PNU-159682 - CAS 202350-68-3

PNU-159682 - CAS 202350-68-3 Catalog number: BADC-00033

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PNU-159682 is a major active metabolite of nemorubicin (MMDX) in human liver microsomes. It is a highly potent DNA topoisomerase II inhibitor with excellent cytotoxicity, and shows >3,000-fold cytotoxic than its parent compound (MMDX and doxorubicin). It is a more potent and well tolerated ADC cytotoxin than doxorubicin.

Category
ADCs Cytotoxin
Product Name
PNU-159682
CAS
202350-68-3
Catalog Number
BADC-00033
Molecular Formula
C32H35NO13
Molecular Weight
641.62
PNU-159682

Ordering Information

Catalog Number Size Price Quantity
BADC-00033 5 mg $688
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Description
PNU-159682 is a major active metabolite of nemorubicin (MMDX) in human liver microsomes. It is a highly potent DNA topoisomerase II inhibitor with excellent cytotoxicity, and shows >3,000-fold cytotoxic than its parent compound (MMDX and doxorubicin). It is a more potent and well tolerated ADC cytotoxin than doxorubicin.
Synonyms
(8S,10S)-7,8,9,10-Tetrahydro-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-octahydro-9-methoxy-1-methyl-1H-pyrano(4',3':4,5)oxazolo(2,3-c)(1,4)oxazin-3-yl)oxy)-5,12-naphthacenedione; 5,12-Naphthacenedione, 7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-octahydro-9-methoxy-1-methyl-1H-pyrano(4',3':4,5)oxazolo(2,3-c)(1,4)oxazin-3-yl)oxy)-, (8S,10S)-; PNU159682; PNU 159682
IUPAC Name
(7S,9S)-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-7-[[(2S,4R,6S,7S,9R,10S)-10-methoxy-6-methyl-5,8,11-trioxa-1-azatricyclo[7.4.0.02,7]tridecan-4-yl]oxy]-8,10-dihydro-7H-tetracene-5,12-dione
Canonical SMILES
CC1C2C(CC(O1)OC3CC(CC4=C(C5=C(C(=C34)O)C(=O)C6=C(C5=O)C=CC=C6OC)O)(C(=O)CO)O)N7CCOC(C7O2)OC
InChI
InChI=1S/C32H35NO13/c1-13-29-16(33-7-8-43-31(42-3)30(33)46-29)9-20(44-13)45-18-11-32(40,19(35)12-34)10-15-22(18)28(39)24-23(26(15)37)25(36)14-5-4-6-17(41-2)21(14)27(24)38/h4-6,13,16,18,20,29-31,34,37,39-40H,7-12H2,1-3H3/t13-,16-,18-,20-,29+,30+,31-,32-/m0/s1
InChIKey
SLURUCSFDHKXFR-WWMWMSKMSA-N
Density
1.58±0.1 g/cm3 (Predicted)
Solubility
Soluble in DMSO, chloroform (slightly), methanol (slightly)
Flash Point
460.9±34.3 °C
Index Of Refraction
1.691
LogP
6.18
PSA
190.75000
Vapour Pressure
0.0±3.2 mmHg at 25°C
In Vitro
PNU-159682 inhibits a panel of human tumor cell lines with IC70 values in the range of 0.07-0.58 nM, and is 2,360- to 790-fold and 6,420- to 2,100-fold more potent than MMDX and doxorubicin, respectively. PNU-159682 (100 μM) weakly inhibits topoisomerase II unknotting activity. PNU-159682 (10 μM)-DNA adducts contain one or two drug molecules bound to double-stranded DNA. PNU-159682 shows cytotoxic effect on CAIX-expressing SKRC-52 cells with IC50 of 25 nM.
In Vivo
PNU-159682 (15 μg/kg, i.v.) shows antitumor activity in mice bearing disseminated murine L1210 leukemia and in MX-1 human mammary carcinoma xenografts at 4 μg/kg. PNU-159682 (25 nmol/kg) exhibits a potent antitumor effect in mice bearing SKRC-52 xenografted tumors.
Application
ADCs Cytotoxin
Appearance
White solid powder
Purity
≥97%
Shelf Life
≥12 months if stored properly
Shipping
Room temperature
Storage
Store at 2-8°C for short term (days to weeks) or -20°C for long term (months to years)
Boiling Point
838.5±65.0 °C at 760 mmHg
1.In vitro hepatic conversion of the anticancer agent nemorubicin to its active metabolite PNU-159682 in mice, rats and dogs: a comparison with human liver microsomes.
