Synthetic Studies in Phytochrome Chemistry

An account is given of the author’s several approaches to the synthesis of the parent chromophore of phytochrome (1), a protein-bound linear tetrapyrrole derivative that controls photomorphogenesis in higher plants. These studies culminated in enantioselective syntheses of both (2R)- and (2S)-phytochromobilin (4), as well as several 13C-labeled derivatives designed to probe the site of Z,E-isomerization during photoexcitation. When reacted in vitro, synthetic 2R-4 and recombinant-derived phytochrome apoprotein N-C produced a protein-bound chromophore with identical difference spectra to naturally occurring 1

Optimization of Pyrrolamide Topoisomerase II Inhibitors Toward Identification of an Antibacterial Clinical Candidate (AZD5099)

AZD5099 (compound <b>63</b>) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compound <b>63</b> showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency versus the drug was low, and reports of clinical resistance due to alteration of the target are few. Hence, <b>63</b> could offer a novel treatment for serious issues of resistance to currently used antibacterials