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Synthesis of new class of indole acetic acid sulfonate derivatives as ectonucleotidases inhibitors
Ectonucleotidases inhibitors (ENPPs, e5′NT (CD73) and h -TNAP) are potential therapeutic candidates for the treatment of cancer. Adenosine, the cancer-developing, and growth moiety is the resultant product of these enzymes. The synthesis of small molecules that can increase the acidic and ionizable...
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Published in: | RSC advances 2023-10, Vol.13 (42), p.29496-29511 |
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Main Authors: | , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Ectonucleotidases inhibitors (ENPPs, e5′NT (CD73) and
h
-TNAP) are potential therapeutic candidates for the treatment of cancer. Adenosine, the cancer-developing, and growth moiety is the resultant product of these enzymes. The synthesis of small molecules that can increase the acidic and ionizable structure of adenosine 5-monophosphate (AMP) has been used in traditional attempts to inhibit ENPPs, ecto-5′-nucleotidase and
h
-TNAP. In this article, we present a short and interesting method for developing substituted indole acetic acid sulfonate derivatives (
5a-5o
), which are non-nucleotide based small molecules, and investigated their inhibitory potential against recombinant
h
-ENPP1,
h
-ENPP3,
h
-TNAP,
h
-e5′NT and
r
-e5′NT. Their overexpression in the tumor environment leads to high adenosine level that results in tumor development as well as immune evasion. Therefore, selective, and potent inhibitors of these enzymes would be expected to decrease adenosine levels and manage tumor development and progression. Our intended outcome led to the discovery of new potent inhibitors like'
5e
(IC
50
against
h
-ENPP1 = 0.32 ± 0.01 μM, 58 folds increased with respect to suramin),
5j
(IC
50
against
h
-ENPP3 = 0.62 ± 0.003 μM, 21 folds increase with respect to suramin),
5c
(IC
50
against
h
-e5′NT = 0.37 ± 0.03 μM, 115 folds increase with respect to sulfamic acid),
5i
(IC
50
against
r
-e5′NT = 0.81 ± 0.05 μM, 95 folds increase with respect to sulfamic acid), and
5g
(IC
50
against
h
-TNAP = 0.59 ± 0.08 μM, 36 folds increase with respect to Levamisole). Molecular docking studies revealed that inhibitors of these selected target enzymes induced favorable interactions with the key amino acids of the active site, including Lys255, Lys278, Asn277, Gly533, Lys528, Tyr451, Phe257, Tyr340, Gln465, Gln434, Lys437, Glu830, Cys818, Asn499, Arg40, Phe417, Phe500, Asn503, Asn599, Tyr281, Arg397, Asp526, Phe419 and Tyr502. Enzyme kinetic studies revealed that potent compounds such as
5j
and
5e
blocked these ectonucleotidases competitively while compounds
5e
and
5c
presented an un-competitive binding mode.
5g
revealed a non-competitive mode of inhibition.
Indole acetic acid sulfonate derivatives as ectonucleotidases inhibitors. |
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ISSN: | 2046-2069 2046-2069 |
DOI: | 10.1039/d3ra04266a |