Ansamitocin P-3

Names

[ Name ]:
Ansamitocin P-3

[Synonym ]:
Ansamitosin P 3
Propanoic acid, 2-methyl-, (1S,2R,3S,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.1.0]hexacosa-10,12,1 4(26),16,18-pentaen-6-yl ester
ANSAMITOCIN P-3
Tam-330
(1S,2R,3S,5S,6S,16E,18E,20R,21S)-11-Chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.1.0]hexacosa-10(26),11,13,16,18-pentaen-6-yl 2- methylpropanoate
2'-De(acetylmethylamino)-2'-methylmaytansine
Propanoic acid, 2-methyl-, (1S,2R,3R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.1.0]hexacosa-10,12,1 4(26),16,18-pentaen-6-yl ester
Anasamitocin P-3
(1S,2R,3R,5S,6S,16E,18E,20R,21S)-11-Chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.1.0]hexacosa-10(26),11,13,16,18-pentaen-6-yl 2- methylpropanoate
Maytansinol isobutyrate
O3-isobutyryl-maytansinol
(3E,5E,7R,84S)-14-chloro-10t,11c-epoxy-84-hydroxy-12c-isobutyryl-15,7r-dimethoxy-3,9c,11t,15-tetramethyl-(84r'H,86c'H)-15-aza-1(1,3)-benzena-8(4,6)-[1,3]oxazinana-cyclopentadecaphane-3,5-diene-82,14-dione

Biological Activity

[Description]:

Ansamitocin P-3 is a microtubule inhibitor. Ansamitocin P-3 is a macrocyclic antitumor antibiotic.

[Related Catalog]:

Signaling Pathways >> Antibody-drug Conjugate >> ADC Cytotoxin

Signaling Pathways >> Cell Cycle/DNA Damage >> Microtubule/Tubulin

Signaling Pathways >> Cytoskeleton >> Microtubule/Tubulin

Natural Products >> Others

Research Areas >> Cancer

[Target]

Microtubule[1]

[In Vitro]

Ansamitocin P3 potently inhibits the proliferation of MCF-7, HeLa, EMT-6/AR1 and MDA-MB-231 cells in culture with a half-maximal inhibitory concentration of 20±3, 50±0.5, 140±17, and 150±1.1 pM, respectively. Further, Ansamitocin P3 is found to bind to purified tubulin in vitro with a dissociation constant (Kd) of 1.3±0.7 µM. The binding of Ansamitocin P3 induces conformational changes in tubulin. Ansamitocin P3 inhibits the proliferation of MCF-7, HeLa, EMT-6/AR1 and MDA-MB-231 cells in culture in a concentration dependent manner. Flow cytometric analysis of PI-stained cells suggests that Ansamitocin P3 inhibits the cell cycle progression of MCF-7 cells in G2/M phase. For example, 26, 50 and 70% of the cells are found to be in G2/M phase in the absence and presence of 50 and 100 pM Ansamitocin P3, respectively[2].

[Cell Assay]

MCF-7, EMT-6/AR1, HeLa and MDA-MB-231 cells are seeded in 96 well plates. Subsequently, cells are incubated with vehicle (0.1% DMSO) or different concentrations (1-1000 pM) of Ansamitocin P3 for 48 h in MCF-7 cells and 24 h for EMT-6/AR1, HeLa and MDA-MB-231 cells, respectively. The half maximal inhibitory concentration of cell proliferation (IC50) for Ansamitocin P3 is determined by sulforhodamine B assay. Four independent experiments are carried out in MCF-7 cells and three independent sets of experiments are performed in EMT-6/AR1, HeLa and MDA-MB-231 cells[2].

[References]

[1]. Kiso T, et al. Screening for microtubule-disrupting antifungal agents by using a mitotic-arrest mutant of Aspergillus nidulans and novel action of phenylalanine derivatives accompanying tubulin loss. Antimicrob Agents Chemother. 2004 May;48(5):1739-48.

[2]. Venghateri JB, et al. Ansamitocin P3 depolymerizes microtubules and induces apoptosis by binding to tubulin at thevinblastine site. PLoS One. 2013 Oct 4;8(10):e75182.

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.3±0.1 g/cm3

[ Boiling Point ]:
833.1±65.0 °C at 760 mmHg

[ Melting Point ]:
190-192℃

[ Molecular Formula ]:
C₃₂H₄₃ClN₂O₉

[ Molecular Weight ]:
635.145

[ Flash Point ]:
457.7±34.3 °C

[ Exact Mass ]:
634.265686

[ PSA ]:
136.16000

[ LogP ]:
5.09

[ Vapour Pressure ]:
0.0±3.2 mmHg at 25°C

[ Index of Refraction ]:
1.583

[ Storage condition ]:
2-8°C

Toxicological Information

CHEMICAL IDENTIFICATION

RTECS NUMBER :: OQ2291000

CHEMICAL NAME :: Maytansine, 2'-de(acetylmethylamino)-2'-methyl-

CAS REGISTRY NUMBER :: 66584-72-3

LAST UPDATED :: 199401

DATA ITEMS CITED :: 4

MOLECULAR FORMULA :: C32-H43-Cl-N2-O9

MOLECULAR WEIGHT :: 635.22

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :: LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 625 ug/kg

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

MUTATION DATA

TYPE OF TEST :: Cytogenetic analysis

TEST SYSTEM :: Rodent - mouse Ascites tumor

DOSE/DURATION :: 4 ug/kg

REFERENCE :: CNREA8 Cancer Research. (Public Ledger Building, Suit 816, 6th & Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- Volume(issue)/page/year: 40,1707,1980

Safety Information

[ Symbol ]:

GHS07

[ Signal Word ]:
Warning

[ Hazard Statements ]:
H302-H315-H319-H332-H335

[ Precautionary Statements ]:
P261-P305 + P351 + P338

[ Personal Protective Equipment ]:
dust mask type N95 (US);Eyeshields;Gloves

[ Hazard Codes ]:
Xn

[ Risk Phrases ]:
20/22-36/37/38

[ Safety Phrases ]:
26-36

[ RIDADR ]:
NONH for all modes of transport

[ RTECS ]:
OQ2293000

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Articles

Enhanced production of ansamitocin P-3 by addition of isobutanol in fermentation of Actinosynnema pretiosum.

Bioresour. Technol. 102 , 1863-1868, (2011)

Supply of isobutanol to enhance the production of anti-tumor agent ansamitocin P-3 (AP-3) in medium containing agro-industrial residues was investigated with analysis of gene transcription, enzyme act...

Amide N-glycosylation by Asm25, an N-glycosyltransferase of ansamitocins.

Chem. Biol. 15(8) , 863-74, (2008)

Ansamitocins are potent antitumor maytansinoids produced by Actinosynnema pretiosum. Their biosynthesis involves the initial assembly of a macrolactam polyketide, followed by a series of postpolyketid...

Determination of the cryptic stereochemistry of the first PKS chain-extension step in ansamitocin biosynthesis by Actinosynnema pretiosum.

ChemBioChem. 7(8) , 1221-5, (2006)

The biosynthesis of the antitumor antibiotic, ansamitocin, involves the assembly of a linear octaketide on the ansamitocin (asm) polyketide synthase (PKS), which is then cyclized to proansamitocin and...