ABSTRACT
(1) Background: carbonic anhydrases (CAs) are attractive targets for the development of new anticancer therapies; in particular, CAs IX and XII isoforms are overexpressed in numerous tumors. (2) Methods: following the tail approach, we have appended a hydrophobic aromatic tail to a pharmacophore responsible for the CA inhibition (aryl sulfonamide, coumarin). As a linker, we have used squaramides, featured with strong hydrogen bond acceptor and donor capacities. (3) Results: Starting from easily accessible dimethyl squarate, the title compounds were successfully obtained as crystalline solids, avoiding the use of chromatographic purifications. Interesting and valuable SARs could be obtained upon modification of the length of the hydrocarbon chain, position of the sulfonamido moiety, distance of the aryl sulfonamide scaffold to the squaramide, stereoelectronic effects on the aromatic ring, as well as the number and type of substituents on C-3 and C-4 positions of the coumarin. (4) Conclusions: For sulfonamides, the best profile was achieved for the m-substituted derivative 11 (Ki = 29.4, 9.15 nM, CA IX and XII, respectively), with improved selectivity compared to acetazolamide, a standard drug. Coumarin derivatives afforded an outstanding selectivity (Ki > 10,000 nM for CA I, II); the lead compound (16c) was a strong CA IX and XII inhibitor (Ki = 19.2, 7.23 nM, respectively). Docking simulations revealed the key ligand-enzyme interactions.
Subject(s)
Neoplasms , Sulfonamides , Antigens, Neoplasm/chemistry , Carbonic Anhydrase IX/metabolism , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrase Inhibitors/pharmacology , Coumarins/chemistry , Coumarins/pharmacology , Molecular Structure , Neoplasms/metabolism , Quinine/analogs & derivatives , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
The mineral profile of beef is a subject of human health interest, but also animal performance and meat quality. This study analyzes the relationships of 20 minerals in beef inductively coupled plasma-optical emission spectrometry (ICP-OES) with three animal performance and 13 beef quality traits analyzed on 182 samples of Longissimus thoracis. Animals' breed and sex showed limited effects. The major sources of variation (farm/date of slaughter, individual animal within group and side/sample within animal) differed greatly from trait to trait. Mineral contents were correlated to animal performance and beef quality being significant 52 out of the 320 correlations at the farm/date level, and 101 out of the 320 at the individual animal level. Five latent factors explained 69% of mineral co-variation. The most important, "Mineral quantity" factor correlated with age at slaughter and with the beef color traits. Two latent factors ("Na + Fe + Cu" and "Fe + Mn") correlated with performance and beef color traits. Two other ("K-B-Pb" and "Zn") correlated with beef chemical composition and the latter also with carcass weight and daily gain, and beef color traits. Beef cooking losses correlated with "K-B-Pb". Latent factor analysis appears be a useful means of disentangling the very complex relationships that the minerals in beef have with animal performance and beef quality traits.
