PBOX-6
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MedKoo CAT#: 531390

CAS#: 290814-68-5

Description: PBOX-6 belongs to a group of tubulin-targeting pyrrolo-1,5-benzoxazepine (PBOX) compounds that potently induce apoptosis in a wide spectrum of cancer cells, including those originating from the four main types of leukemia and those exhibiting multi-drug resistance (IC50 = 2.28 μM/HL60-MDR1, 2.86 μM/HL60-BCG2, 1.91 μM/HL60; IC50 = 4.71 μM/A2780-ADR, 4.10 μM/A2780). PBOX-6 inhibits the assembly of purified tubulin in cell-free assays and causes microtubule depolymerization in MCF-7 cells by binding a tubulin site distinct from those targeted by vinblastine and colchicine. When administered via intratumoral injection (7.5 mg/kg/day) in vivo, PBOX-6 is reported to significantly inhibit tumour growth in a murine model of neuroblastoma and a CML model of the imatinib-resistant T315I mutants.

Chemical Structure

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PBOX-6
CAS# 290814-68-5
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 531390
Name: PBOX-6
CAS#: 290814-68-5
Chemical Formula: C25H20N2O3
Exact Mass: 396.15
Molecular Weight: 396.446
Elemental Analysis: C, 75.74; H, 5.09; N, 7.07; O, 12.11

Price and Availability

Size Price Availability Quantity
5mg USD 350 2 Weeks
10mg USD 550 2 Weeks
25mg USD 950 2 Weeks
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Synonym: PBOX-6; PBOX6; PBOX 6;

IUPAC/Chemical Name: 6-(Naphthalen-1-yl)benzo[b]pyrrolo[1,2-d][1,4]oxazepin-7-yl dimethylcarbamate

InChi Key: SOIZAFVNIXAZFQ-UHFFFAOYSA-N

InChi Code: InChI=1S/C25H20N2O3/c1-26(2)25(28)30-24-21-14-8-16-27(21)20-13-5-6-15-22(20)29-23(24)19-12-7-10-17-9-3-4-11-18(17)19/h3-16H,1-2H3

SMILES Code: O=C(OC1=C(C2=C3C=CC=CC3=CC=C2)OC4=CC=CC=C4N5C1=CC=C5)N(C)C

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO

Shelf Life: >3 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:

Product Data:
Product Data
Instruction:
View handling instruction
Biological target: PBOX 6 is a pyrrolo-1,5-benzoxazepine (PBOX) compound, acts as a microtubule-depolymerizing agent and an apoptotic agent.
In vitro activity: PBOX-6, a potent member of the series, caused activation of a member of the caspase-3 family of proteases. In addition, the caspase-3-like inhibitor z-DEVD-fmk, but not the caspase-1-like inhibitor z-YVAD-fmk prevented PBOX-6-induced apoptosis, suggesting that caspase 3-like proteases are involved in the mechanism by which PBOX compounds induce apoptosis. The release of cytochrome c into the cytosol in HL-60 cells in response to PBOX-6 suggests that this cellular response may be important in the mechanism by which PBOX-6 induces apoptosis. Reference: J Pharmacol Exp Ther. 2000 Apr;293(1):48-59. https://pubmed.ncbi.nlm.nih.gov/10734152/
In vivo activity: Injections were initiated on day 8 when there was no significant difference in tumour volume between the control and the PBOX-treated groups. By day 10, PBOX-6 had significantly reduced tumour growth when compared to control group. At the experimental end point, day 18, mice were killed by CO2 asphyxiation and a splenectomy was performed. The vehicle-treated group showed gross enlargement of spleens, or splenomegaly a clinical symptom of advanced disease, when compared to the PBOX-6-treated group, with a 3.7-fold increase in weight from 163.3±39.51 to 608.7±105.3 mg (P-value: 0.0027,**) (Figure 4C). This is likely to be due to the reduced tumour burden of PBOX-treated animals. Reference: Br J Cancer. 2010 May 11;102(10):1474-82. https://pubmed.ncbi.nlm.nih.gov/20407438/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 33.3 84.07

