Benzolactone enamides

Figure 3.12 Structures of V-ATPase binding benzolactone enamide natural products.

A1 and concanamycin A—two established V-ATPase inhibitors.163 This observation was confirmed by both in vitro enzyme assays and in vivo activity studies in mutant yeast. These studies indicated that, while the benzolactone enamides were potent V-ATPase inhibitors, a profound selectivity occurred between the mammalian and fungal enzymes. Subsequent studies by De Brabander determined that salicylihalamide A binds irreversibly to the trans-membranous proton-translocating domain via A-acyliminium chemistry.164... 

With analogues of the benzolactone enamides now readily obtained synthetically,170 materials from these studies are now progressing rapidly toward clinical studies. Here, the structure of the natural products identified during... 

The isolation of the benzolactone enamide salicylihalamide A 17101 (Scheme 6.1 Part 2) was guided by the NCI s Drug Discovery Research and Development, Developmental Therapeutics Program screen for differential cytotoxicity, which showed that the Australian sample of Haliclona possessed a unique 60 cell line profile. Nanomolar potency was evident in the melanoma cell lines (GI50 = 7 nM) and a COMPARE analysis of the 60 cell line data indicated vascular ATPase (V-ATPase) activity potential. Further study of this structure class determined that salicylihalamide A is equipotent to the V-ATPase standards bafilomycin A and concanamycin A,273 but unlike these standards, selectively inhibits mammalian V-ATPases. 

Petri, A. F., KUhnert, S. M., Scheufler, F., Maier, M. E. (2003). Application of size-selective macrolactonizations to the synthesis of benzolactone-enamide core structures. Synthesis, 940-955. 

An intramolecular B-alkyl Suzuki coupling has been used to construct the core macrocyclic structure of benzolactone enamide salicylhalamide A [165], Thus, dia-stereoselective hydroboration of acyclic alkenyl iodide 183 with (dppf)PdCl2 cata-lyst/NaOH gave the macrocyclic lactone 184 in 48% yield. Because of the high dilution, a large amount of catalyst (20 mol%) was used. The steric hindrance at the ester group probably retards the cleavage of the lactone under basic conditions (Scheme 3.96). 

One closely related family to resorcinylic macroHdes are the saUcylate enamide macrolides, which are secondary marine metabolites with a 12-membered ring benzolactone and a dienyl enamide side chain. SaHcyhhalamide A (34) is a potent inhibitor of the mammalian vacuolar ATPase and exerts great diSerential cytotoxicity in the National Cancer Institute (NCI) 60 ceU lines [23]. Other members... 

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