The enzyme trypanothione reductase (TR), together with its substrate, the glutathione-spermidine conjugate trypanothione, plays an essential role in protecting parasitic trypanosomatids against oxidative stress and is a target for drug design. Here we show that a naturally occurring spermine derivative, the antihypertensive agent kukoamine A [N1N12-bis(dihydrocaffeoyl)-spermine] inhibits TR as a mixed inhibitor (Ki = 1.8 microM, Kii = 13 microM). Kukoamine shows no significant inhibition of human glutathione reductase (Ki > 10 mM) and thus provides a novel selective drug lead. The corresponding N1N8-bis(dihydrocaffeoyl)spermidine derivative was synthesized and acted as a purely competitive inhibitor with Ki = 7.5 microM. A series of mono- and di-acylated spermines and spermidines were synthesized to gain an insight into the effect of polyamine chain length, the nature and position of the acyl substituent and the importance of conformational mobility. These compounds inhibited TR with Ki values ranging from 11 to 607 microM.
A new class of bidentate ligands utilizing a phosphine-aminophosphine structure has been prepared on a ferrocenylethyl backbone in a straightforward and scalable fashion from acetylferrocene. The unique property of the alpha-ferrocenyl carbonium ion that allows the replacement of a variety of "leaving groups" with retention of configuration greatly facilitates the synthesis, and a number of ligands have been prepared by varying the nitrogen and phosphorus substituents on the aminophosphine. These readily prepared phosphinoferrocenylaminophosphines, known as BoPhoz ligands, show surprising hydrolytic and air stability, with no degradation after 3 years open to the air. The rhodium complexes of these ligands show exceedingly high enantioselectivities (generally >95% ee) and activities often in excess of 50,000 catalyst turnovers per hour for the asymmetric hydrogenation of a wide variety of dehydro-alpha-amino acid and itaconic acid derivatives. They also show high activity and good to excellent enantioselectivity for the hydrogenation of a number of alpha-ketoesters.
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