Carbonic anhydrase inhibitors. Identification of selective inhibitors of the human mitochondrial isozymes VA and VB over the cytosolic isozymes I and II from a natural product-based phenolic library

被引：63

作者：

Davis, Rohan A. ^{[2
]}

Innocenti, Alessio ^{[1
]}

Poulsen, Sally-Ann ^{[2
]}

Supuran, Claudiu T. ^{[1
]}

机构：

[1] Univ Florence, Lab Chim Bioinorgan, I-50019 Florence, Italy

[2] Griffith Univ, Eskitis Inst, Nathan, Qld 4111, Australia

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 01期

关键词：

Carbonic anhydrase; Natural product; Phenols; Mitochondrial isoforms; Selective enzyme inhibitors; PLANT ENDIANDRA-ANTHROPOPHAGORUM; X-RAY; STRUCTURE ELUCIDATION; MASS-SPECTROMETRY; SALICYLIC-ACID; GENUS XYLARIA; XIV; MICROFUNGUS; SULFONAMIDE; TARGET;

D O I：

10.1016/j.bmc.2009.11.021

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We have investigated the enzyme inhibition characteristics of a natural product (NP)-based phenolic library against a panel of human carbonic anhydrases (hCAs, EC 4.2.1.1) which included hCAs I and II (cytosolic) and hCA VA/VB (mitochondrial isoforms). Most of these compounds were weak, micromolar inhibitors of the two cytosolic hCAs (K(I)s > 10 mu M) but showed good hCA VA/VB inhibitory activity with inhibition constants in the range of 70-125 nM. The selectivity ratios for inhibiting the mitochondrial over the cytosolic isoforms for these phenol derivatives were in the range of 120-3800, making them the most isoform-selective compounds for inhibiting hCA VA/VB known to date. The CA VA/VB enzymes are involved in biosynthetic processes such as gluconeogenesis, lipogenesis and ureagenesis, and no pharmacological inhibitors with good selectivity are currently available. Thus the NP inhibitors identified during these studies are excellent leads for obtaining even more effective compounds that selectively target mitochondrial hCAs, and also have the potential to be used as tools for understanding the physiological processes that are regulated by the two mitochondrial CA isoforms. (C) 2009 Elsevier Ltd. All rights reserved.

引用

下载

页码：14 / 18

页数：5

共 50 条

[31] Carbonic anhydrase inhibitors. Inhibition of isozymes I, II, IV, V, and IX with anions isosteric and isoelectronic with sulfate, nitrate, and carbonate
Innocenti, A
Vullo, D
Scozzafava, A
Supuran, CT
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (03) : 567 - 571
[32] Carbonic anhydrase inhibitors. Inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, IX, and XII with Schiff's bases incorporating chromone and aromatic sulfonamide moieties, and their zinc complexes
Puccetti, L
Fasolis, G
Vullo, D
Chohan, ZH
Scozzafava, A
Supuran, CT
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (12) : 3096 - 3101
[33] Carbonic anhydrase inhibitors. Aromatic/heterocyclic sulfonamides incorporating phenacetyl, pyridylacetyl and thienylacetyl tails act as potent inhibitors of human mitochondrial isoforms VA and VB
Guzel, Ozlen
Innocenti, Alessio
Scozzafava, Andrea
Salman, Aydin
Supuran, Claudiu T.
BIOORGANIC & MEDICINAL CHEMISTRY, 2009, 17 (14) : 4894 - 4899
[34] Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides incorporating thioureido-sulfanilyl scaffolds
Puccetti, L
Fasolis, G
Cecchi, A
Winum, JY
Gamberi, A
Montero, JL
Scozzafava, A
Supuran, CT
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (09) : 2359 - 2364
[35] Carbonic anhydrase inhibitors: Synthesis and inhibition of the human cytosolic isozymes I and II and transmembrane isozymes IX, XII (cancer-associated) and XIV with 4-substituted 3-pyridinesulfonamides
Brzozowski, Zdzislaw
Slawinski, Jaroslaw
Saczewski, Franciszek
Innocenti, Alessio
Supuran, Claudiu T.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2010, 45 (06) : 2396 - 2404
[36] Carbonic anhydrase inhibitors. Interaction of isozymes I, II, IV, V, and IX with phosphates, carbamoyl phosphate, and the phosphonate antiviral drug foscarnet
Rusconi, S
Innocenti, A
Vullo, D
Mastrolorenzo, A
Scozzafava, A
Supuran, CT
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (23) : 5763 - 5767
[37] Carbonic anhydrase inhibitors. Inhibition of the cytosolic and tumor-associated carbonic anhydrase isozymes I, II, and IX with a series of 1,3,4-thiadiazole- and 1,2,4-triazole-thiols
Almajan, GL
Innocenti, A
Puccetti, L
Manole, G
Barbuceanu, S
Saramet, I
Scozzafava, A
Supuran, CT
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (09) : 2347 - 2352
[38] Carbonic anhydrase inhibitors. Inhibition of the cytosolic and tumor-associated carbonic anhydrase isozymes I, II and IX with some 1,3,4-oxadiazole- and 1,2,4-triazole-thiols
Almajan, Gabriela Laura
Barbuceanu, Stefania-Felicia
Innocenti, Alessio
Scozzafava, Andrea
Supuran, Claudiu T.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2008, 23 (01) : 101 - 107
[39] Carbonic anhydrase activators. The selective serotonin reuptake inhibitors fluoxetine, sertraline and citalopram are strong activators of Isozymes I and II
Casini, A
Caccia, S
Scozzafava, A
Supuran, CT
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (16) : 2765 - 2768
[40] Carbonic anhydrase inhibitors. Inhibition of mammalian isoforms I-XIV with a series of natural product polyphenols and phenolic acids
Innocenti, Alessio
Sarikaya, S. Beyza Oeztuerk
Gulcin, Ilhami
Supuran, Claudiu T.
BIOORGANIC & MEDICINAL CHEMISTRY, 2010, 18 (06) : 2159 - 2164

← 1 2 3 4 5 →