A novel acyclic oligomycin A derivative formed via retro-aldol rearrangement of oligomycin A

Abstract

The antibiotic oligomycin A in the presence of K 2 CO 3 and n-Bu 4 NHSO 4 in chloroform in phase-transfer conditions afforded a novel derivative through the initial retro-aldol fragmentation of the 8,9 bond, followed by further transformation of the intermediate aldehyde. NMR, MS and quantum chemical calculations showed that the novel compound is the acyclic oligomycin A derivative, in which the 8,9 carbon bond is disrupted and two polyfunctional branches are connected with spiroketal moiety in positions C-23 and C-25. The tri-O-acetyl derivative of the novel derivative was prepared. The acyclic oligomycin A derivative retained the ability to induce apoptosis in tumor cells at low micromolar concentrations, whereas its antimicrobial potencies decreased substantially. The derivative virtually lost the inhibitory activity against F 0 F 1 ATP synthasecontaining proteoliposomes, strongly suggesting the existence of the target(s) beyond F 0 F 1 ATP synthase that is important for the antitumor potency of oligomycin A. INTRODUCTIONThe macrolide antibiotic oligomycin A (1) has long been considered a valuable experimental tool for studies of energy metabolism. The major pharmacological activity of 1 is the suppression of oxidative phosphorylation and a decrease of intracellular ATP content due to interaction with the oligomycin-sensitivity-conferring protein component of F 0 F 1 ATP synthase. 1 These effects of 1 are of particular importance for the interference with ATP-dependent outward transport and the reversal of drug-resistant phenotypes in bacterial and mammalian cells. 2,3 Furthermore, growing interest in the mechanisms of energy disbalance in disease, to the most part (but not limited to) of cancer, opened the way to the application of 1 as a potent cytotoxic agent. Design of new compounds based on 1 scaffold is of interest, as F 0 F 1 ATP synthase inhibitors are drug candidates for the treatment of bacterial infections and cancer. 4 Recently, we reported the modifications at the C 7 carbonyl group and the C 2 ¼ C 3 double bond of the antibiotic. 5 Search for rather selective methods of modifications of 1 prompted us to study the behavior of the molecule in the conditions of phase-transfer reactions.

Study on retroaldol degradation products of antibiotic oligomycin A

“…The first product (2) of retroaldol degradation of oligomycin A (1) with the intact lactone bond was obtained when 1 was stirred at room temperature with K 2 CO 3 and n-Bu 4 NHSO 4 in CHCl 3 in phasetransfer conditions. 7 Compound 2 was generated through the initial retroaldol fragmentation of the 8,9 bond. It is worth noting that in this case the retroaldol degradation occurred under mild conditions at room temperature, and the lactone bond was not hydrolyzed (Figure 1).…”

“…Recently, we have prepared a series of oligomycin derivatives modified at the macrolactone ring, 4,5 at the side chain (at C33), 6 and also that with the open macrolactone ring. 7 Studies of structure-activity relationships for the model bacterial strain ATCC-19609, supersensitive to oligomycin, and cancer cells K-562 and HCT-116 permitted to suggest the existence of the target(s) beyond F 0 F 1 -ATP synthase that is important for the antitumor potency of oligomycin A. A part of the oligomycin A structure C5-C13 represents a highly reactive moiety containing several b-hydroxy ketone moieties capable of retroaldol degradation in relatively mild conditions.…”

High-Throughput Screen of Microbial Metabolites Identifies F1FO ATP Synthase Inhibitors as New Leads for Naegleria fowleri Infection

“…There are six different types of oligomycins, A, B, C, D, E, F, based on the R groups attached to the macrolide ring and sugar . Of these, oligomycin A has been studied extensively and limited structure–activity relationship studies were conducted to develop oligomycin A derivatives that can overcome the limitations of oligomycin. − Oligomycin D, on the other hand, was studied in a limited capacity, and it exhibited lower toxicity than oligomycins A, B, and C when administered intraperitoneally (i.p.) in mice.…”

Acadesine Triggers Non-apoptotic Death in Tumor Cells

“…On the day when the experiment was supposed to take place, dilutions of the sample in the culture medium were prepared. The MTT assay, staining with propidium iodide and Annexin V conjugated to fluorescein isothiocyanate (FITC ), determination of the cell cycle by flow cytofluorometry, and electrophoretic analysis of the integrity of genomic DNA were used to assess acadesine cytotoxicity [15, 16]. An apoptosis inductor, alkyl cationic glycerolipid rac- N- {4-[(2-ethoxy-3-octadecyloxy)prop-1-yloxycarbonyl] butyl}-N ’ -methylimidazolium iodide, was used as the control compound in individual experiments [17].…”