Total synthesis and biological evaluation of halipeptins A and D and analogues

Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA.
Journal of the American Chemical Society (Impact Factor: 11.44). 05/2006; 128(13):4460-70. DOI: 10.1021/ja060064v
Source: PubMed

ABSTRACT The marine-derived halipeptins A (1a) and D (1d) and their analogues 3a, 3d and 4a, 4d were synthesized starting from building blocks 10, 13, 14a or 14d, 15, and 16. The first strategy for assembling the building blocks, involving a macrolactamization reaction to form the 16-membered ring hydroxy thioamide 52d as a precursor, furnished the epi-isoleucine analogue (4d) of halipeptin D, whereas a second approach involving thiazoline formation prior to macrolactamization led to a mixture of halipeptins A (1a) and D (1d) and their analogues 3a, 3d (epimers at the indicated site) and 4a, 4d (epimers at the indicated site). The same route starting with D-Ala resulted in the exclusive formation of the epimeric halipeptin D analogue 3d. The synthesized halipeptins, together with the previously constructed oxazoline analogues 5d and 6d, were subjected to biological evaluation revealing anti-inflammatory properties for 1a, 1d, and 6d while being noncytotoxic against human colon cancer cells (HCT-116).


Available from: Manuela Rodriquez, May 28, 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: This paper describes the synthesis of new enantiomerically pure 2-cyanoethyl-oxazolines in one step starting from a wide range of amino alcohols and 4-ethoxy-4-iminobutanenitrile with high to good yields (73% - 96%) via an appropriate procedure which can be used for a selective synthesis of mono-oxazolines. A simple operation as well as a practical separation are additional eco-friendly attributes of this method. All the synthesized compounds were identified and characterized with their physicochemical features and their spectral data ((1)HNMR, (13)C NMR and TOFMS ES(+)). Among the prepared mono-oxazolines, the mono-oxazoline (3a) [ 3-[(4S)-4-Benzyl-4,5-dihydro-1,3-oxazol-2-yl] propanenitrile] was tested to detect some biological activities. This compound was studied in vitro given the various types of pharmacological properties characterizing these compounds such as antioxidant, antimicrobial and analgesic activities. The antioxidant activity and mechanism of (3a) were identified using various in vitro antioxidant assays including 1,1-diphenyl-2-picryl-hydrazyl (DPPH•), and superoxide anion radicals (O2(• -)) scavenging activity. In addition, compared to Quercetin, the tested synthetic product reveals a relatively-strong antiradical activity towards the DPPH (activity percentage of 81.22%) free radicals and significantly decreased the reactive oxygen species such as (O2(.-)) formation evaluated by the non-enzymatic (Nitroblue tetrazolium/riboflavine) and the enzymatic (xanthine/xanthine oxidase) systems. Related activity values were, respectively, 66% and 60.30%. The oxazoline (3a) showed a high ability to reduce the O2(.-) generation and proved to be a very potent radical scavenger. On the other hand, the analgesic property of the 3[(4S)-benzyl-4,5-dihydro-1,3-oxazol-2-yl] propanenitrile (3a) was demonstrated. The subcutaneous administration of (3a) produced a significant reduction in the number of abdominal constrictions amounting to 73.81% in the acetic acid writhing test in mice. In addition to these advances, the oxazoline (3a) has been investigated as an antimicrobial agent. Our results showed that this molecule exhibited various levels of antibacterial effect against all the tested bacterial strains.
    Chemico-biological interactions 04/2014; DOI:10.1016/j.cbi.2014.04.003 · 2.98 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This work describes the first Pd-catalyzed allylic alkylation of thioamides. Various thioamides were efficiently alpha-allylated in high yields and with excellent selectivity for monoallylation under mild reaction conditions. The process not only provides a facile method for the synthesis of functionalized thioamides, but also presents a useful transformation for synthetically important thioamides.
    Tetrahedron Letters 11/2013; 54(48):6501-6503. DOI:10.1016/j.tetlet.2013.09.081 · 2.39 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A direct method to construct 2-oxazolines and 2-thiazolines from corresponding allylic amides and thioamides is reported. The redox-neutral intramolecular hydrofunctionalization is enabled by a dual catalyst system comprised of the 9-mesityl-N-methyl acridinium tetrafluoroborate and phenyl disulphide and exhibits complete selectivity for the ¬anti-Markovnikov regioisomeric products. The cyclization of allylic thioamides is postulated to operate via a modified mechanism in which oxidation of the thioamide, rather than the alkene, is responsible for the observed reactivity.
    Chemical Science 09/2014; 6(1). DOI:10.1039/C4SC02331E · 8.60 Impact Factor