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At least 667 records · Page 37Linked to original sources
PubMed2002

Spongistatin synthetic studies. An efficient, second-generation construction of an advanced ABCD intermediate.

[reaction: see text] A short, efficient, and stereocontrolled synthesis of (-)-4, an advanced ABCD subunit of the spongistatins, has been achieved. Central to the synthetic strategy is the multicomponent linchpin union of silyl dithianes with epoxides to access both the AB and CD fragments. Fragment coupling was then achieved via an efficient stereoselective aldol reaction. The linear sequence required 22 steps and proceeded in 4.0% overall yield.

Animals↗
PubMed2002

Diastereoselective synthesis of the C(17)-C(28) fragment (the C-D spiroketal unit) of spongistatin 1 (altohyrtin A) via a kinetically controlled iodo-spiroketalization reaction.

[reaction: see text] A convergent and stereocontrolled synthesis of spiroketal 15 corresponding to the C-D fragment of spongistatin 1 has been accomplished by a sequence utilizing a kinetically controlled intramolecular iodo-spiroketalization of glycal 2, which in turn was synthesized via a ring-closing metathesis reaction.

Ethers, Cyclic↗
PubMed2002

Synthesis of the C(2)-C(13) fragment (the A-B spiroketal unit) of spongistatin 1 (altohyrtin A): use of a common intermediate for the synthesis of both spongistatin spiroketals.

[reaction: see text] A convergent synthesis of 14 corresponding to the A-B spiroketal core of spongistatin 1 has been accomplished via an iodo-spiroketalization reaction of glycal 9, which was synthesized in three steps from a late-stage intermediate used in our synthesis of the C-D spiroketal fragment of spongistatin 1. Elaboration of 14 to the A-B spiroketal 15 was accomplished in three steps.

Ethers, Cyclic↗
PubMed2003

Total synthesis of (+)-spongistatin 1. An effective second-generation construction of an advanced EF Wittig salt, fragment union, and final elaboration.

A stereocontrolled, total synthesis of (+)-spongistatin 1 (1) has been achieved. Union of a second-generation EF Wittig salt (+)-3 with the advanced ABCD aldehyde (-)-4, followed by regioselective macrolactonization and global deprotection afforded (+)-spongistatin 1 (1). The longest linear sequence, 29 steps, proceeded in 0.5% overall yield.

Aldehydes↗
PubMed2004

Spongistatin synthetic studies. evolution of a scalable synthesis for the EF fragment of (+)-Spongistatin 1 exploiting a Petasis-Ferrier union/rearrangement tactic.

[structure: see text] An efficient, stereocontrolled, and scalable second-generation synthesis of (+)-3, an advanced EF subtarget for the total synthesis of (+)-spongistatin 1, has been achieved. Highlights of the strategy include preparation of the F-ring pyran via a Petasis-Ferrier union/rearrangement sequence and installation of the chlorodiene side chain employing a cyanohydrin alkylation. The longest linear sequence, 26 steps, proceeds in 8.3% overall yield.

Animals↗
PubMed1999

A method for constructing the C44-C51 side chain of altohyrtin C.

[formula: see text] A method to construct the C44-C51 side chain of altohyrtin C has been developed and applied to a model aldehyde derived from D-glucose. The approach relies on a Wittig reaction to couple the side chain to an aldehyde and utilizes an allylic diazene rearrangement to place the C45 double bond in the correct position.

Aldehydes↗
PubMed1991

Effects of palytoxin on guinea pig tracheal strips.

The effects of palytoxin (PTX) on airway smooth muscle were investigated in opened rings of guinea pig trachea. Concentrations of PTX from 10 pM to 100 nM caused contractions of tracheal strips, with maximal contractions approximately 80% of those in response to 120 mM potassium. Tension increased to its maximum in approximately 5 min with 100 nM PTX, then decreased to or near resting tension over the next 60 min. Contractions were larger when the epithelium was removed. Exposure to high (100 nM) concentrations of PTX markedly reduced subsequent contractions to PTX but had less effect on potassium-induced contractions. In zero-calcium solution the rate of contraction was slowed but the maximal contraction was not reduced. The addition of a calcium channel blocker (verapamil) markedly reduced the contractions and a calcium chelator (EGTA) abolished them. Contractions to PTX in zero-calcium media suggested that tracheal cartilage was serving as a calcium source, as it has been previously reported to do. Potassium removal and sodium reduction also greatly reduced contractions. These data are consistent with other observations suggesting that PTX may form pores through which sodium leaks into the cell. PTX was also found to differ from ouabain in its mode of action.

Acrylamides↗
PubMed2005

Oocyte-based screening of cytokinesis inhibitors and identification of pectenotoxin-2 that induces Bim/Bax-mediated apoptosis in p53-deficient tumors.

