Synthesis, Profiling, and Bioactive Conformation of trans‐Cyclopropyl Epothilones

Abstract

A series of new 3‐deoxy‐C(12),C(13)‐trans‐cyclopropyl‐epothilones have been prepared, bearing benzothiazole, quinoline, thiazol‐5‐ylvinyl, or isoxazol‐3‐ylvinyl side chains. For analogs with fused aromatic side chains, macrocyclic ring‐closure was based on ring‐closing olefin metathesis (RCM) of a precursor incorporating the fully elaborated heavy atom framework of the target structure (including the side chain moiety), while side chain attachment for the thiazole and isoxazole‐containing 16‐desmethyl analogs was performed only after establishment of the macrolactone core. Two approaches were elaborated for a macrocyclic aldehyde as the common precursor for the latter analogs that involved ring‐closure either by RCM or by macrolactonization. Benzothiazole‐ and quinoline‐based analogs were found to be highly potent antiproliferative agents; the two analogs with a thiazol‐5‐ylvinyl or an isoxazol‐3‐ylvinyl side chain likewise showed good antiproliferative activity but were significantly less potent than the parent epothilone A. Surprisingly, the desaturation of the C(10)−C(11) bond in these analogs was associated with a virtually complete loss in antiproliferative activity, which likely reflects a requirement for a ca. 60 ° C(10)−C(11) torsion angle in the tubulin‐bound conformation of 12,13‐trans‐epothilones.

Easy and convenient millimole‐scale synthesis of new, potential biomarkers for gamma‐hydroxybutyric acid (GHB) intake: Feasible for analytical laboratories

“…Fractions containing the target compound were combined, and the solvent was evaporated under reduced pressure. Subsequently, a deprotection step was done in TFA/DCM (20% v/v), which is sufficient for the removal of C‐terminal tert ‐butyl protection group 20 . Deprotection was done overnight, and TLC indicated a quantitative conversion.…”

“…Cleavage of the labile TBDMS‐protecting group was observed in the heated ESI source. The final step was done in TFA/DCM (20% TFA) 20 . Deprotection was performed overnight, and TLC indicated a quantitative conversion.…”

“…Purified GHB‐amino acid precursor ( GHB‐amino acid‐OtBu ) was dissolved in 5 ml TFA/DCM (20% final [v/v]) as previously described in publications 19,20 . The mixture was stirred overnight at room temperature.…”

Synthesis, Microtubule-Binding Affinity, and Antiproliferative Activity of New Epothilone Analogs and of an EGFR-Targeted Epothilone-Peptide Conjugate

“…The elaboration of aldehyde 8 into the epothilone macrocyclic framework in a first step entailed Julia–Kocienski olefination with sulfone 9 ( Scheme 1 ) [ 34 ]. The reaction was best carried out under Barbier conditions in the presence of two equivalents of LiHMDS, which furnished the desired olefin in a 72% yield with ca.…”

“…A solution of LiHMDS (618 mg, 3.969 mmol) in THF (1 mL) was added to a solution of sulfone 9 [ 34 ] (1.07 g, 1.680 mmol) and aldehyde 8 (1.3 g, 2.028 mmol) in THF (5 mL) at −78°C. The mixture was stirred for 1 h at −78 °C and allowed to warm to rt over a period of 1 h. After quenching the reaction with sat.…”