SJG-136

• CAT Number: I002776
• CAS Number: 232931-57-6
• Molecular Formula: C31H32N4O6
• Molecular Weight: 556.61
• Purity: ≥95%
• Target: DNA cross-linking
• Solubility: 10 mM in DMSO
• Storage: Store at -20°C
• IC50: 0.83 nM (TGI)
• InChI: InChI=1S/C31H32N4O8/c1-16-14-34-24(28(36)32-22-8-6-18(40-3)12-20(22)30(34)38)26(16)42-10-5-11-43-27-17(2)15-35-25(27)29(37)33-23-9-7-19(41-4)13-21(23)31(35)39/h6-9,12-13,24-27H,1-2,5,10-11,14-15H2,3-4H3,(H,32,36)(H,33,37)
• InChIKey: BJSOOANQHCJYPG-UHFFFAOYSA-N
• SMILES: O=C1N2C(C(OCCCOC(C(N3C4)C(NC5=CC=C(OC)C=C5C3=O)=O)C4=C)C(C2)=C)C(NC6=CC=C(OC)C=C16)=O

SJG-136 is a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity.IC50 value: 0.83 nM (TGI)Target: DNA cross-linkingin vitro: The dimeric pyrrolobenzodiazepine SJG-136 has potent in vitro antiproliferative activity associated with binding in the minor groove of DNA and formation of covalent interstrand DNA cross-links. [1] Sensitive cell lines exhibit total growth inhibition and 50% lethality after treatment with as little as 0.83 and 7.1 nmol/L SJG-136, respectively. Cell lines sensitive to SJG-136 exhibited an LC50 with as little as 7.1 nM and total growth inhibition (TGI) with as little as 0.83 nM.[2] SJG-136 selectively cross-links guanine residues located on opposite strands of DNA, and exhibits potent in vitro cytotoxicity. SJG-136 is active over a wide dosage range in athymic mouse xenografts. [3]in vivo: SJG-136 half-life, clearance and volume of distribution values were 9 min, 190 ml/min/m2, and 1780 ml/m2, respectively. SJG-136 did not accumulate in plasma during treatment with 25 μg/kg/day for 5 days. Treatment with SJG-136 produced the anticipated DNA interstrand cross-links, as well as DNA strand breaks, in rat PBMCs. Oxidative metabolism of SJG-136 in rat liver microsomes was catalyzed by CYP3A isoforms and produced a previously unreported monomeric metabolite. [1]

Reference

1:Activity of the DNA minor groove cross-linking agent SG2000 (SJG-136) against canine tumours. Mellinas-Gomez M, Spanswick VJ, Paredes-Moscosso SR, Robson M, Pedley RB, Thurston DE, Baines SJ, Stell A, Hartley JA.BMC Vet Res. 2015 Aug 19;11:215. doi: 10.1186/s12917-015-0534-2. PMID: 26282406 Free PMC Article2:γ-H2AX foci formation as a pharmacodynamic marker of DNA damage produced by DNA cross-linking agents: results from 2 phase I clinical trials of SJG-136 (SG2000). Wu J, Clingen PH, Spanswick VJ, Mellinas-Gomez M, Meyer T, Puzanov I, Jodrell D, Hochhauser D, Hartley JA.Clin Cancer Res. 2013 Feb 1;19(3):721-30. doi: 10.1158/1078-0432.CCR-12-2529. Epub 2012 Dec 18. PMID: 23251007 Free Article3:Nuclear magnetic resonance solution structures of inter- and intrastrand adducts of DNA cross-linker SJG-136. Hopton SR, Thompson AS.Biochemistry. 2011 May 31;50(21):4720-32. doi: 10.1021/bi102017e. Epub 2011 May 3. PMID: 21488658 4:Phase I pharmacokinetic and pharmacodynamic study of SJG-136, a novel DNA sequence selective minor groove cross-linking agent, in advanced solid tumors. Puzanov I, Lee W, Chen AP, Calcutt MW, Hachey DL, Vermeulen WL, Spanswick VJ, Liao CY, Hartley JA, Berlin JD, Rothenberg ML.Clin Cancer Res. 2011 Jun 1;17(11):3794-802. doi: 10.1158/1078-0432.CCR-10-2056. Epub 2011 Feb 23. PMID: 21346148 Free PMC Article5:Pharmacokinetics, pharmacodynamics and metabolism of the dimeric pyrrolobenzodiazepine SJG-136 in rats. Reid JM, Buhrow SA, Kuffel MJ, Jia L, Spanswick VJ, Hartley JA, Thurston DE, Tomaszewski JE, Ames MM.Cancer Chemother Pharmacol. 2011 Sep;68(3):777-86. doi: 10.1007/s00280-010-1517-4. Epub 2010 Dec 28. PMID: 21188379 6:The pyrrolobenzodiazepine dimer SJG-136 forms sequence-dependent intrastrand DNA cross-links and monoalkylated adducts in addition to interstrand cross-links. Rahman KM, Thompson AS, James CH, Narayanaswamy M, Thurston DE.J Am Chem Soc. 2009 Sep 30;131(38):13756-66. doi: 10.1021/ja902986x. PMID: 19725510 7:A phase I trial of SJG-136 (NSC#694501) in advanced solid tumors. Janjigian YY, Lee W, Kris MG, Miller VA, Krug LM, Azzoli CG, Senturk E, Calcutt MW, Rizvi NA.Cancer Chemother Pharmacol. 2010 Apr;65(5):833-8. doi: 10.1007/s00280-009-1088-4. Epub 2009 Aug 12. PMID: 19672598 Free PMC Article8:Phase I study of sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. Hochhauser D, Meyer T, Spanswick VJ, Wu J, Clingen PH, Loadman P, Cobb M, Gumbrell L, Begent RH, Hartley JA, Jodrell D.Clin Cancer Res. 2009 Mar 15;15(6):2140-7. doi: 10.1158/1078-0432.CCR-08-1315. Epub 2009 Mar 10. PMID: 19276288 Free Article9:Cloning and characterization of the biosynthetic gene cluster for tomaymycin, an SJG-136 monomeric analog. Li W, Chou S, Khullar A, Gerratana B.Appl Environ Microbiol. 2009 May;75(9):2958-63. doi: 10.1128/AEM.02325-08. Epub 2009 Mar 6. PMID: 19270147 Free PMC Article10:Determination of chemically reduced pyrrolobenzodiazepine SJG-136 in human plasma by HPLC-MS/MS: application to an anticancer phase I dose escalation study. Wade Calcutt M, Lee W, Puzanov I, Rothenberg ML, Hachey DL.J Mass Spectrom. 2008 Jan;43(1):42-52. PMID: 17683023