Simple One-Pot Synthesis of Disulfide Fragments for Use in Disulfide-Exchange Screening

Disulfide exchange screening is a method for evaluating the binding of small molecule fragments to proteins that have at least one accessible cysteine. While operationally simple, it does require a large library of small fragment molecules bearing disulfide-containing side chains. These specialized fragments are not available commercially and this has limited the adoption of the method. We report here a convenient one-pot procedure that enables facile preparation of disulfide screening fragments while also producing less of an environmental impact. The new synthetic method involves the initial formation of symmetric disulfides, followed by a disulfide exchange reaction in which the symmetrical dimer is converted into the final screening fragment by introduction of a solubilizing ‘cap’. The method is amenable to parallel synthetic methods and can be carried out in air without the need for the specialized equipment typically required for performing organic synthesis

Simple One-Pot Synthesis of Disulfide Fragments for Use in Disulfide-Exchange Screening

Disulfide exchange screening is a method for evaluating the binding of small molecule fragments to proteins that have at least one accessible cysteine. While operationally simple, it does require a large library of small fragment molecules bearing disulfide-containing side chains. These specialized fragments are not available commercially and this has limited the adoption of the method. We report here a convenient one-pot procedure that enables facile preparation of disulfide screening fragments while also producing less of an environmental impact. The new synthetic method involves the initial formation of symmetric disulfides, followed by a disulfide exchange reaction in which the symmetrical dimer is converted into the final screening fragment by introduction of a solubilizing ‘cap’. The method is amenable to parallel synthetic methods and can be carried out in air without the need for the specialized equipment typically required for performing organic synthesis

Toward Understanding How the Lactone Moiety of Discodermolide Affects Activity

A series of simplified discodermolide analogues have been designed and synthesized in an attempt to understand the role of the lactone ring. These synthetic efforts have led to an unsubstituted butyrolactone 9 being generated, which shows improved activity over the natural product

Structure−Activity Relationships of 9-Substituted-9-Dihydroerythromycin-Based Motilin Agonists: Optimizing for Potency and Safety

A series of 9-dihydro-9-acetamido-N-desmethyl-N-isopropyl erythromycin A analogues and related derivatives was generated as motilin agonists. The compounds were optimized for potency while showing both minimal antibacterial activity and hERG inhibition. As the substituent on the amide was increased in lipophilicity the potency and hERG inhibition increased, while polar groups lowered potency, without significantly impacting hERG inhibition. The N-methyl acetamide 7a showed the optimal in vitro profile and was probed further by varying the chain length to the macrocycle as well as changing the macrocycle scaffold. 7a remained the compound with the best in vitro properties

Design, Synthesis, and Evaluation of Analogues of (+)-14-Normethyldiscodermolide

The design, syntheses, and biological evaluation of nine totally synthetic analogues of the microtubule-stabilizing agent (+)-14-normethyldiscodermolide (2) are reported. Simplification at the C(21)−C(24) terminal diene and at the C(1)−C(5) lactone moieties reveals significant structure−activity relationships

Design, Synthesis, and Evaluation of Carbamate-Substituted Analogues of (+)-Discodermolide

The design, syntheses, and biological evaluation of 22 totally synthetic analogues of the potent microtubule-stabilizing agent (+)-discodermolide (1) have been achieved. Structure−activity relationships of the C(19) carbamate were defined, exploiting two synthetically simplified scaffolds, as well as the parent (+)-discodermolide framework