Vassilios I. Moutsos

Total Synthesis of Combretastatins D

Targeting the wrong isomer, we achieved a synthesis of two natural combretastatins, thanks to an unusual dehydration mechanism and the original incorrect assignment of the natural product. The key step for both syntheses was the application of a Mitsunobu-type macrolactonization of saturated seco acids (below). The synthetic route is effective, simple, and convergent, and may be useful for the synthesis of related derivatives.

A general synthetic route towards bastadins. Part 2: Synthesis of the western part of bastadins 4–16, and fully functionalized macrocycle of bastadin 12

Abstract A general synthetic route for the construction of the western part of the macrocyclic bastadins 4–16 is presented. The western and the eastern segements were coupled using the imidazolide of the corresponding acid. The bromine at position Y 2 may be added at this advanced step regiospecifically, strengthening the convergence of the presented approach. Finally, the fully functionalized α,ω-aminoacid is cyclized with EDC affording the macrocyclic ring of bastadin-12 in 72% yield (3.5% overall yield).

A general synthetic route towards bastadins. Part 1: Synthesis of the eastern part of bastadins 4–16

Abstract A general synthetic route for the construction of the eastern part of the macrocyclic bastadins 4–16 is presented. The brominated biaryl ethers are synthesized using the iodonium salt method. The synthesis is accomplished within 18 steps in 15.5% overall yield.

Synthetic Bastadins Modify the Activity of Ryanodine Receptors in Cultured Cerebellar Granule Cells

Although the interactions of several natural bastadins with the RyR1 isoform of the ryanodine receptor in sarcoplasmic reticulum has been described, their structure-dependent interference with the RyR2 isoform, mainly expressed in cardiac muscle and brain neurons, has not been studied. In this work, we examined calcium transients induced by natural bastadin 10 and several synthetic bastadins in cultured cerebellar granule cells known to contain RyR2. The fluorescent calcium indicator fluo-3 and confocal microscopy were used to evaluate changes in the intracellular Ca2+ concentration (Cai), and the involvement of ryanodine receptors was assessed using pharmacological tools. Our results demonstrate that apart from the inactive BAST218F6 (a bisdebromo analogue of bastadin 10), synthetic bastadin 5, and synthetic analogues BAST217B, BAST240 and BAST268 (at concentrations >20 µM) increased Cai in a concentration-dependent, ryanodine- and FK-506-sensitive way, with a potency significantly exceeding that of 20 mM caffeine. Moreover, the same active bastadins at a concentration of 5 µM in the presence of ryanodine prevented a thapsigargin-induced increase in Cai. These results indicate that bastadins, acting in a structure-dependent manner, modify the activity of RyR2 in primary neuronal culture and provide new information about structure-related pharmacological properties of bastadins.

Stabilization of microtubules by combretastatin D derivatives

The effect of five derivatives of Combretastatin D on tubulin polymerization was investigated. All of them were found to stabilize microtubules to various degrees. The derivatives bearing polar substituents were found to be the most active.

Contents Vol. 15, 2006–2007

40 Croucher Advanced Study Institute (ASI): Signaling in Cell Growth and Differentiation. Organized by: Department of Biochemistry, The Hong Kong University of Science and Technology