Biotransformation of colchicinoids into their corresponding 3-O-glucosyl derivatives by selected strains of Bacillus megaterium.

Natural colchicinoids and their semisynthetic derivatives are important active ingredients for pharmaceutical applications. Thiocolchicoside (3-demethoxy-3-glucosyloxythiocolchicine) is used in several countries as standard therapy for the treatment of diseases of the muscle-skeletal system, due to its potent antiinflammatory and myorelaxant properties. Manufacturing of thiocolchicoside requires a key step, the regioselective demethylation and glucosylation of chemically derivative thiocolchicine. High selectivity and efficiency of this transformation cannot be achieved in a satisfactory way with a chemical approach. In particular, the chemical demethylation, a part from requiring toxic and aggressive reagents, generates a complex mixture of products with no industrial usefulness. We report herein an efficient, direct and green biotransformation of thiocolchicine into thiocolchicoside, performed by a specific strain of Bacillus megaterium. The same process, with minor modifications, can be used to convert the by-product 3-O-demethyl-thiocolchicine into thiocolchicoside. In addition, we describe the B. megaterium strain selection process and the best conditions for this effective double biotransformation. The final product has a pharmaceutical quality, and the process has been industrialised.

Highly diastereoselective synthesis of enantiopure naphthylaminoalcohols with analgesic properties.

The diastereoselective synthesis via Grignard reaction of enantiopure analgesic naphthylaminoalcohols has been performed. The chiral racemic key intermediate 3-dimethylamino-2-methyl-1-(naphthalen-2-yl)propan-1-one and enantiomers were prepared and transformed into the desired compounds by addition of the organometallic reagent. The chemical characterization of all diastereoisomers was accomplished by 1H NMR and HPLC analyses and the absolute configuration assigned by CD spectroscopy. The in vitro and in vivo profile has also been evaluated.