Synthesis of novel, simplified, C-7 substituted eleutheside analogues with potent microtubule-stabilizing activity

The synthesis of a number of novel, simplified, C-7 substituted eleutheside analogues with potent tubulin-assembling and microtubule-stabilizing properties is described, using ring closing metathesis as the key-step for obtaining the 6-10 fused bicyclic ring system. The RCM precursors were synthesized starting from aldehyde 3 [prepared in six steps on a multigram scale from R-(−)-carvone in 30% overall yield] via multiple stereoselective Hafner-Duthaler allyltitanations and/or Brown allylborations. ‘Second generation’ RCM-catalyst 15 gave the desired ring closed ten-membered carbocycles as single Z stereoisomers in good yields. The RCM stereochemical course (100% Z) is likely to reflect thermodynamic control. Molecular mechanics and semi-empirical calculations also show that the Z stereoisomers of these ten-membered carbocycles are consistently more stable than the E. The crucial role of the homoallylic and allylic substituents and of their protecting groups for the efficiency of the RCM reactions is discussed. In particular, we have found that p-methoxyphenyl (PMP) protected allylic alcohols, the products of a stereoselective oxyallylation, are compatible with the RCM reaction and give better yields than the corresponding free allylic alcohols. One of the simplified analogues of the natural product (44, lacking inter alia the C-4/C-7 ether bridge) retains potent microtubule-stabilizing activity. However, the cytotoxicity tests did not parallel the potent tubulin-assembling and microtubule-stabilizing properties: limited cytotoxicity was observed against three common tumor cell lines (human ovarian carcinoma, human colon carcinoma and human leukemia cell lines, IC₅₀ in the μM range), approximately two orders of magnitude less than paclitaxel (IC₅₀ in the nM range). The mechanism of cell cycle arrest induced by compound 44 is similar to that obtained with paclitaxel.     

Direct l-doublet transitions in the 0110 state of cyanogen chloride and cyanogen bromide

Direct l doublet transitions have been observed for the 01¹0 state of the ³⁵Cl¹²C¹⁴N and ³⁷Cl¹²C¹⁴N isotopic species of cyanogen chloride and the ⁷⁹Br¹²C¹⁴N and ⁸¹Br¹²C¹⁴N isotopic species of cyanogen bromide in the frequency range 4–22 GHz. The l-doubling constants (q⁰, q¹, q²) and the asymmetry parameters (ηeQq_z) of the halogen nuclear quadrupole coupling tensors have been derived. The constants q¹ have been calculated form the vibrational force fields of Whiffen for the four cyanogen halides using the formulation of Watson. Agreement with the observed values is found to be 10% or better and for cyanogen fluoride and cyanogen chloride the isotopic shifts in q¹ are also well predicted.     

A calibration curve at 2000 meters (A.S.L.): alpine valleys as field laboratories for teaching environmental monitoring to undergraduate students

High-altitude alpine valleys may be considered as ideal field laboratories for the interdisciplinary teaching of Environmental Sciences to undergraduate students in a Laurea degree, since different typologies of sampling sites (rivers, lakes, glaciers) may be found within walking distance, and students are encouraged to develop cooperative learning activities. Scientific data have been collected by 1st year students at the University of Insubria in Como during a teaching program in Ventina Valley and Caronno Valley near Sondrio (Italy). Analytical and geochemical results will be presented and discussed on the basis of organic deposition and water-rock interactions.     

Quaternionic hyperfunctions on five-dimensional varieties in ℍ2

In this article we introduce a new notion of differential forms to describe the cohomology associated to the sheaf of regular functions in several quaternionic variables. We then use these differential forms to introduce and describe concretely a sheaf of quaternionic hyperfunctions as boundary values of regular functions in two quaternionic variables. We show how these ideas can be generalized to the case of monogenic functions in two vector variables with values in a Clifford algebra.