PIBROZELESIN HYDROBROMIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C32H36BrN5O8.BrH
Molecular Weight	779.473
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Br.COC(=O)C1=C(C)NC2=C(OC(=O)N3CCN(C)CC3)C=C4N(C[C@@H](CBr)C4=C12)C(=O)C5=CC6=C(N5)C(OC)=C(OC)C(OC)=C6

InChI

InChIKey=YMALQNICPSISCA-GMUIIQOCSA-N

InChI=1S/C32H36BrN5O8.BrH/c1-16-23(31(40)45-6)25-24-18(14-33)15-38(20(24)13-21(27(25)34-16)46-32(41)37-9-7-36(2)8-10-37)30(39)19-11-17-12-22(42-3)28(43-4)29(44-5)26(17)35-19;/h11-13,18,34-35H,7-10,14-15H2,1-6H3;1H/t18-;/m1./s1

HIDE SMILES / InChI

Molecular Formula	C32H36BrN5O8
Molecular Weight	698.561
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Molecular Formula	BrH
Molecular Weight	80.912
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/12040295 | https://www.ncbi.nlm.nih.gov/pubmed/8200853 | https://www.ncbi.nlm.nih.gov/pubmed/10857997 | https://www.cancer.gov/publications/dictionaries/cancer-drug/def/pibrozelesin | https://adisinsight.springer.com/drugs/800003110

Pibrozelesin (KW-2189) is a semisynthetic water-soluble derivative of the antineoplastic antibiotic duocarmycin B2. Activated by carboxyl esterase, pibrozelesin alkylates DNA by binding to adenine-thymine (A-T)-rich sequences in the minor groove of DNA, thereby inhibiting DNA replication and inducing apoptosis. KW-2189 induced DNA strand breaks in H69 cells in a concentration-dependent manner. DNA cleavage is one of the major mechanisms of KW-2189-mediated cytotoxicity. KW-2189 showed evidence of anti-tumor activity in hepatocellular carcinoma (HCC). However, because of significant and prolonged hematologic toxicity, when given as a single dose every 6 weeks, further development of this drug in HCC is not possible. Pibrozelesin had been in phase II clinical trial for the treatment of advanced malignant melanoma and advanced renal cell carcinoma. No activity in metastatic renal cell carcinoma was demonstrated and the lack of significant antitumor activity in advanced malignant melanoma treatment was shown.

Originator

Approval Year

PubMed

Title	Date	PubMed
A novel antitumor antibiotic, KW-2189 is activated by carboxyl esterase and induces DNA strand breaks in human small cell lung cancer cells.	1994 Apr	8200853
Differential effect of duocarmycin A and its novel derivative DU-86 on DNA strand breaks in HeLa S3 cells.	1994 Dec	7852193
Characteristics of antitumor activity of KW-2189, a novel water-soluble derivative of duocarmycin, against murine and human tumors.	1994 May 1	8162588
Intracellular carboxyl esterase activity is a determinant of cellular sensitivity to the antineoplastic agent KW-2189 in cell lines resistant to cisplatin and CPT-11.	1995 Jan	7737904
In vitro enhancement of antitumor activity of a water-soluble duocarmycin derivative, KW-2189, by caffeine-mediated DNA-repair inhibition in human lung cancer cells.	1997 Nov	9439677
Phase I study of the duocarmycin semisynthetic derivative KW-2189 given daily for five days every six weeks.	1998 Sep	9748127
Novel cyclopropapyrroloindole derivative (AT-3510) bearing methoxycarbonyl and trifluoromethyl groups.	1999 Apr 22	10212131
Synthesis and antitumor activity of duocarmycin derivatives: modification of segment-A of A-ring pyrrole compounds.	1999 Jul 29	10425104
Synthesis and antitumor activity of duocarmycin derivatives: modification at C-8 position of A-ring pyrrole compounds bearing the simplified DNA-binding groups.	2000 Feb	10722161
A phase II pilot study of KW-2189 in patients with advanced renal cell carcinoma.	2000 May	10857997
Phase II trial of KW2189 in patients with advanced malignant melanoma.	2002 Jun	12040295
hnRNP L enhances sensitivity of the cells to KW-2189.	2004 Feb 20	14696094
Use of KW-2189, a DNA minor groove-binding agent, in patients with hepatocellular carcinoma: a north central cancer treatment group (NCCTG) phase II clinical trial.	2007	19065716

Patents

Sample Use Guides

In Vivo Use Guide

0.4 mg/m2 for Cycle I. Cycles were repeated every 5 to 6 weeks with escalations to 0.5 mg/m2.

Route of Administration: Intravenous

Substance Class	Chemical Created by `admin` on `Sat Dec 16 06:45:10 GMT 2023` Edited by `admin` on `Sat Dec 16 06:45:10 GMT 2023`
Record UNII	0481JCC90T
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

PIBROZELESIN HYDROBROMIDE

Official Name

English

PIBROZELESIN HYDROBROMIDE [USAN]

Common Name

English

METHYL (S)-8-(BROMOMETHYL)-3,6,7,8-TETRAHYDRO-4-HYDROXY-2-METHYL-6-((5,6,7-TRIMETHOXYINDOL-2-YL)CARBONYL)BENZO(1,2-B:4,3-B')DIPYRROLE-1-CARBOXYLATE, 4-METHYL-1-PIPERAZINECARBOXYLATE (ESTER), MONOHYDROBROMIDE

Common Name

English

Pibrozelesin hydrobromide [WHO-DD]

Common Name

English

BENZO(1,2-B:4,3-B')DIPYRROLE-1-CARBOXYLIC ACID, 8-(BROMOMETHYL)-3,6,7,8-TETRAHYDRO-2-METHYL-4-(((4-METHYL-1-PIPERAZINYL)CARBONYL)OXY)-6-((5,6,7-TRIMETHOXY-1H-INDOL-2-YL)CARBONYL)-, METHYL ESTER, HYDROBROMIDE (1:1)

Systematic Name

English

KW-2189

Code

English

PIBROZELESIN HBR

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C2156