Brostallicin - CAS 203258-60-0
Catalog number:
203258-60-0
Category:
Inhibitor
Not Intended for Therapeutic Use. For research use only.
Molecular Formula:
C30H36BrClN12O5
Molecular Weight:
723.58
COA:
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Targets:
Others
Description:
Brostallicin, a-bromo-acrylamido tetra-pyrrole derivative, is a second-generation minor groove binder (MGB) structurally related to distamycin A with potential antineoplastic activity. Compared with that of other minor groove binders, this agent appears to bind covalently to DNA in a different manner and its activity does not depend on a functional DNA mismatch repair (MMR) mechanism.
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Purity:
>98%
Appearance:
White crystalline powder with a mild odor
Synonyms:
4-[[4-[[4-[[4-(2-bromoprop-2-enoylamino)-1-methylpyrrole-2-carbonyl]amino]-1-methylpyrrole-2-carbonyl]amino]-1-methylpyrrole-2-carbonyl]amino]-N-[2-(diaminomethylideneamino)ethyl]-1-methylpyrrole-2-carboxamide; brostallicin; PNU 166196; PNU-166196; PNU166196
MSDS:
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Density:
1.14 g/cm3
InChIKey:
RXOVOXFAAGIKDQ-UHFFFAOYSA-N
InChI:
1S/C30H35BrN12O5/c1-16(31)25(44)36-17-9-22(41(3)12-17)27(46)38-19-11-24(43(5)14-19)29(48)39-20-10-23(42(4)15-20)28(47)37-18-8-21(40(2)13-18)26(45)34-6-7-35-30(32)33/h8-15H,1,6-7H2,2-5H3,(H,34,45)(H,36,44)(H,37,47)(H,38,46)(H,39,48)(H4,32,33,35)
Canonical SMILES:
CN1C=C(C=C1C(=O)NCCN=C(N)N)NC(=O)C2=CC(=CN2C)NC(=O)C3=CC(=CN3C)NC(=O)C4=CC(=CN4C)NC(=O)C(=C)Br
1.Zebularine partially reverses GST methylation in prostate cancer cells and restores sensitivity to the DNA minor groove binder brostallicin.
Sabatino MA1, Geroni C, Ganzinelli M, Ceruti R, Broggini M. Epigenetics. 2013 Jun;8(6):656-65. doi: 10.4161/epi.24916. Epub 2013 Jun 14.
Brostallicin is a DNA minor groove binder that shows enhanced antitumor activity in cells with high glutathione S-transferase (GST)/glutathione content. Prostate cancer cells present, almost invariably, methylation of the GSTP1 gene promoter and, as a consequence, low levels of GST-pi expression and activity. In these cells, brostallicin shows very little activity. We tested whether pretreatment of heavily GST-methylated prostate cancer cells with demethylating agents could enhance the activity of brostallicin. Human prostate cancer cells LNCaP and DU145 were used for these studies both in vitro and in vivo. The demethylating agent zebularine was used in combination with brostallicin. Methylation specific PCR and pyrosequencing were used to determine the level of GST methylation. Pretreatment with demethylating agents enhanced the in vitro activity of brostallicin in LNCaP cells. Zebularine, in particular, induced an enhancement of activity in vivo comparable to that obtained by transfecting the human GSTP1 gene in LNCaP cells in vitro.
2.Brostallicin (PNU-166196), a new minor groove DNA binder: preclinical and clinical activity.
Lorusso D1, Mainenti S, Pietragalla A, Ferrandina G, Foco G, Masciullo V, Scambia G. Expert Opin Investig Drugs. 2009 Dec;18(12):1939-46. doi: 10.1517/13543780903401284.
Brostallicin (PNU-166196), a-bromo-acrylamido tetra-pyrrole derivative, showed high cytotoxic potency and myelotoxicity dramatically reduced compared with other minor groove DNA-binding agents. In the presence of high intracellular glutathione concentrations, which are associated with resistance to chemotherapy, brostallicin performs a DNA minor groove attack leading to alkylation of DNA nucleophilic functions. In preclinical models, the antitumor activity of brostallicin has been tested in ovarian cancer xenografts, L1210 murine leukemia models, renal, colon and prostatic cancer cells and glutathione-S-transferase (GST) transfected human breast carcinoma cells. In clinical setting, the antitumor activity of brostallicin has been tested in ovarian cancer and in soft tissue sarcoma patients. A clear therapeutic advantage is also observed in preclinical models when brostallicin is combined with anticancer agents such as cisplatin (CDDP), doxorubicin, irinotecan and docetaxel.
3.Brostallicin versus doxorubicin as first-line chemotherapy in patients with advanced or metastatic soft tissue sarcoma: an European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group randomised phase II and pharmacogenetic study.
Gelderblom H1, Blay JY2, Seddon BM3, Leahy M4, Ray-Coquard I2, Sleijfer S5, Kerst JM6, Rutkowski P7, Bauer S8, Ouali M9, Marreaud S9, van der Straaten RJ10, Guchelaar HJ10, Weitman SD11, Hogendoorn PC12, Hohenberger P13. Eur J Cancer. 2014 Jan;50(2):388-96. doi: 10.1016/j.ejca.2013.10.002. Epub 2013 Nov 8.
AIM: Brostallicin is a DNA minor groove binder that has shown activity in patients with soft tissue sarcoma (STS) failing first-line therapy. The present study assessed the safety and efficacy of first-line brostallicin in patients with advanced or metastatic STS >60 years or not fit enough to receive combination chemotherapy. A prospective explorative pharmacogenetic analysis was undertaken in parallel.
4.Role of glutathione transferases in the mechanism of brostallicin activation.
Pezzola S1, Antonini G, Geroni C, Beria I, Colombo M, Broggini M, Marchini S, Mongelli N, Leboffe L, MacArthur R, Mozzi AF, Federici G, Caccuri AM. Biochemistry. 2010 Jan 12;49(1):226-35. doi: 10.1021/bi901689s.
Brostallicin is a novel and unique glutathione transferase-activated pro-drug with promising anticancer activity, currently in phase I and II clinical evaluation. In this work, we show that, in comparison with the parental cell line showing low GST levels, the cytotoxic activity of brostallicin is significantly enhanced in the human breast carcinoma MCF-7 cell line, transfected with either human GST-pi or GST-mu. Moreover, we describe in detail the interaction of brostallicin with GSH in the presence of GSTP1-1 and GSTM2-2, the predominant GST isoenzymes found within tumor cells. The experiments reported here indicate that brostallicin binds reversibly to both isoenzymes with K(d) values in the micromolar range (the affinity being higher for GSTM2-2). Direct evidence that both GSTP1-1 and GSTM2-2 isoenzymes catalyze the Michael addition reaction of GSH to brostallicin has been obtained both by an HPLC-MS technique and by a new fluorometric assay.
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CAS 203258-60-0 Brostallicin

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