144510-96-3 Usage
Description
Pixantrone, also known as Pixuvri (BBR-2778), is an antineoplastic drug that belongs to the group of antitumor antibiotics. It is an analogue of Mitoxantrone and is specifically designed to address the cardiotoxicity seen in earlier agents by replacing a 1,4-dihydroxyanthracene-9,10-dione core with a benzoisoquinoline-5,10-dione ring system. Pixantrone inhibits topoisomerase II by intercalating with DNA and is also believed to form covalent adducts with the N-2 amino group of guanine. It is less cytotoxic than other anthracycline derivatives but shows good antitumor activity in vivo in various preclinical tumor models, including leukemia and lymphoma models. Pixantrone has demonstrated significantly reduced cardiotoxicity compared to the anthracyclines doxorubicin and mitroxantrone.
Uses
Used in Oncology:
Pixantrone is used as an antineoplastic agent for the treatment of relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) in adult patients who have failed on at least two previous therapies. It is particularly effective due to its reduced cardiotoxicity compared to other anthracycline derivatives.
Used in Multiple Sclerosis Treatment:
Pixantrone is used as a treatment for multiple sclerosis, showing similar potency to Mitoxantrone with fewer toxic effects on cardiac tissue.
Used in Alzheimer's Disease Research:
Studies suggest that Pixantrone significantly reduces amyloid beta (A beta(1-42)) neurotoxicity, a mechanism implicated in Alzheimer's disease, making it a potential therapeutic agent for this condition.
Used in Anti-inflammatory and Immunosuppressive Applications:
Pixantrone is also used as an anti-inflammatory and immunosuppressive glucocorticoid steroid, providing relief from inflammation and suppressing the immune system in various conditions.
Originator
University of Vermont (United States)
Clinical Use
Pixuvri (Pixantrone dimaleate) is a novel aza-anthracenedione derivative approved in Europe for the
treatment of adult patients with non-Hodgkin B-cell lymphoma. It is also being pursued as a
treatment for various cancers, and specifically as an alternative to other structurally-related drugs like
mitoxantrone, employed for treatment of breast cancer, acute myeloid leukemia (AML), and non-
Hodgkins lymphoma.Pixantrone dimaleate has been designed to maintain antitumor efficacy while
decreasing highly cardiotoxic side effects observed during treatment with other related anti-tumor
anthracenedione derivatives. Like many anthracenedione drugs, the mechanism of action for pixantrone dimaleate likely includes a number of pathways and processes, with studies suggesting
intercalation into DNA and/or interference with DNA –Topoisomerase II activity, leading to subsequent
protein associated-DNA strand breaks and eventually to cell death.
Synthesis
Pixantrone dimaleate, also
known as BBR 2778, was originally synthesized by professors Krapcho and Hacker at the University of
Vermont, and determination of in-vitro tumor cell cytotoxicity was co-identified by the Boehringer
Mannheim Italia research center and the University of Vermont. After the merger of Boehringer
Mannheim with La-Roche, Novuspharm, and Cell Therapeautics, Inc., pixantrone dimaleate has been
developed and marketed by Cell Therapeutics, Inc.The manufacturing scale synthesis of pixantrone dimaleate relies on several process modifications, from the original synthesis reported by Krapcho in 1994.169 This modified procedure has provided
active pharmaceutical ingredient (API) in high purity (>99%) and is acceptable for use in
pharmaceutical applications (the scheme). Beginning with pyridine 3,4-dicarboxylic acid (129),
generation of the corresponding anhydride 130 proceeded in 76% yield upon treatment with refluxing
Ac2O. Next, an AlCl3-promoted Friedel-Crafts reaction of 1,4-difluorobenzene (131) with 130 under
reflux conditions provided a mixture of nicotinic acid isomers 132a/132b in 84% yield, which were
carried directly to the next step. Cyclization with fuming H2SO4 yielded the desired difluorobenzoisoquinoline-
dione core 133, which was further functionalized with ethylenediamine (134) to provide
the free base of pixantrone. Subjection of the pixantrone free base to aqueous acetic anhydride and
maleic acid provided pixantrone dimaleate (XX) in 92% yield over 3 steps.
Drug interactions
Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine, increased risk
of agranulocytosis.
Live vaccines: risk of generalised infections - avoid.
Metabolism
Pixantrone may be metabolised in the liver and/or
excreted in the bile. As metabolism appears to be limited,
biliary excretion of unchanged pixantrone may be the
major elimination pathway. Acetylated metabolites were
pharmacologically inactive and metabolically stable.
In human urine, the compound was mainly excreted
unchanged, and very small amounts of phase I and phase
II acetylated metabolites were found.
Check Digit Verification of cas no
The CAS Registry Mumber 144510-96-3 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,4,4,5,1 and 0 respectively; the second part has 2 digits, 9 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 144510-96:
(8*1)+(7*4)+(6*4)+(5*5)+(4*1)+(3*0)+(2*9)+(1*6)=113
113 % 10 = 3
So 144510-96-3 is a valid CAS Registry Number.
InChI:InChI=1/C17H19N5O2/c18-4-7-21-12-1-2-13(22-8-5-19)15-14(12)16(23)10-3-6-20-9-11(10)17(15)24/h1-3,6,9,21-22H,4-5,7-8,18-19H2
144510-96-3Relevant articles and documents
6,9-Bisbenzoisoquinoline-5,10-diones. A Novel Class of Chromophore-Modified Antitumor Anthracene-9,10-diones: Synthesis and Antitumor Evaluations
Krapcho, A. Paul,Petry, Mary E.,Getahun, Zelleka,Landi, John J.,Stallman, John,et al.
, p. 828 - 837 (2007/10/02)
Synthetic procedures have been developed which lead to the 2-aza congeners 3 and several related N-oxides 4.The analoques 3 exhibited a wide range of in vitro cytotoxicity against L1210 leukemia, the human colon adenocarcinoma cell line LoVo, and the doxorubicin resistant LoVo/DX cell line.Selected analogues of 3 showed significant P388 antileukemic activity in mice with 3c exhibiting high activity.This activity was also retained in the related N-oxide 4a.These heterocyclic bioisosteric models are representative of the first anthracene-9,10-diones which display antileukemic activity comparable to mitoxantrone.
