Full details of the total synthesis of phostriecin (2), the assignment of its relative and absolute stereochemistry, and the resultant structural reassignment of the natural product previously represented as sultriecin (1), a phosphate versus sulfate monoester, are detailed. Studies with authentic material confirmed that phostriecin, but not sultriecin, is an effective and selective inhibitor of protein phosphatase 2A (PP2A) defining a mechanism of action responsible for its antitumor activity. The extension of the studies to the synthesis and evaluation of a series of key synthetic analogues is disclosed that highlights the importance of the natural product phosphate monoester (vs sulfate or free alcohol, both inactive and >250-fold), the α,β-unsaturated lactone (12-fold), and the hydrophobic Z,Z,E-triene tail (C12-C22, ca. 200-fold) including the unique importance of its unsaturation (50-fold, and no longer PP2A selective).

2010-02-24·Journal of the American Chemical Society1区 · 化学

Total Synthesis, Assignment of the Relative and Absolute Stereochemistry, and Structural Reassignment of Phostriecin (aka Sultriecin)

1区 · 化学

Article

作者: Burke, Christopher P. ; Haq, Nadia ; Boger, Dale L.

A total synthesis of phostriecin (2), previously known as sultriecin (1), its structural reassignment as a phosphate versus sulfate monoester, and the assignment of its relative and absolute stereochemistry are disclosed herein. Key elements of the work, which provided first the originally assigned sulfate monoester 1 and then the reassigned and renamed phosphate monoester 2, relied on diagnostic (1)H NMR spectroscopic properties of the natural product for the assignment of relative and absolute stereochemistry as well as the subsequent structural reassignment, and a convergent asymmetric total synthesis to provide the unequivocal authentic materials. Key steps of the synthetic approach include a Brown allylation for diastereoselective introduction of the C9 stereochemistry, an asymmetric CBS reduction to establish the lactone C5-stereochemistry, diastereoselective oxidative ring expansion of an alpha-hydroxyfuran to access the pyran lactone precursor, and single-step installation of the sensitive Z,Z,E-triene unit through a chelation-controlled cuprate addition with installation of the C11 stereochemistry. The approach allows ready access to analogues that can now be used to probe important structural features required for protein phosphatase 2A inhibition, the mechanism of action defined herein.

2008-06-01·Experimental oncology

Promotive effects of hyperthermia on the cytostatic activity to Ehrlich ascites tumor cells by diverse delta-alkyllactones.

Article

作者: Yoshimura, N ; Miwa, N ; Asada, R ; Kageyama, K ; Tanaka, H

AIMTo evaluate promotive effects of hyperthermia on antitumor activity of new delta-alkyllactones (DALs) of low molecular weight (184-254 Da), chemically synthesized, which are different from natural macrocyclic lactones of high molecular weight (348-439 Da), such as camptothecin and sultriecin.METHODSA suspension of Ehrlich ascites tumor (EAT) cells was mixed with a DAL in a glass tube, heated at 37 or 42 degrees C for 30 min in a water bath, and cultured at 37 degrees C for 20 or 72 h. Cell viability was measured by the mitochondrial dehydrogenase- based WST-1 assay. DALs incorporated into EAT cells was extracted and measured by gas-liquid chromatography.RESULTSThe reduction of cell viability by DALs was markedly enhanced upon the treatment at 42 degrees C compared to that at 37 degrees C. At 37 degrees C, delta-hexadecalactone (DH16:0) and delta-tetradecalactone (DTe14:0) displayed cytostatic activity (at 100 microM survival level: 20.7%, 66.1%; at 50 microM--41.2%, 82.4%, respectively). Their activity was more marked at 42 degrees C (at 100 microM 10.6%, 27.6%; at 50 microM 30.6, 37.5%, ibid). The other DALs, delta-undecalactone (DU11:0), delta-dodecalactone (DD12:0), and delta-tridecanolactone (DTr13:0) were almost ineffective. Evaluation of survival rate in the cells treated for 30 min by DALs with the next culturing of EAT cells for 72 h resulted in the enhanced carcinostatic activity of DH16:0 and DTe14:0 even at concentrations as low as 25 microM at either 37 degrees C (18.5%, 78.5%, ibid) or 42 degrees C (5.0%, 42.0%, ibid), but the others exhibited slight activity or none. DH16:0 was effective at either 37 degrees C (36.0%) or 42 degrees C (23.0%) even at a lower dose of 10 microM. At the same time only the most cytostatic DH16:0 was incorporated into EAT cells and the rate of incorporation was more at 42 degrees C than at 37 degrees C.CONCLUSIONDelta-hexadecanolactone (DH16:0) exhibited the most cytostatic effect that was significantly enhanced by hyperthermia. It allows to consider it as a potent antitumor agent, especially in combination with hyperthermia.

100 项与 Sultriecin 相关的药物交易

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