Optimization and Mechanistic Studies of Psammaplin A Type Antibacterial Agents Active against Methicillin-ResistantStaphylococcus aureus (MRSA)

Abstract

As described in the preceding article, utilizing a novel combinatorial disulfide exchange strategy, a library of psammaplin A (1) analogues was constructed and screened for antibacterial activity leading to the identification of a collection of diverse lead compounds. These combinatorial leads were subsequently refined, through parallel synthesis, to afford a series of highly potent antibacterial agents (e.g. 17, 57, 58, 69, and 70), some possessing greater than 50-fold higher activities than the natural product. Evaluation of the selectivity and serum binding properties of some of the most promising compounds and preliminary studies directed at deciphering the mechanism of action of this novel class of antibacterial agents are also included.

Epigenetic profiling of the antitumor natural product psammaplin A and its analogues

“…Psammaplin A 1 is the prototype of a collection of metabolites isolated from sponges 1 that are biosynthesized by linear connections of (bromo)tyrosines and modified cysteines. 12 Their biological activities, common to most of the bromotyrosine/cysteine constructs, range from antimicrobial 54 to anticancer. 1,6 The inhibi-tion of several enzymes that impact different stages on the onset and progression of cancer such as topoisomerase II (growth), 14 the zinc-dependent metalloproteinase aminopeptidase N (APN, tumor cell invasion or angiogenesis), 21 HDAC and DNMT (chromatin remodeling), 3 among others, likely conspire to account for the reported anticancer activities of PsA in several cancer cell lines and in the A549 lung xenograft mouse model.…”

“…All previous synthetic approaches to 1 have focused on the final construction of the dimeric disulfide structure by condensation of the corresponding carboxylic acid with the symmetrical diamine cystamine. Both Hoshino et al 53 and Nicolaou et al 54,55 installed the oxime function after the synthesis of the corresponding pyruvic acid derived from L-tyrosine, in a sequence that afforded 1 in moderate overall yields. Nicolaou then screened in antibacterial assays a 3828-membered library of heterodimeric psammaplin A analogues 15 obtained from symmetrical precursors by combinatorial scrambling via catalytically-induced disulfide exchange reactions.…”

Comparison of the Full Catalytic Cycle of Hydroformylation Mediated by Mono‐ and Bis‐Ligated Triphenylphosphine–Rhodium Complexes by Using DFT Calculations

“…3‐Phenylsulfanylpropan‐1‐amine (3b): 17 To a suspension of NaH [65 % in mineral oil, 4.51 g, 120 mmol, washed with anhydrous hexane (3 × 25 mL)] in anhydrous DMF (30 mL) was slowly added a solution of phthalimide (14.71 g, 100 mmol) in anhydrous DMF (95 mL) at 0 °C under an argon atmosphere. The reaction mixture was stirred for 1 h until the generation of hydrogen gas ceased, then a solution of 1‐bromo‐3‐phenylsulfanylpropane (27.74 g, 120 mmol) in anhydrous DMF (125 mL) was slowly added.…”

Natural Products from Tongan Marine Organisms

“…Compound 15 is considered to be the first isolated natural product containing both oxime and disulfide moieties. Psammaplin A ( 15 ) inhibits the activities of several key enzymes in prokaryotic and eukaryotic systems, including those involved in epigenetic control of gene expression, DNA replication, angiogenesis, microbial detoxification, and tumor cell growth [ 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. For this reason, psammaplin A ( 15 ) has become a major research focus for chemists and pharmacologists and has been proposed as a natural prodrug [ 55 ].…”