Top1 inhibitor 1 - CAS 2302772-05-8

Top1 inhibitor 1 - CAS 2302772-05-8 Catalog number: BADC-00674

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Top1 inhibitor 1 (compound 28) is a potent human topoisomerase I (Top1) inhibitor with an IC50 value of 29 nM.

General Information

Category
ADCs Cytotoxin
Product Name
Top1 inhibitor 1
CAS
2302772-05-8
Catalog Number
BADC-00674
Molecular Formula
C24H22N6O2
Molecular Weight
426.47

Chemical Structure

  • Top1 inhibitor 1
Canonical SMILES
COC(C=C1)=CC=C1C2=CC=C(N=CC(C3=NN=CO3)=C4NCCCN5C=NC=C5)C4=C2
1.Discovery and Mechanistic Study of Tailor-Made Quinoline Derivatives as Topoisomerase 1 Poison with Potent Anticancer Activity
Kundu B, Das SK, Paul Chowdhuri S, Pal S, Sarkar D, Ghosh A, Mukherjee A, Bhattacharya D, Das BB, Talukdar A
To overcome chemical limitations of camptothecin (CPT), we report design, synthesis, and validation of a quinoline-based novel class of topoisomerase 1 (Top1) inhibitors and establish that compound 28 ( N-(3-(1 H-imidazol-1-yl)propyl)-6-(4-methoxyphenyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine) exhibits the highest potency in inhibiting human Top1 activity with an IC50 value of 29 ± 0.04 nM. Compound 28 traps Top1-DNA cleavage complexes (Top1ccs) both in the in vitro cleavage assays and in live cells. Point mutation of Top1-N722S fails to trap compound 28-induced Top1cc because of its inability to form a hydrogen bond with compound 28. Unlike CPT, compound 28 shows excellent plasma serum stability and is not a substrate of P-glycoprotein 1 (permeability glycoprotein) advancing its potential anticancer activity. Finally, we provide evidence that compound 28 overcomes the chemical instability of CPT in human breast adenocarcinoma cells through generation of persistent and less reversible Top1cc-induced DNA double-strand breaks as detected by γH2AX foci immunostaining after 5 h of drug removal.

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