DEM in water at pH 8. Lactam 12 was transformed into the iso-6-6-6 analogues 4a-4f. The cytotoxic activities of the 6-6-6 and. i.so-66-6 analogues against H.T29 cancer cells were compared with those of the 5-6-5 and 6-6-5 tetraponerines and. with those of solenopsin analogues. 2009 Wiley-VCH Verlag GmbH & Co. KGaA.
