Aclarubicin Chemical Properties

Melting point:

151-153° (dec)

alpha 

D24 -11.5° (c = 1 in methylene chloride)

Boiling point:

756.05°C (rough estimate)

Density 

1.2261 (rough estimate)

refractive index 

1.6220 (estimate)

storage temp. 

2-8°C

solubility 

Dichloromethane (Slightly), DMSO (Slightly), Methanol (Slightly)

form 

Yellow powder with orange cast.

pka

6.41±0.70(Predicted)

color 

Yellow powder

Stability:

Light Sensitive

CAS DataBase Reference

57576-44-0(CAS DataBase Reference)

Safety Information

Hazard Codes 

T

Risk Statements 

25

Safety Statements 

36/37/39-45

RIDADR 

3249

RTECS 

QI9279300

HazardClass 

6.1(a)

PackingGroup 

II

Toxicity

LD50 in mice (mg/kg): 22.6 i.p., 33.7 i.v. (Oki)

Aclarubicin Usage And Synthesis

Description

Aclarubicin was found in the culture broth of Streptomyces galilaeus MA144-M1 by Umezawa et al. of the Institute of Microbial Chemistry in 1975. It was produced along with structurally related compounds showing antileukemic activity and named aclacinomycin A. Sanraku-Ocean cooperated in isolating aclacinomycin A as a yellow crystalline powder and evaluated its strong antileukemic activity and low cardiac toxicity. Its generic name was changed to aclarubicin on the recommendation of the World Health Organization.

Originator

Aclacinon ,Yamanouchi ,Japan ,1981

Uses

Aclarubicin is an anthracycline antibiotic. It is used in the treatment of cancer.

Uses

Antineoplastic.

Definition

ChEBI: An anthracycline antibiotic that is produced by Streptomyces galilaeus and also has potent antineoplastic activity.

Manufacturing Process

100 ml of this medium was sterilized at 120°C for 15 min in a 500 ml Sakaguchi-shaking flask which was inoculated from an agar slant culture of Streptomyces galilaeus MA144-M1 by platinum loop. Incubation proceeded for 48 hr at 28°C on a reciprocal shaker. 10 L of the previously sterilized medium in a 20 L stainless steel jar fermenter were aseptically inoculated with 200 ml of the above seed cultures. Fermentation was carried out at 28°C for 32 hours with agitation (240 rpm) and aeration (5 L/min). The cultured broth obtained was adjusted to pH 4.5, mixed with an adsorbent siliceous earth material and filtered from the mycelium. The filtrate and cake obtained thereby were extracted separately. The cake was suspended in acetone (3 L/kg wet cake), stirred for 2 hr and filtered, and the cake was further extracted with acetone once again. The extracts thus obtained were evaporated to one-tenth volume in vacuum. The culture filtrate was adjusted to pH 6.8 and extracted twice with one-third volume of ethyl acetate, and the ethyl acetate extracts were concentrated to one-tenth volume in vacuum.
Twenty grams of the resulting oily substances were mixed with 20 grams of silicic acid (Mallinckrodt Chemical Co.), applied to a column 40 cm in length and 4.5 cm in diameter filled with silicic acid, and eluted with a benzeneacetone- methanol mixture. The initial eluate which eluted with a 1:1:0 mixture was discarded and the active fractions eluted with 1:3:0 and 1:3:0.3 mixtures were collected and concentrated to dryness in vacuum. 11.5 g of this crude substance was then dissolved in a small amount of ethyl acetate and applied to the same silicic acid column as above. After discarding the initial eluates by the 1:1 and 2:1 benzene-acetone mixtures, aclacinomycin B fractions were first eluted with the above mixtures of 1:3 and 1:5 ratio, and aclacinomycin A fractions were then eluted with the 1:5:0.5 and 1:5:1 benzene-acetone-methanol mixtures. The eluates were dried over anhydrous sodium sulfate and concentrated to dryness in vacuum. 4.8 g of crude aclacinomycin A and 3.5 g of aclacinomycin B were obtained as yellow powder. 2.0 g of crude aclacinomycin A obtained as above were dissolved in a small amount of chloroform, applied to a column 20 cm in length and 20 cm in diameter filled with 30 g of silicic acid. After eluting off the pigments containing aglycone and aclacinomycin B and other impurities with chloroform and 1.5% methanol-containing chloroform, aclacinomycin A fractions were eluted with 2% methanol-containing chloroform, and concentrated to dryness in vacuum. 53 mg of yellow powder of aclacinomycin A was obtained. Its melting point was 129°C to 135°C.

Therapeutic Function

Antitumor, Antibiotic

Biological Activity

aclacinomycin a is a dual inhibitor of topoisomerase i and ii [1]. aclacinomycin a is an anticancer drug which can reduce the tumor with minimal damage to normal cells. aclacinomycin a shows potency against a wide variety of solid tumours and haematological malignancies. in a549, hepg2 and mcf-7 cells, aclacinomycin a shows cytotoxic activity with ic50 values of 0.27μm, 0.32μm and 0.62μm, respectively. aclacinomycin a induces cell apoptosis in these cells and the effects change to be necrosis when the incubation time is prolonged. aclacinomycin a is demonstrated to increase the activity of both caspase-3 and caspase-8, thus inducing the activation of parp. apart from that, as an inhibitor of opoisomerases, aclacinomycin a is found to induce dna damage in v79 and irs-2 cells. aclacinomycin a is used to treat acute leukaemias, lymphomas and other solid tumors through its inhibition of topo ii [1, 2].

Safety Profile

Poison by ingestion,intraperitoneal, subcutaneous, and intravenous routes. Anexperimental teratogen. Other experimental reproductiveeffects. Mutation data reported. An eye and subcutaneousirritant. When heated to decomposition it emits toxicfumes of

Enzyme inhibitor

This non-peptidic aclacinomycin antibiotic (FW = 811.88 g/mol; CAS CAS 57576-44-0; Source: strain of Streptomyces galilaeus), also known as aclarubicin, induces DNA strand scission. Target(s): nitric oxide synthase; RNA biosynthesis; DNA polymerase I; RNA polymerase, Escherichia coli; reverse transcriptase, avian myeloblastosis virus; Na+/K+-exchanging ATPase; Ca2+-transporting ATPase; cyclicnucleotide phosphodiesterase; electron transport and oxidative phosphorylation, mitochondrial; DNA helicase; DNA topoisomerase II; 20S proteasome, chymotrypsin-like activity; DNA topoisomerase I; 3'-5' DNA helicase, Plasmodium falciparum.

target

20S proteasome

References

[1] hajji n, mateos s, pastor n, domínguez i, cortés f. induction of genotoxic and cytotoxic damage by aclarubicin, a dual topoisomerase inhibitor. mutat res. 2005 may 2;583(1):26-35.
[2] rogalska a, szwed m, jó wiak z. aclarubicin-induced apoptosis and necrosis in cells derived from human solid tumours. mutat res. 2010 jul 19;700(1-2):1-10.

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