In this study, we demonstrate that a loss of p53 sensitizes tumor cells to actin damage. Using a novel oocyte-based screening system, we identified natural compounds that inhibit cytokinesis. Among these, pectenotoxin-2 (PTX-2), which was first identified as a cytotoxic entity in marine sponges, which depolymerizes actin filaments, was found to be highly effective and more potent to activate an intrinsic pathway of apoptosis in p53-deficient tumor cells compared to those with functional p53 both in vitro and in vivo. Other agents that depolymerize or knot actin filaments were also found to be toxic to p53-deficient tumors. In p53-deficient cells, PTX-2 triggers apoptosis through mitochondrial dysfunction, and this is followed by the release of proapoptotic factors and caspase activation. Furthermore, we observed Bax activation and Bim induction only in p53-deficient cells after PTX-2 treatment. RNA interference of either Bim or Bax resulted in the inhibition of caspases and apoptosis induced by PTX-2. However, the small interfering RNAs (SiRNA) of Bim blocked a conformational change of Bax, but Bax SiRNA did not affect Bim expression. Therefore, these results suggest that Bim triggers apoptosis by activating Bax in p53-deficient tumors upon actin damage, and that actin inhibitors may be potent chemotherapeutic agents against p53-deficient tumors.

Actins↗
PubMed2004

A two-directional synthesis of the C58-C71 fragment of palytoxin.

A two directional approach, in which asymmetric dihydroxylation and reduction reactions were used to control absolute configuration, was exploited in the preparation of a C(2)-symmetrical dipyranone. The homotopic dihydropyran (DHP) rings of this precursor were differentiated statistically using by a Prevost reaction and further functionalisation. A second Prevost reaction was used to functionalise the other DHP; global deprotection and peracetylation gave a protected version of the C(58)-C(71) fragment of palytoxin. Methods which might be of value in future synthetic work were developed for the stereoselective functionalisation of THP rings similar to those found in this fragment.

Acetylation↗
PubMed2005

The stereocontrolled total synthesis of altohyrtin A/spongistatin 1: the AB-spiroacetal segment.

The convergent synthesis of the C1-C15 AB-spiroacetal subunit of altohyrtin A/spongistatin 1 is described. This highly stereocontrolled synthesis relies on matched boron aldol reactions of chiral methyl ketones, under Ipc(2)BCl mediation, to establish the C5, C9 and C11 stereocentres, and formation of the desired thermodynamic spiroacetal under acidic conditions. The scalable synthetic sequence developed provided access to multi-gram quantities of , thus enabling the successful completion of the total synthesis of altohyrtin A/spongistatin 1, as reported in Part 4.

Acetals↗
PubMed2005

The stereocontrolled total synthesis of altohyrtin A/spongistatin 1: the CD-spiroacetal segment.

Stereocontrolled syntheses of the C16-C28 CD-spiroacetal subunit of altohyrtin A/spongistatin 1 , relying on kinetic and thermodynamic control of the spiroacetal formation, are described. The kinetic control approach resulted in a slight preference (60 : 40) for the desired spiroacetal isomer. The thermodynamic approach allowed ready access to the desired spiroacetal by acid-promoted equilibration, chromatographic separation of the C23 epimers and resubjection of the undesired isomer to the equilibration conditions. This scalable synthetic sequence provided multi-gram quantities of , thus enabling the successful completion of the total synthesis of altohyrtin A/spongistatin 1, as reported in Part 4 of this series.

Acetals↗
PubMed2005

The stereocontrolled total synthesis of altohyrtin A/spongistatin 1: the southern hemisphere EF segment.

The fully functionalised C29-C51 southern hemisphere of altohyrtin A/spongistatin 1 , incorporating the E- and F-ring tetrahydropyran rings and the unsaturated side chain, has been synthesised in a highly convergent and stereocontrolled manner. Key steps in the synthesis of this phosphonium salt include four highly diastereoselective, substrate-controlled, boron aldol reactions to establish key C-C bonds and accompanying stereocentres, where the introduction of the chlorodiene side chain and the C47 hydroxyl-bearing centre were realised by exploiting remote stereoinduction from the F-ring tetrahydropyran.

Acetals↗
PubMed2005

The stereocontrolled total synthesis of altohyrtin A/spongistatin 1: fragment couplings, completion of the synthesis, analogue generation and biological evaluation.

The antimitotic marine macrolide altohyrtin A/spongistatin 1 has been synthesised in a highly convergent and stereocontrolled manner, thus contributing to the replenishment of the largely exhausted material from the initial isolation work. Coupling of the AB- and CD-spiroacetal subunits by a stereoselective aldol reaction was achieved by using either a lithium (67 : 33 dr) or boron enolate (90 : 10 dr). A highly (Z)-selective Wittig coupling was used to unite the northern hemisphere aldehyde with the southern hemisphere phosphonium salt . Deprotection and subsequent regioselective macrolactonisation on a triol seco-acid completed the synthesis of altohyrtin A. Two structural analogues were also prepared and evaluated as growth inhibitory agents against a range of human tumour cell lines, including Taxol-resistant strains, alongside altohyrtin A and paclitaxel (Taxol), revealing that dehydration in the E-ring is tolerated and results in enhanced cytotoxicity (at the low picomolar level), whereas the presence of the full C44-C51 side-chain appears to be crucial for biological activity.

Acetals↗