This study was aimed at assessing the potential use of emulsion electrospinning to prepare core-shell structured ultrafine fibers as carriers for therapeutic proteins. It focused on the effect of fiber structure on the release profiles and structural stability of encapsulated proteins. In the case of bovine serum albumin (BSA) which was selected as a model protein, poly-DL-lactide ultrafine fibers prepared by emulsion electrospinning using a lower volume ratio of aqueous to organic phase, showed higher structural integrity of core-shell fiber as assessed by laser confocal scanning microscope (LCSM). This structural property can reduce the initial drug burst and improved the ability of the device to provide sustained therapeutic action. Fickian release was observed for the initial 60% of protein release. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and size exclusion chromatography (SEC) were used to assess the primary structure of BSA. These studies indicated that ultra-sonication caused denaturation of protein molecules, while the core-shell structured electrospun fibers protected the structural integrity of encapsulated protein during incubation in the medium. Fourier transform infrared (FTIR) analyses showed that the electrospinning process had much less effect on the secondary structure of protein than ultra-sonication. In vitro degradation study showed that the protein release from fibers led to more significant mass loss, higher molecular weight reduction and larger molecular weight distribution of the matrix residues, compared with fibers without protein inoculation. These data suggest that emulsion electrospinning can provide a useful core-sheath structure, which may serve as a promising scaffold for sustainable, controllable, and effective release of bioactive proteins in tissue engineering and other applications.
The Republic of Maldives' black marine sponge Hyrtios erecta has been found to contain three cancer cell-line inhibitory pentacyclic sesterterpenes designated sesterstatins 1-3 (2-4). One of the sesterterpenes, sesterstatin 2, specifically inhibited the Gram-positive opportunist Staphylococcus aureus. All three of the P-388 lymphocytic-leukemia-active (ED50 0.46 to 4.3 micrograms/mL) sesterstatins were obtained in trace quantities (3.0 x 10-7 to 5.4 x 10-7% yields) and represent structural variations on the more usual scalarin-type porifera sesterterpenes. The structures were elucidated by highfield (500 MHz) 2D NMR techniques augmented by HRMS results.
Total synthesis of the eighteen-membered ring cyclodepsipeptide believed to be respirantin (1b) has been achieved. The key step in the synthesis is an intramolecular transesterification of the β-ketoester alcohol 6 to afford the protected macrocycle 5. The synthetic product was shown to be identical to a natural product presumed to be respirantin (1b) and the absolute stereochemistry of 6 of the 7 asymmetric centers of cyclodepsipeptide 1b was unequivocally established. Respirantin (1b) was found to be a remarkable inhibitor of cancer cell growth and related to the antimycin family of antibiotics.In the preceding report, we summarized the isolation and structures of three exceptional cancer cell growth inhibitory cyclodepsipeptides from the bacterium Kitasatospora sp. found on the Beaufort Sea coast of the Alaska North Slope. 1a One of these corresponded to a unique structure and was designated kitastatin 1 (1a) (Figure 1) while the other two cyclodepsipeptides on the basis of reported NMR assignments were presumed to be respirantin (1b) and a valeryl modification (1c). 1b Respirantin (1b) was first reported in 1993 1b as an insecticidal antibiotic isolated from a Streptomyces species found in a soil sample from Japan and shown to have cyclodepsipeptide structure 1b based on analysis of its spectroscopic properties. The stereochemistry was not determined. Kitastatin 1 (1a) and respirantin (1b) contain a blastmycic acid unit also found in the antimycins 2 such as 2 and neoantimycin 3 . An unusual structural feature is the β-ketoester linkage (carbons 6-8) in the 18-membered depsipeptide macrocycle. In order to obtain sufficient material for more extensive biological evaluation as well as overall to determine the stereochemistry and absolute configuration of kitastatin 1 (1a) and respirantin (1b), we undertook research to develop a total synthesis of 1b with flexibility to enable future SAR development. Herein we report the successful results. Results and DiscussionInspection of the kitastatin 1 (1a) and respirantin (1b) macrocycle revealed that they are composed of common amino acids, or α-hydroxycarboxylic acids derived from them, along with the β-ketoester unit. Since the absolute stereochemistry of 1a and 1b was undetermined at the onset of this study, our initial target 1b was selected by assuming the most common Sconfiguration for the constituent amino acids and their presumed α-hydroxy derivatives. Fortunately, that proved to be the correct choice among the 256 possible optical isomers. A retrosynthetic analysis of the ultimately successful route to respirantin (1b) is presented in Scheme 1. Prior antimycin syntheses 2 offered good precedent for appending the protected benzoic acid 3 to amino substituted macrocycles. However other issues that needed to be * To whom correspondence should be addressed. Tel: (480) . E-mail: bpettit@asu.edu. NIH Public AccessAuthor Manuscript J Nat Prod. Author manuscript; available in PMC 2008 December 8. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Autho...
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