Preparing Stock Solutions

The following data is based on the product molecular weight 396.45 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Mc Gee MM, Hyland E, Campiani G, Ramunno A, Nacci V, Zisterer DM. Caspase-3 is not essential for DNA fragmentation in MCF-7 cells during apoptosis induced by the pyrrolo-1,5-benzoxazepine, PBOX-6. FEBS Lett. 2002 Mar 27;515(1-3):66-70. doi: 10.1016/s0014-5793(02)02440-7. PMID: 11943196. 2. Zisterer DM, Campiani G, Nacci V, Williams DC. Pyrrolo-1,5-benzoxazepines induce apoptosis in HL-60, Jurkat, and Hut-78 cells: a new class of apoptotic agents. J Pharmacol Exp Ther. 2000 Apr;293(1):48-59. PMID: 10734152. 3. Bright SA, McElligott AM, O'Connell JW, O'Connor L, Carroll P, Campiani G, Deininger MW, Conneally E, Lawler M, Williams DC, Zisterer DM. Novel pyrrolo-1,5-benzoxazepine compounds display significant activity against resistant chronic myeloid leukaemia cells in vitro, in ex vivo patient samples and in vivo. Br J Cancer. 2010 May 11;102(10):1474-82. doi: 10.1038/sj.bjc.6605670. Epub 2010 Apr 20. PMID: 20407438; PMCID: PMC2869169. 4. Greene LM, Fleeton M, Mulligan J, Gowda C, Sheahan BJ, Atkins GJ, Campiani G, Nacci V, Lawler M, Williams DC, Zisterer DM. The pyrrolo-1,5-benzoxazepine, PBOX-6, inhibits the growth of breast cancer cells in vitro independent of estrogen receptor status and inhibits breast tumour growth in vivo. Oncol Rep. 2005 Nov;14(5):1357-63. PMID: 16211309.
In vitro protocol: 1. Mc Gee MM, Hyland E, Campiani G, Ramunno A, Nacci V, Zisterer DM. Caspase-3 is not essential for DNA fragmentation in MCF-7 cells during apoptosis induced by the pyrrolo-1,5-benzoxazepine, PBOX-6. FEBS Lett. 2002 Mar 27;515(1-3):66-70. doi: 10.1016/s0014-5793(02)02440-7. PMID: 11943196. 2. Zisterer DM, Campiani G, Nacci V, Williams DC. Pyrrolo-1,5-benzoxazepines induce apoptosis in HL-60, Jurkat, and Hut-78 cells: a new class of apoptotic agents. J Pharmacol Exp Ther. 2000 Apr;293(1):48-59. PMID: 10734152.
In vivo protocol: 1. Bright SA, McElligott AM, O'Connell JW, O'Connor L, Carroll P, Campiani G, Deininger MW, Conneally E, Lawler M, Williams DC, Zisterer DM. Novel pyrrolo-1,5-benzoxazepine compounds display significant activity against resistant chronic myeloid leukaemia cells in vitro, in ex vivo patient samples and in vivo. Br J Cancer. 2010 May 11;102(10):1474-82. doi: 10.1038/sj.bjc.6605670. Epub 2010 Apr 20. PMID: 20407438; PMCID: PMC2869169. 2. Greene LM, Fleeton M, Mulligan J, Gowda C, Sheahan BJ, Atkins GJ, Campiani G, Nacci V, Lawler M, Williams DC, Zisterer DM. The pyrrolo-1,5-benzoxazepine, PBOX-6, inhibits the growth of breast cancer cells in vitro independent of estrogen receptor status and inhibits breast tumour growth in vivo. Oncol Rep. 2005 Nov;14(5):1357-63. PMID: 16211309.

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1: Lennon JC, Butini S, Campiani G, O'Meara A, Williams DC, Zisterer DM. Involvement of AMP-activated protein kinase in mediating pyrrolo-1,5-benzoxazepine-induced apoptosis in neuroblastoma cells. Invest New Drugs. 2016 Oct;34(5):663-76. doi: 10.1007/s10637-016-0366-3. Epub 2016 Jun 22. PubMed PMID: 27334143.

2: O'Callaghan K, Palagano E, Butini S, Campiani G, Williams DC, Zisterer DM, O'Sullivan J. Induction of apoptosis in oral squamous carcinoma cells by pyrrolo-1,5-benzoxazepines. Mol Med Rep. 2015 Sep;12(3):3748-3754. doi: 10.3892/mmr.2015.3832. Epub 2015 May 25. PubMed PMID: 26005189.

