TY - JOUR
T1 - Selective carbonic anhydrase IX and XII inhibitors based around a functionalized coumarin scaffold
AU - Huwaimel, Bader I.
AU - Jonnalagadda, Sravan K.
AU - Jonnalagadda, Shirisha
AU - Kumari, Shikha
AU - Nocentini, Alessio
AU - Supuran, Claudiu T.
AU - Trippier, Paul C.
N1 - Funding Information:
We thank the National Cancer Institute of the National Institutes of Health (R01 CA226436), the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (R01 HD106590), University of Nebraska Medical Center, and Fred and Pamela Buffett Cancer Center Grant (P30 CA036727) for funding (P.C.T). B.I.H thanks the University of Hail, Hail, Saudi Arabia for a graduate scholarship. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2023 The Authors. Drug Development Research published by Wiley Periodicals LLC.
PY - 2023/6
Y1 - 2023/6
N2 - Inhibition of specific carbonic anhydrase (CA) enzymes is a validated strategy for the development of agents to target cancer. The CA isoforms IX and XII are overexpressed in various human solid tumors wherein they play a critical role in regulating extracellular tumor acidification, proliferation, and progression. A series of novel sulfonamides based on the coumarin scaffold were designed, synthesized and characterized as potent and selective CA inhibitors. Selected compounds show significant activity and selectivity over CA I and CA II to target the tumor-associated CA IX and CA XII with high inhibition activity at the single digit nanomolar level. Twelve compounds were identified to be more potent compared with acetazolamide (AAZ) control to inhibit CA IX while one was also more potent than AAZ to inhibit CA XII. Compound 18f (Ki's = 955 nM, 515 nM, 21 nM and 5 nM for CA's I, II, IX, and XII, respectively) is highlighted as a novel CA IX and XII inhibitor for further development.
AB - Inhibition of specific carbonic anhydrase (CA) enzymes is a validated strategy for the development of agents to target cancer. The CA isoforms IX and XII are overexpressed in various human solid tumors wherein they play a critical role in regulating extracellular tumor acidification, proliferation, and progression. A series of novel sulfonamides based on the coumarin scaffold were designed, synthesized and characterized as potent and selective CA inhibitors. Selected compounds show significant activity and selectivity over CA I and CA II to target the tumor-associated CA IX and CA XII with high inhibition activity at the single digit nanomolar level. Twelve compounds were identified to be more potent compared with acetazolamide (AAZ) control to inhibit CA IX while one was also more potent than AAZ to inhibit CA XII. Compound 18f (Ki's = 955 nM, 515 nM, 21 nM and 5 nM for CA's I, II, IX, and XII, respectively) is highlighted as a novel CA IX and XII inhibitor for further development.
KW - carbonic anhydrase IX inhibitors
KW - carbonic anhydrases XII inhibitor
KW - coumarin
KW - structure–activity relationship
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U2 - 10.1002/ddr.22049
DO - 10.1002/ddr.22049
M3 - Article
C2 - 36872587
AN - SCOPUS:85149488805
SN - 0272-4391
VL - 84
SP - 681
EP - 702
JO - Drug Development Research
JF - Drug Development Research
IS - 4
ER -