Quintieri L1, Fantin M, Palatini P, De Martin S, Rosato A, Caruso M, Geroni C, Floreani M. Biochem Pharmacol. 2008 Sep 15;76(6):784-95. doi: 10.1016/j.bcp.2008.07.003. Epub 2008 Jul 11.
We recently demonstrated that nemorubicin (MMDX), an investigational antitumor drug, is converted to an active metabolite, PNU-159682, by human liver cytochrome P450 (CYP) 3A4. The objectives of this study were: (1) to investigate MMDX metabolism by liver microsomes from laboratory animals (mice, rats, and dogs of both sexes) to ascertain whether PNU-159682 is also produced in these species, and to identify the CYP form(s) responsible for its formation; (2) to compare the animal metabolism of MMDX with that by human liver microsomes (HLMs), in order to determine which animal species is closest to human beings; (3) to explore whether differences in PNU-159682 formation are responsible for previously reported species- and sex-related differences in MMDX host toxicity. The animal metabolism of MMDX proved to be qualitatively similar to that observed with HLMs since, in all tested species, MMDX was mainly converted to PNU-159682 by a single CYP3A form.
2.The interaction of nemorubicin metabolite PNU-159682 with DNA fragments d(CGTACG)(2), d(CGATCG)(2) and d(CGCGCG)(2) shows a strong but reversible binding to G:C base pairs.
Mazzini S1, Scaglioni L, Mondelli R, Caruso M, Sirtori FR. Bioorg Med Chem. 2012 Dec 15;20(24):6979-88. doi: 10.1016/j.bmc.2012.10.033. Epub 2012 Nov 3.
The antitumor anthracycline nemorubicin is converted by human liver microsomes to a major metabolite, PNU-159682 (PNU), which was found to be much more potent than its parent drug toward cultured tumor cells and in vivo tumor models. The mechanism of action of nemorubicin appears different from other anthracyclines and until now is the object of studies. In fact PNU is deemed to play a dominant, but still unclear, role in the in vivo antitumor activity of nemorubicin. The interaction of PNU with the oligonucleotides d(CGTACG)(2), d(CGATCG)(2) and d(CGCGCG)(2) was studied with a combined use of (1)H and (31)P NMR spectroscopy and by ESI-mass experiments. The NMR studies allowed to establish that the intercalation between the base pairs of the duplex leads to very stable complexes and at the same time to exclude the formation of covalent bonds. Melting experiments monitored by NMR, allowed to observe with high accuracy the behaviour of the imine protons with temperature, and the results showed that the re-annealing occurs after melting.
3.Formation and antitumor activity of PNU-159682, a major metabolite of nemorubicin in human liver microsomes.
Quintieri L1, Geroni C, Fantin M, Battaglia R, Rosato A, Speed W, Zanovello P, Floreani M. Clin Cancer Res. 2005 Feb 15;11(4):1608-17.
PURPOSE: Nemorubicin (3'-deamino-3'-[2''(S)-methoxy-4''-morpholinyl]doxorubicin; MMDX) is an investigational drug currently in phase II/III clinical testing in hepatocellular carcinoma. A bioactivation product of MMDX, 3'-deamino-3'',4'-anhydro-[2''(S)-methoxy-3''(R)-oxy-4''-morpholinyl]doxorubicin (PNU-159682), has been recently identified in an incubate of the drug with NADPH-supplemented rat liver microsomes. The aims of this study were to obtain information about MMDX biotransformation to PNU-159682 in humans, and to explore the antitumor activity of PNU-159682.

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