3: Lennon JC, Bright SA, Carroll E, Butini S, Campiani G, O'Meara A, Williams DC, Zisterer DM. The novel pyrrolo-1,5-benzoxazepine, PBOX-6, synergistically enhances the apoptotic effects of carboplatin in drug sensitive and multidrug resistant neuroblastoma cells. Biochem Pharmacol. 2014 Feb 15;87(4):611-24. doi: 10.1016/j.bcp.2013.12.017. Epub 2014 Jan 6. PubMed PMID: 24406249.

4: Greene LM, Nolan DP, Regan-Komito D, Campiani G, Williams DC, Zisterer DM. Inhibition of late-stage autophagy synergistically enhances pyrrolo-1,5-benzoxazepine-6-induced apoptotic cell death in human colon cancer cells. Int J Oncol. 2013 Sep;43(3):927-35. doi: 10.3892/ijo.2013.1989. Epub 2013 Jun 25. PubMed PMID: 23799546.

5: Nathwani SM, Cloonan SM, Stronach M, Campiani G, Lawler M, Williams DC, Zisterer DM. Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce cell cycle arrest and apoptosis in prostate cancer cells. Oncol Rep. 2010 Dec;24(6):1499-507. PubMed PMID: 21042745.

6: Bright SA, McElligott AM, O'Connell JW, O'Connor L, Carroll P, Campiani G, Deininger MW, Conneally E, Lawler M, Williams DC, Zisterer DM. Novel pyrrolo-1,5-benzoxazepine compounds display significant activity against resistant chronic myeloid leukaemia cells in vitro, in ex vivo patient samples and in vivo. Br J Cancer. 2010 May 11;102(10):1474-82. doi: 10.1038/sj.bjc.6605670. Epub 2010 Apr 20. PubMed PMID: 20407438; PubMed Central PMCID: PMC2869169.

7: Bright SA, Campiani G, Deininger MW, Lawler M, Williams DC, Zisterer DM. Sequential treatment with flavopiridol synergistically enhances pyrrolo-1,5-benzoxazepine-induced apoptosis in human chronic myeloid leukaemia cells including those resistant to imatinib treatment. Biochem Pharmacol. 2010 Jul 1;80(1):31-8. doi: 10.1016/j.bcp.2010.02.019. Epub 2010 Mar 3. PubMed PMID: 20206141.

8: Nathwani SM, Butler S, Fayne D, McGovern NN, Sarkadi B, Meegan MJ, Lloyd DG, Campiani G, Lawler M, Williams DC, Zisterer DM. Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce apoptosis in multi-drug-resistant cancer cells. Cancer Chemother Pharmacol. 2010 Aug;66(3):585-96. doi: 10.1007/s00280-009-1200-9. Epub 2009 Dec 18. PubMed PMID: 20020128.

9: Nathwani SM, Butler S, Meegan MJ, Campiani G, Lawler M, Williams DC, Zisterer DM. Dual targeting of tumour cells and host endothelial cells by novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines. Cancer Chemother Pharmacol. 2010 Jan;65(2):289-300. doi: 10.1007/s00280-009-1033-6. PubMed PMID: 19479253.

10: Bane FT, Bannon JH, Pennington SR, Campiani G, Williams DC, Zisterer DM, Mc Gee MM. The microtubule-targeting agents, PBOX-6 [pyrrolobenzoxazepine 7-[(dimethylcarbamoyl)oxy]-6-(2-naphthyl)pyrrolo-[2,1-d] (1,5)-benzoxazepine] and paclitaxel, induce nucleocytoplasmic redistribution of the peptidyl-prolyl isomerases, cyclophilin A and pin1, in malignant hematopoietic cells. J Pharmacol Exp Ther. 2009 Apr;329(1):38-47. doi: 10.1124/jpet.108.148130. Epub 2009 Jan 8. Erratum in: J Pharmacol Exp Ther. 2011 Aug;338(2):729. Campaini, Giuseppe [corrected to Campiani, Giuseppe]. PubMed PMID: 19131583.

