Falsini Matteo, Squarcialupi Lucia, Catarzi Daniela, Varano Flavia, Betti Marco, Di Cesare Mannelli Lorenzo, Tenci Barbara, Ghelardini Carla, Tanc Muhammet, Angeli Andrea, Supuran Claudiu T, Colotta Vittoria
Sezione di Farmaceutica e Nutraceutica, Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Università degli Studi di Firenze , Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
Sezione di Farmacologia e Tossicologia, Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Università degli Studi di Firenze , Viale Pieraccini 6, 50139 Firenze, Italy.
J Med Chem. 2017 Jul 27;60(14):6428-6439. doi: 10.1021/acs.jmedchem.7b00766. Epub 2017 Jul 11.
In this paper, we describe the discovery of the 3-hydroxyquinazoline-2,4-dione as a useful scaffold to obtain potent inhibitors of the tumor-associated human carbonic anhydrases (hCAs) IX and XII. A set of derivatives (1-29), bearing different substituents on the fused benzo ring (Cl, NO, NH, CF, ureido, amido, heterocycles), were synthesized, and several of them showed nanomolar activity in inhibiting the hCA IX and XII isoforms, while they were ineffective against the cytosolic enzymes hCAs I and II. Some selected compounds were tested for their antiproliferative activity against HT-29 colon cancer cell lines. After 48 h of treatment with the lower dose (30 μM), derivatives 12, 14, 15, and 19 were significantly active, inducing a mortality by about 50% in both normoxia and hypoxia. This finding led us to hypothesize for these compounds more than one mechanism of action involving both CAs IX and XII and other not yet identified target(s).
在本文中，我们描述了3-羟基喹唑啉-2,4-二酮作为一种有用的骨架用于获得肿瘤相关的人碳酸酐酶（hCAs）IX和XII的有效抑制剂的发现。合成了一组在稠合苯环上带有不同取代基（Cl、NO、NH、CF、脲基、酰胺基、杂环）的衍生物（1-29），其中一些在抑制hCA IX和XII同工型方面表现出纳摩尔活性，而对胞质酶hCAs I和II无效。对一些选定的化合物进行了针对HT-29结肠癌细胞系的抗增殖活性测试。用较低剂量（30μM）处理48小时后，衍生物12、14、15和19具有显著活性，在常氧和低氧条件下均诱导约50%的死亡率。这一发现使我们推测这些化合物存在不止一种作用机制，涉及CAs IX和XII以及其他尚未确定的靶点。
