LMP744 - CAS 308246-52-8
Category: Inhibitor
Not Intended for Therapeutic Use. For research use only.
Molecular Formula:
C24H24N2O7
Molecular Weight:
452.46
COA:
Inquire
Targets:
Topoisomerase
Description:
LMP744, also known as NSC706744, is a novel indenoisoquinoline topoisomerase I inhibitor.
Synonyms:
6-(3-(2-hydroxyethyl)amino-1-propyl)-5,6-dihydro-2,3-dimethoxy-8,9-methylenedioxy-5,11-dioxo-11H-indeno(1,2-)isoquinoline; MJ-III-65; NSC 706744; NSC-706744; NSC706744; uglysy8 cpd
Storage:
Store in a cool and dry place (or refer to the Certificate of Analysis).
MSDS:
Inquire
Boiling Point:
748.1±60.0 ℃ at 760 Torr
Melting Point:
231-234 ℃
Density:
1.46±0.1 g/cm3
InChIKey:
QCSDJDQOJBQTDV-UHFFFAOYSA-N
InChI:
1S/C24H24N2O7/c1-30-17-8-13-16(11-18(17)31-2)24(29)26(6-3-4-25-5-7-27)22-14-9-19-20(33-12-32-19)10-15(14)23(28)21(13)22/h8-11,25,27H,3-7,12H2,1-2H3
Canonical SMILES:
COC1=C(C=C2C(=C1)C3=C(C4=CC5=C(C=C4C3=O)OCO5)N(C2=O)CCCNCCO)OC
1.Novel Fluoroindenoisoquinoline Non-Camptothecin Topoisomerase I Inhibitors.
Marzi L;Agama K;Murai J;Difilippantonio S;James A;Peer CJ;Figg WD;Beck D;Elsayed MSA;Cushman M;Pommier Y Mol Cancer Ther. 2018 Aug;17(8):1694-1704. doi: 10.1158/1535-7163.MCT-18-0028. Epub 2018 May 10.
Contrary to other anticancer targets, topoisomerase I (TOP1) is targeted by only one chemical class of FDA-approved drugs: topotecan and irinotecan, the derivatives of the plant alkaloid, camptothecin. The indenoisoquinolines LMP400, LMP744, and LMP776 are novel noncamptothecin TOP1 inhibitors in clinical trial, which overcome the limitations of camptothecins. To further improve metabolic stability, their methoxy groups have been replaced by fluorine, as in the fluoroindenoisoquinolines NSC 781517 (LMP517), NSC 779135 (LMP135), and NSC 779134 (LMP134). We tested the induction and stability of TOP1 cleavage complexes (TOP1cc), and the induction and persistence of DNA damage measured by histone H2AX phosphorylation (γH2AX) compared with their parent compounds LMP744 and LMP776 in leukemia CCRF-CEM and colon carcinoma HCT116 cells. The fluoroindenoisoquinolines induced TOP1cc and γH2AX at nanomolar concentrations, and at higher levels than the parent indenoisoquinolines. The fluoroindenoisoquinoline LMP135 showed greater antitumor activity than topotecan in small-cell lung cancer cell H82 xenografts. It was also more potent than topotecan in the NCI-60 cancer cell line panel. Bioinformatics tools (http://discover.
2.Cellular topoisomerase I inhibition and antiproliferative activity by MJ-III-65 (NSC 706744), an indenoisoquinoline topoisomerase I poison.
Antony S;Kohlhagen G;Agama K;Jayaraman M;Cao S;Durrani FA;Rustum YM;Cushman M;Pommier Y Mol Pharmacol. 2005 Feb;67(2):523-30. Epub 2004 Nov 5.
To overcome camptothecin's (CPT) lactone instability, reversibility of the drug-target interaction, and drug resistance, attempts to synthesize compounds that are CPT-like in their specificity and potency yet display a unique profile have been underway. In this pursuit, we have identified one of the idenoisoquinoline derivatives, MJ-III-65 (NSC 706744; 6-[3-(2-hydroxyethyl)amino-1-propyl]-5,6-dihydro-2,3-dimethoxy-8,9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline) with both similarities and differences from CPT. MJ-III-65 traps topoisomerase I (Top1) reversibly like CPT but with different DNA sequence preferences. Consistent with Top1 poisoning, protein-linked DNA breaks were detected in cells treated with MJ-III-65 at nanomolar concentrations. These MJ-III-65-induced protein-linked DNA breaks were resistant to reversal after an hour of drug removal, compared with CPT, which completely reversed. Studies in human cells in culture found MJ-III-65 to be cytotoxic. Furthermore, limited cross-resistance was observed in camptothecin-resistant cell lines. MJ-III-65 also exhibits antitumor activity in mouse tumor xenografts.
3.NCI Comparative Oncology Program Testing of Non-Camptothecin Indenoisoquinoline Topoisomerase I Inhibitors in Naturally Occurring Canine Lymphoma.
Burton JH;Mazcko CN;LeBlanc AK;Covey JM;Ji JJ;Kinders RJ;Parchment RE;Khanna C;Paoloni M;Lana SE;Weishaar K;London CA;Kisseberth WC;Krick E;Vail DM;Childress MO;Bryan JN;Barber LG;Ehrhart EJ;Kent MS;Fan TM;Kow KY;Northup N;Wilson-Robles H;Tomaszewski JE;Holleran JL;Muzzio M;Eiseman J;Beumer JH;Doroshow JH;Pommier Y Clin Cancer Res. 2018 Jul 30. pii: clincanres.1498.2018. doi: 10.1158/1078-0432.CCR-18-1498. [Epub ahead of print]
PURPOSE: ;Only one chemical class of topoisomerase I (TOP1) inhibitors is FDA approved, the camptothecins with irinotecan and topotecan widely used. Because of their limitations (chemical instability, drug efflux-mediated resistance, and diarrhea), novel TOP1 inhibitors are warranted. Indenoisoquinoline non-camptothecin topoisomerase I (TOP1) inhibitors overcome chemical instability and drug resistance that limit camptothecin use. Three indenoisoquinolines, LMP400 (Indotecan), LMP776 (Indimitecan) and LMP744, were examined in a phase I study for lymphoma-bearing dogs to evaluate differential efficacy, pharmacodynamics, toxicology and pharmacokinetics.;EXPERIMENTAL DESIGN: ;Eighty-four client-owned dogs with lymphomas were enrolled in dose-escalation cohorts for each indenoisoquinoline, with an expansion phase for LMP744. Efficacy, tolerability, pharmacokinetics and target engagement were determined.;RESULTS: ;The maximally tolerated doses (MTDs) were 17.5 mg/m;2;for LMP 776 and 100 mg/m;2;for LMP744; bone marrow toxicity was dose-limiting; up to 65 mg/m;2;LMP400 was well-tolerated and MTD was not reached. None of the drugs induced notable diarrhea. Sustained tumor accumulation was observed for LMP744;gH2AX induction was demonstrated in tumors 2 and 6 hours after treatment; a decrease in TOP1 protein was observed in most lymphoma samples across all compounds and dose levels, which is consistent with the fact that tumor response was also observed at low doses LMP744.
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CAS 308246-52-8 LMP744

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