11: Greene LM, Campiani G, Lawler M, Williams DC, Zisterer DM. BubR1 is required for a sustained mitotic spindle checkpoint arrest in human cancer cells treated with tubulin-targeting pyrrolo-1,5-benzoxazepines. Mol Pharmacol. 2008 Feb;73(2):419-30. Epub 2007 Nov 8. PubMed PMID: 17991869.

12: Greene LM, Kelly L, Onnis V, Campiani G, Lawler M, Williams DC, Zisterer DM. STI-571 (imatinib mesylate) enhances the apoptotic efficacy of pyrrolo-1,5-benzoxazepine-6, a novel microtubule-targeting agent, in both STI-571-sensitive and -resistant Bcr-Abl-positive human chronic myeloid leukemia cells. J Pharmacol Exp Ther. 2007 Apr;321(1):288-97. Epub 2007 Jan 3. PubMed PMID: 17202400.

13: McGrath LB, Onnis V, Campiani G, Williams DC, Zisterer DM, Mc Gee MM. Caspase-activated DNase (CAD)-independent oligonucleosomal DNA fragmentation in chronic myeloid leukaemia cells; a requirement for serine protease and Mn2+-dependent acidic endonuclease activity. Apoptosis. 2006 Sep;11(9):1473-87. PubMed PMID: 16820964.

14: Mulligan JM, Greene LM, Cloonan S, Mc Gee MM, Onnis V, Campiani G, Fattorusso C, Lawler M, Williams DC, Zisterer DM. Identification of tubulin as the molecular target of proapoptotic pyrrolo-1,5-benzoxazepines. Mol Pharmacol. 2006 Jul;70(1):60-70. Epub 2006 Mar 29. PubMed PMID: 16571652.

15: Greene LM, Fleeton M, Mulligan J, Gowda C, Sheahan BJ, Atkins GJ, Campiani G, Nacci V, Lawler M, Williams DC, Zisterer DM. The pyrrolo-1,5-benzoxazepine, PBOX-6, inhibits the growth of breast cancer cells in vitro independent of estrogen receptor status and inhibits breast tumour growth in vivo. Oncol Rep. 2005 Nov;14(5):1357-63. PubMed PMID: 16211309.

16: Mc Gee MM, Greene LM, Ledwidge S, Campiani G, Nacci V, Lawler M, Williams DC, Zisterer DM. Selective induction of apoptosis by the pyrrolo-1,5-benzoxazepine 7-[[dimethylcarbamoyl]oxy]-6-(2-naphthyl)pyrrolo-[2,1-d] (1,5)-benzoxazepine (PBOX-6) in Leukemia cells occurs via the c-Jun NH2-terminal kinase-dependent phosphorylation and inactivation of Bcl-2 and Bcl-XL. J Pharmacol Exp Ther. 2004 Sep;310(3):1084-95. Epub 2004 May 13. PubMed PMID: 15143129.

17: Mc Gee MM, Hyland E, Campiani G, Ramunno A, Nacci V, Zisterer DM. Caspase-3 is not essential for DNA fragmentation in MCF-7 cells during apoptosis induced by the pyrrolo-1,5-benzoxazepine, PBOX-6. FEBS Lett. 2002 Mar 27;515(1-3):66-70. PubMed PMID: 11943196.

18: Mc Gee MM, Campiani G, Ramunno A, Nacci V, Lawler M, Williams DC, Zisterer DM. Activation of the c-Jun N-terminal kinase (JNK) signaling pathway is essential during PBOX-6-induced apoptosis in chronic myelogenous leukemia (CML) cells. J Biol Chem. 2002 May 24;277(21):18383-9. Epub 2002 Feb 20. PubMed PMID: 11856743.

19: Zisterer DM, McGee MM, Campiani G, Ramunno A, Fattorusso C, Nacci V, Lawler M, Williams DC. Pyrrolo-1,5-benzoxazepines: a new class of apoptotic agents. Biochem Soc Trans. 2001 Nov;29(Pt 6):704-6. PubMed PMID: 11709059.

20: Mc Gee MM, Campiani G, Ramunno A, Fattorusso C, Nacci V, Lawler M, Williams DC, Zisterer DM. Pyrrolo-1,5-benzoxazepines induce apoptosis in chronic myelogenous leukemia (CML) cells by bypassing the apoptotic suppressor bcr-abl. J Pharmacol Exp Ther. 2001 Jan;296(1):31-40. PubMed PMID: 11123359.