Investigating the Selectivity of Metalloenzyme Inhibitors

Abstract

The inhibitory activity of a broad group of known metalloenzyme inhibitors against a panel of metalloenzymes was evaluated. Clinically approved inhibitors were selected as well as several other reported metalloprotein inhibitors, in order to represent a broad range of metal binding groups (MBGs), including hydroxamic acid, carboxylate, hydroxypyridinonate, thiol, and N-hydroxyurea functional groups. A panel of metalloenzymes, including carbonic anhydrase (hCAII), several matrix metalloproteinases (MMPs), angiotensin converting enzyme (ACE), histone deacetylase (HDAC-2), and tyrosinase (TY) was selected based on their clinical importance for a range of pathologies. In addition, each inhibitor was evaluated for its ability to remove Fe3+ from holo-transferrin to gauge the ability of the inhibitors to access Fe3+ from a primary transport protein. The results show that the metalloenzyme inhibitors are quite selective for their intended targets, suggesting that despite their ability to bind metal ions, metalloprotein inhibitors are not prone to widespread off-target enzyme inhibition activity.

Efficient synthesis of N-acylbenzotriazoles using tosyl chloride: en route to suberoylanilide hydroxamic acid (SAHA)

“…Reported methods for the synthesis of SAHA utilized suberoyl chloride, 14 suberic acid, 15 and suberic acid monomethyl ester 16 as starting materials. The disadvantages of these methods include low overall yields (15-51%), [14][15][16] tedious chomatographic work-up, 14 and the use of relatively expensive starting materials and reagents. 16 In the present study reaction of suberic acid (4) with equimolar amount of p-toluenesulfonyl chloride and benzotriazole in the presence of TEA gave compound 5 in 95 % yield.…”

“…The disadvantages of these methods include low overall yields (15-51%), [14][15][16] tedious chomatographic work-up, 14 and the use of relatively expensive starting materials and reagents. 16 In the present study reaction of suberic acid (4) with equimolar amount of p-toluenesulfonyl chloride and benzotriazole in the presence of TEA gave compound 5 in 95 % yield. Stirring of 5 with aniline at 25 o C in methylene chloride for 1h affords suberanilic acid 6 in 96 % yield.…”

Angiotensin I-Converting Enzyme (ACE) Inhibitory Activity of Ursolic Acid Isolated from Thymus vulgaris, L.

“…The hydroxy groups of apigenin and the hydroxy groups and/or the carboxy group of rosmarinic acid might bind to the catalytic zinc ion present at the active centre of ACE. These functional groups appear to increase the potency to inhibit ACE (Li et al, 2008;Shukor et al, 2013;Day and Cohen, 2013). From our results and the inhibitory activities of 1 against aromatase and protein tyrosine phosphatase 1B, it appears that the carboxy group at C-17 and/or the hydroxy group at C-3 of 1 is required for ACE inhibition, since these functional groups might bind to the catalytically functional zinc ion in the active centre of ACE (Zhang et al, 2006;Gnoatto et al, 2008;Tundis et al, 2013).…”

5-Membered cyclic hydroxamic acids as HDAC inhibitors

“…Side chain elongation was performed from appropriate aldehydes (12) and tributyl phosphonium bromide (13) prepared after literature precedent depicted in Scheme 2 18 . Acetals 14a-e prepared by this methodology were deprotected to give the target aldehydes 8c-g. Further reaction of them with earlier prepared phosphonium bromides 7a-b afforded protected cyclic hydroxamic acids 9a-k. Deprotection of the O-THP protecting group with AcOH in THF-H 2 O mixture yielded title compounds 10a-i.…”

“…Some of the compounds with these new ZBGs bind to HDACs with nM binding capacity. During the last decade, Cohen's group [12][13][14][15] has investigated several new ZBGs for Zn-dependant enzymes, particularly matrix metalloproteinases. Among a wide variety of cyclic ketones and lactones they proposed some cyclic hydroxamic and thiohydroxamic acids [13][14][15] .…”