Insertion of metal carbenes into the anilinic N–H bond of unprotected aminobenzenesulfonamides delivers low nanomolar inhibitors of human carbonic anhydrase IX and XII isoforms

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Insertion of metal carbenes into the anilinic N–H bond of unprotected aminobenzenesulfonamides delivers low nanomolar inhibitors of human carbonic anhydrase IX and XII isoforms. / Sharonova, Tatiana ; Paramonova, Polina ; Kalinin, Stanislav; Bunev, Alexander; Gasanov, Rovshan; Nocentini, Alessio; Sharoyko, Vladimir ; Tennikova, Tatiana B.; Dar'in, Dmitry; Supuran, Claudiu T.; Krasavin, Mikhail.

In: European Journal of Medicinal Chemistry, Vol. 218, 113352, 01.06.2021.

Research output: Contribution to journal › Article › peer-review

BibTeX

@article{b4f0129caa6043faac5f1009a5b82a4c,

title = "Insertion of metal carbenes into the anilinic N–H bond of unprotected aminobenzenesulfonamides delivers low nanomolar inhibitors of human carbonic anhydrase IX and XII isoforms",

abstract = "Herein we report the synthesis of a set of thirty-four primary sulfonamides generated via formal N–H-insertion of metal carbenes into anilinic amino group of sulfanilamide and its meta-substituted analog. Obtained compounds were tested in vitro as inhibitors of four physiologically significant isoforms of the metalloenzyme human carbonic anhydrase (hCA, EC 4.2.1.1). Many of the synthesized sulfonamides displayed low nanomolar Ki values against therapeutically relevant hCA II, IX, and XII, whereas they did not potently inhibit hCA I. Provided the promising activity profiles of the substances towards tumor-associated hCA IX and XII isozymes, single-concentration MTT test was performed for the entire set. Disappointingly, most of the discovered hCA inhibitors did not significantly suppress the growth of cancer cells either in normoxia or CoCl2 induced hypoxic conditions. The only two compounds exerting profound antiproliferative effect turned out to be modest hCA inhibitors. Their out of the range activity in cells is likely attributive to the presence of Michael acceptor substructure which can potentially act either through the inhibition of Thioredoxin reductases (TrxRs, EC 1.8.1.9) or nonspecific covalent binding to cell proteins.",

keywords = "ancer cells; Carbonic anhydrase; Diazo compounds; Enzyme inhibitors; Hypoxic environment; Metal carbenes; MTT-Test; Nanomolar inhibition; N–H insertion; Primary sulfonamides; Stopped-flow assay; The {\textquoteleft}SAFE{\textquoteright} protocol, Carbonic anhydrase, Enzyme inhibitors, Diazo compounds, The 'SAFE' protocol, Metal carbenes, N-H insertion, Primary sulfonamides, Stopped-flow assay, Nanomolar inhibition, Cancer cells, MTT-Test, Hypoxic environment, ALPHA-CLASS, THERAPEUTIC APPLICATIONS, DRUG DISCOVERY, GAMMA, SULFONAMIDES, SELECTIVITY, HYDRATION, KETONES",

author = "Tatiana Sharonova and Polina Paramonova and Stanislav Kalinin and Alexander Bunev and Rovshan Gasanov and Alessio Nocentini and Vladimir Sharoyko and Tennikova, {Tatiana B.} and Dmitry Dar'in and Supuran, {Claudiu T.} and Mikhail Krasavin",

year = "2021",

month = jun,

day = "1",

doi = "10.1016/j.ejmech.2021.113352",

language = "English",

volume = "218",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Insertion of metal carbenes into the anilinic N–H bond of unprotected aminobenzenesulfonamides delivers low nanomolar inhibitors of human carbonic anhydrase IX and XII isoforms

AU - Sharonova, Tatiana

AU - Paramonova, Polina

AU - Kalinin, Stanislav

AU - Bunev, Alexander

AU - Gasanov, Rovshan

AU - Nocentini, Alessio

AU - Sharoyko, Vladimir

AU - Tennikova, Tatiana B.

AU - Dar'in, Dmitry

AU - Supuran, Claudiu T.

AU - Krasavin, Mikhail

PY - 2021/6/1

Y1 - 2021/6/1

N2 - Herein we report the synthesis of a set of thirty-four primary sulfonamides generated via formal N–H-insertion of metal carbenes into anilinic amino group of sulfanilamide and its meta-substituted analog. Obtained compounds were tested in vitro as inhibitors of four physiologically significant isoforms of the metalloenzyme human carbonic anhydrase (hCA, EC 4.2.1.1). Many of the synthesized sulfonamides displayed low nanomolar Ki values against therapeutically relevant hCA II, IX, and XII, whereas they did not potently inhibit hCA I. Provided the promising activity profiles of the substances towards tumor-associated hCA IX and XII isozymes, single-concentration MTT test was performed for the entire set. Disappointingly, most of the discovered hCA inhibitors did not significantly suppress the growth of cancer cells either in normoxia or CoCl2 induced hypoxic conditions. The only two compounds exerting profound antiproliferative effect turned out to be modest hCA inhibitors. Their out of the range activity in cells is likely attributive to the presence of Michael acceptor substructure which can potentially act either through the inhibition of Thioredoxin reductases (TrxRs, EC 1.8.1.9) or nonspecific covalent binding to cell proteins.

AB - Herein we report the synthesis of a set of thirty-four primary sulfonamides generated via formal N–H-insertion of metal carbenes into anilinic amino group of sulfanilamide and its meta-substituted analog. Obtained compounds were tested in vitro as inhibitors of four physiologically significant isoforms of the metalloenzyme human carbonic anhydrase (hCA, EC 4.2.1.1). Many of the synthesized sulfonamides displayed low nanomolar Ki values against therapeutically relevant hCA II, IX, and XII, whereas they did not potently inhibit hCA I. Provided the promising activity profiles of the substances towards tumor-associated hCA IX and XII isozymes, single-concentration MTT test was performed for the entire set. Disappointingly, most of the discovered hCA inhibitors did not significantly suppress the growth of cancer cells either in normoxia or CoCl2 induced hypoxic conditions. The only two compounds exerting profound antiproliferative effect turned out to be modest hCA inhibitors. Their out of the range activity in cells is likely attributive to the presence of Michael acceptor substructure which can potentially act either through the inhibition of Thioredoxin reductases (TrxRs, EC 1.8.1.9) or nonspecific covalent binding to cell proteins.

KW - ancer cells; Carbonic anhydrase; Diazo compounds; Enzyme inhibitors; Hypoxic environment; Metal carbenes; MTT-Test; Nanomolar inhibition; N–H insertion; Primary sulfonamides; Stopped-flow assay; The ‘SAFE’ protocol

KW - Carbonic anhydrase

KW - Enzyme inhibitors

KW - Diazo compounds

KW - The 'SAFE' protocol

KW - Metal carbenes

KW - N-H insertion

KW - Primary sulfonamides

KW - Stopped-flow assay

KW - Nanomolar inhibition

KW - Cancer cells

KW - MTT-Test

KW - Hypoxic environment

KW - ALPHA-CLASS

KW - THERAPEUTIC APPLICATIONS

KW - DRUG DISCOVERY

KW - GAMMA

KW - SULFONAMIDES

KW - SELECTIVITY

KW - HYDRATION

KW - KETONES

UR - http://www.scopus.com/inward/record.url?scp=85103120535&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2021.113352

DO - 10.1016/j.ejmech.2021.113352

M3 - Article

AN - SCOPUS:85103120535

VL - 218

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

M1 - 113352

ER -

ID: 75748323