TY - JOUR

T1 - Pyridazinone-substituted benzenesulfonamides display potent inhibition of membrane-bound human carbonic anhydrase IX and promising antiproliferative activity against cancer cell lines

AU - Krasavin, Mikhail

AU - Shetnev, Anton

AU - Baykov, Sergey

AU - Kalinin, Stanislav

AU - Nocentini, Alessio

AU - Sharoyko, Vladimir

AU - Poli, Giulio

AU - Tuccinardi, Tiziano

AU - Korsakov, Mikhail

AU - Tennikova, Tatiana B.

AU - Supuran, Claudiu T.

PY - 2019/4/15

Y1 - 2019/4/15

N2 - An expanded set of pyridazine-containing benzene sulfonamides was investigated for inhibition of four human carbonic anhydrase isoforms, which revealed a pronounced inhibition trend toward hCA IX, a cancer-related, membrane-bound isoform of the enzyme. Comparison of antiproliferative effects of these compounds against cancer (PANC-1) and normal (ARPE-19) cells at 50 μM concentration narrowed the selection of compounds to the eight which displayed selective growth inhibition toward the cancer cells. More detailed investigation in concentration-dependent mode against normal (ARPE-19) and two cancer cell lines (PANC-1 and SK-MEL-2) identified two lead compounds one of which displayed a notable cytotoxicity toward pancreatic cancer cells while the other targeted the melanoma cells. These findings significantly expand the knowledge base concerning the hCA IX inhibitors whose inhibitory potency against a recombinant enzyme translates into selective anticancer activity under hypoxic conditions which are aimed to model the environment of a growing tumor.

AB - An expanded set of pyridazine-containing benzene sulfonamides was investigated for inhibition of four human carbonic anhydrase isoforms, which revealed a pronounced inhibition trend toward hCA IX, a cancer-related, membrane-bound isoform of the enzyme. Comparison of antiproliferative effects of these compounds against cancer (PANC-1) and normal (ARPE-19) cells at 50 μM concentration narrowed the selection of compounds to the eight which displayed selective growth inhibition toward the cancer cells. More detailed investigation in concentration-dependent mode against normal (ARPE-19) and two cancer cell lines (PANC-1 and SK-MEL-2) identified two lead compounds one of which displayed a notable cytotoxicity toward pancreatic cancer cells while the other targeted the melanoma cells. These findings significantly expand the knowledge base concerning the hCA IX inhibitors whose inhibitory potency against a recombinant enzyme translates into selective anticancer activity under hypoxic conditions which are aimed to model the environment of a growing tumor.

KW - Cancer cells

KW - carbonic anhydrase

KW - Growth inhibition assay

KW - Hypoxic environment

KW - Isoform-selective inhibitors

KW - Periphery groups

KW - Phthalazinone

KW - Primary sulfonamides

KW - Pyridazinone

KW - Subnanomolar inhibition

KW - Humans

KW - Structure-Activity Relationship

KW - Cell Survival/drug effects

KW - Carbonic Anhydrase IX/antagonists & inhibitors

KW - Dose-Response Relationship, Drug

KW - Carbonic Anhydrase Inhibitors/chemical synthesis

KW - Molecular Structure

KW - Sulfonamides/chemical synthesis

KW - Cell Proliferation/drug effects

KW - Cell Line

KW - Pyridazines/chemistry

KW - Models, Molecular

KW - Antineoplastic Agents/chemical synthesis

KW - Ligands

KW - Antigens, Neoplasm/metabolism

KW - SULFONAMIDES

KW - SULFOCHLORINATION

KW - PROFILE

KW - BIOLOGICAL EVALUATION

KW - PANEL

KW - ANALOGS

UR - http://www.scopus.com/inward/record.url?scp=85062155225&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2019.02.044

DO - 10.1016/j.ejmech.2019.02.044

M3 - Article

C2 - 30826507

AN - SCOPUS:85062155225

VL - 168

SP - 301

EP - 314

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -