Stereochemical variations on the colchicine motif. Part 2.1 Unexpected tetracyclic isoxazole derivatives

Abstract

Attempts to expand the colchicine B-ring in 7-oxodeacetamidothiocolchicine 1 by a Beckmann-type rearrangement lead to unexpected tetracyclic isoxazole derivatives 2 and 3. The syntheses, crystal and solution structures, conformational interconversions and binding properties to tubulin are reported. The molecules exist as mixtures of two enantiomeric conformations due to hindered rotation around the A and C rings, which are twisted by dihedral angles of 62° (1) and 46° (2) in the crystal. Solid, solution and gas phase (according to MM2) structures are compared. Dynamic 1H NMR analyses give the following thermodynamic parameters for the rotation around the A–C pivot bond: (1) ωG‡381K = 77.4; (2) ωG‡300K = 60.7; ωH‡ = 55.6 ± 1.6 kJ mol-1; ωS‡ = -16.7 ± 15 J mol-1 K-1; (3) ωG‡298K = 60.1, ωH‡ = 59.9 ± 2.0 J mol-1 and ωS‡ = -0.7 ± 15 J mol-1 K-1. The drugs 1 and 2 depolymerize microtubules by binding to tubulin according to both in vitro and in vivo studies, but 1 is considerably more active than 2. Compound 3 does not seem to bind notably to tubulin.