An efficient synthesis of C-1 derivatives of 7-deoxypancratistatin is reported. The key steps include the following: selective opening of an epoxide with aluminum acetylide in the presence of an aziridine; solid-state silica-gel-catalyzed opening of an aziridine; oxidative cleavage of a phenanthrene core and its recyclization to phenanthridone to provide the key C-1 aldehyde 22. The conversion of this aldehyde to C-1 acetoxymethyl and C-1 hydroxymethyl derivatives is described along with the evaluation of their biological activity against several cancer cell lines and in an apoptosis study. The C-1 acetoxymethyl derivative has shown promising activity comparable to that of the natural product. In addition, a total synthesis of trans-dihydrolycoricidine and a formal total synthesis of 7-deoxypancratistatin are reported from aldehyde 22. Detailed experimental and spectral data are provided for all new compounds.thudlicky@brocku.ca .
A series of benzoate esters (methyl, ethyl, n-Pr, i-Pr, n-Bu, t-Bu, allyl, and propargyl) were subjected to enzymatic dihydroxylation by E. coli JM 109(pDTG 601) strain in a whole-cell fermentation. The cis-cyclohexadienediols were obtained in yields of approximately 1g/L except for n-propyl- and i-propyl benzoate which were found to be poor substrates. n-Butyl and t-butyl benzoates were not oxidized at all. The absolute stereochemistry for all metabolites was determined by comparison with a standard prepared from (1S-cis)-3-bromo-3,5-cyclohexadiene-1,2-diol, whose absolute configuration is well established. The free diols were found to be quite stable compared to other cis-dihydrodiols of this type, however, their acetonides underwent a dimerization via a regio- and stereoselective Diels-Alder cycloaddition. The diol derived from ethyl benzoate was subjected to a stereo- and regioselective inverse electron demand Diels-Alder cycloadditions with several dienophiles. The new adducts were completely characterized. The hetero-Diels-Alder reaction of this diol with an acyl nitroso dienophile yielded regio- and stereoselectively a bicyclic oxazine, which upon reduction provided a useful derivative of amino shikimate that can be exploited in an approach to oseltamivir (Tamiflu) and other amino cyclitols. The diol was also converted to carba-alpha-L-galactopyranose to demonstrate its potential utility as a source of pseudo sugars. Experimental and spectral data are provided for all new compounds.
Solid-state silica-gel-catalyzed opening of aziridine 6 provided phenanthrene 7, whose oxidative cleavage, recyclization, and further elaboration furnished the C-1 aldehyde and carboxylic acid derivatives of 7-deoxypancratistatin for potential analogue synthesis.
The natural compound pancratistatin (PST) is a non-genotoxic inducer of apoptosis in a variety of cancers. It exhibits cancer selectivity as non-cancerous cells are markedly less sensitive to PST. Nonetheless, PST is not readily synthesized and is present in very low quantities in its natural source to be applied clinically. We have previously synthesized and evaluated several synthetic analogues of 7-deoxypancratistatin, and found that JC-TH-acetate-4 (JCTH-4), a C-1 acetoxymethyl analogue, possessed similar apoptosis inducing activity compared to PST. In this study, notoriously chemoresistant osteosarcoma (OS) cells (Saos-2, U-2 OS) were substantially susceptible to JCTH-4-induced apoptosis through mitochondrial targeting; JCTH-4 induced collapse of mitochondrial membrane potential (MMP), increased reactive oxygen species (ROS) production in isolated mitochondria, and caused release of apoptosis inducing factor (AIF) and endonuclease G (EndoG) from isolated mitochondria. Furthermore, JCTH-4 selectively induced autophagy in OS cells. Additionally, we investigated the combinatory effect of JCTH-4 with the natural compound curcumin (CC), a compound found in turmeric spice, previously shown to possess antiproliferative properties. CC alone had no observable effect on Saos-2 and U-2 OS cells. However, when present with JCTH-4, CC was able to enhance the cytotoxicity of JCTH-4 selectively in OS cells. Such cytotoxicity by JCTH-4 alone and in combination with CC was not observed in normal human osteoblasts (HOb) and normal human fetal fibroblasts (NFF). Therefore, this report illustrates a new window in combination therapy, utilizing a novel synthetic analogue of PST with the natural compound CC, for the treatment of OS.
Emulsion stability plays a crucial role for mass transfer and downstream processing in organic-aqueous bioprocesses based on whole microbial cells. In this study, emulsion stability dynamics and the factors determining them during two-liquid phase biotransformation were investigated for stereoselective styrene epoxidation catalyzed by recombinant Escherichia coli. Upon organic phase addition, emulsion stability rapidly increased correlating with a loss of solubilized protein from the aqueous cultivation broth and the emergence of a hydrophobic cell fraction associated with the organic-aqueous interface. A novel phase inversion-based method was developed to isolate and analyze cellular material from the interface. In cell-free experiments, a similar loss of aqueous protein did not correlate with high emulsion stability, indicating that the observed particle-based emulsions arise from a convergence of factors related to cell density, protein adsorption, and bioreactor conditions. During styrene epoxidation, emulsion destabilization occurred correlating with product-induced cell toxification. For biphasic whole-cell biotransformations, this study indicates that control of aqueous protein concentrations and selective toxification of cells enables emulsion destabilization and emphasizes that biological factors and related dynamics must be considered in the design and modeling of respective upstream and especially downstream processes.
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