Mitoguazone

Names

[ CAS No. ]:
459-86-9

[ Name ]:
Mitoguazone

[Synonym ]:
Mitoguazone
Me-GAG
Pyruvaldehyde bis(amidinohydrazone)
2,2'-(1-Methyl-1,2-ethanediylidene)bis(hydrazinecarbimidamide)
methylglyoxal bis-(guanylhydrazone)
1,1'-((methylethanediylidene)dinitrilo)diguanidine
2,2'-(1-methyl-1,2-ethanediylidene)bis-hydrazinecarboximidamid
methyl-g
MGBG
methyl-gag
1,1'-((methylethanediylidene)dinitrilo)di-guanidin

Biological Activity

[Description]:

Mitoguazone (Methylglyoxal-bis(guanylhydrazone)) is a synthetic polycarbonyl derivative with potent antineoplastic activity. Mitoguazone is a brain-penetrant and competitive S-adenosyl-methionine decarboxylase (SAMDC) inhibitor that disrupts polyamine biosynthesis. Mitoguazone induces cell apoptosis. Mitoguazone inhibits HIV DNA integration into the cellular DNA in both monocytes and macrophages. Mitoguazone has the potential for acute leukemia, Hodgkin's and non-Hodgkin's lymphoma treatment[1][2][3][4].

[Related Catalog]:

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> Anti-infection >> HIV

Research Areas >> Infection

[In Vitro]

Mitoguazone competitively inhibits spermidine synthesis in lymphocytes at concentrations as low as 0.5 μg/mL. Levels of 30 μg/mL or more inhibit protein synthesis and mitochondrial respiration[1]. The ability of Mitoguazone to induce apoptosis by inhibiting the polyamine pathway is assessed in three Burkitt's lymphoma cell lines (Raji, Ramos and Daudi) and one prostate carcinoma cell line (MPC 3). Mitoguazone induces apoptosis in all the different human cancer cell lines tested in a concentration- and time-dependent way, and triggers a p53-independent programmed cell death in the human breast cancer MCF7 cell line[2].

[In Vivo]

The influence of different stages of leukemia P388 on the pharmacokinetics of the antineoplastic agent Mitoguazone in mice is investigated. Independent of the tumor stage investigated, the total clearance of mitoguazone is slightly reduced reflecting a moderate increase of AUC in the serum of leukemia-bearing animals. Furthermore, in an advanced tumor stage the drug levels in kidneys, liver, spleen and serum are found to be elevated to some extent in comparison to tumor-free controls in contrast to an earlier stage of leukemia[5].

[References]

[1]. J Rizzo, et al. Pharmacokinetic Profile of Mitoguazone (MGBG) in Patients With AIDS Related non-Hodgkin's Lymphoma. Invest New Drugs. 1996;14(2):227-34.

[2]. K Davidson, et al. Mitoguazone Induces Apoptosis via a p53-independent Mechanism. Anticancer Drugs. 1998 Aug;9(7):635-40.

[3]. Xia Jin, et al. Inhibition of HIV Expression and Integration in Macrophages by Methylglyoxal-Bis-Guanylhydrazone. J Virol. 2015 Nov;89(22):11176-89.

[4]. A M Levine, et al. Mitoguazone Therapy in Patients With Refractory or Relapsed AIDS-related Lymphoma: Results From a Multicenter Phase II Trial. J Clin Oncol. 1997 Mar;15(3):1094-103.

[5]. R Amlacher, et al. Influence of Leukemia P388 on the Pharmacokinetics of Mitoguazone in B6D2F1 Mice. Pharmazie. 1990 May;45(5):364-6.

Chemical & Physical Properties

[ Density]:
1.55g/cm3

[ Boiling Point ]:
436.6ºC at 760mmHg

[ Molecular Formula ]:
C₅H₁₂N₈

[ Molecular Weight ]:
184.20200

[ Flash Point ]:
217.8ºC

[ Exact Mass ]:
184.11800

[ PSA ]:
148.52000

[ LogP ]:
0.69610

[ Vapour Pressure ]:
7.99E-08mmHg at 25°C

[ Index of Refraction ]:
1.692

Toxicological Information

CHEMICAL IDENTIFICATION

RTECS NUMBER :: MF3860000

CHEMICAL NAME :: Guanidine, 1,1'-((methylethanediylidene)dinitrilo)di-

CAS REGISTRY NUMBER :: 459-86-9

LAST UPDATED :: 199612

DATA ITEMS CITED :: 4

MOLECULAR FORMULA :: C5-H12-N8

MOLECULAR WEIGHT :: 184.25

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: >150 mg/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 1260 mg/kg

SEX/DURATION :: male 7 day(s) pre-mating female 7 day(s) pre-mating - 7 day(s) after conception

TOXIC EFFECTS :: Reproductive - Fertility - female fertility index (e.g. # females pregnant per # sperm positive females; # females pregnant per # females mated)

MUTATION DATA

TYPE OF TEST :: DNA inhibition

TEST SYSTEM :: Mammal - cattle Lymphocyte

DOSE/DURATION :: 8 umol/L

REFERENCE :: CNREA8 Cancer Research. (Public Ledger Building, Suit 816, 6th & Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- Volume(issue)/page/year: 37,3169,1977