Ansamitocin P 3' - CAS 66547-09-9

Ansamitocin P 3' - CAS 66547-09-9 Catalog number: BADC-00189

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Ansamitocin P 3' is an isomer of Ansamitocin P-3, a potent anti-tumor maytansinoid antibiotic found in Actinosynnema pretiosum, a maytansine analog which displays potent cytotoxicity against the human solid tumor cell lines A-549 and HT-29.

Category
ADCs Cytotoxin
Product Name
Ansamitocin P 3'
CAS
66547-09-9
Catalog Number
BADC-00189
Molecular Formula
C32H43ClN2O9
Molecular Weight
635.14
Ansamitocin P 3'

Ordering Information

Catalog Number Size Price Quantity
BADC-00189 25 mg $285
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Description
Ansamitocin P 3' is an isomer of Ansamitocin P-3, a potent anti-tumor maytansinoid antibiotic found in Actinosynnema pretiosum, a maytansine analog which displays potent cytotoxicity against the human solid tumor cell lines A-549 and HT-29.
Synonyms
Ansamitocin P3'; AP-3'; Ansamitocin P-3'; Maytansinol butyrate, Maytansinoid AP-3'. Antibiotic C 15003P3'; iso-Ansamitocin P-3
IUPAC Name
(14S,16S,32S,33S,2R,4S,10E,12E,14R)-86-chloro-14-hydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-12,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl butyrate
Canonical SMILES
CCCC(=O)OC1CC(=O)N(C2=C(C(=CC(=C2)CC(=CC=CC(C3(CC(C(C4C1(O4)C)C)OC(=O)N3)O)OC)C)OC)Cl)C
InChI
InChI=1S/C32H43ClN2O9/c1-8-10-27(37)43-25-16-26(36)35(5)21-14-20(15-22(40-6)28(21)33)13-18(2)11-9-12-24(41-7)32(39)17-23(42-30(38)34-32)19(3)29-31(25,4)44-29/h9,11-12,14-15,19,23-25,29,39H,8,10,13,16-17H2,1-7H3,(H,34,38)/b12-9+,18-11+/t19-,23+,24-,25+,29+,31+,32+/m1/s1
InChIKey
WLKHTIAFMSHJLG-BYXOJEECSA-N
Density
1.30±0.1 g/cm3 at 20°C 760 Torr
Solubility
Soluble in ethanol (1 mg/ml), methanol (10 mg/ml), DMF (20 mg/ml)
Melting Point
182-185°C
Flash Point
457.7±34.3 °C
Index Of Refraction
1.583
LogP
5.09
PSA
136.16000
Vapour Pressure
0.0±3.2 mmHg at 25°C
In Vitro
Ansamitocin P3 is a structural analogue of maytansine for its anticancer activity. Ansamitocin P3 potently inhibited 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. Ansamitocin P3 strongly depolymerized both interphase and mitotic microtubules and perturbed chromosome segregation at its proliferation inhibitory concentration range. Treatment of ansamitocin P3 activated spindle checkpoint surveillance proteins, Mad2 and BubR1 and blocked the cells in mitotic phase of the cell cycle. Subsequently, cells underwent apoptosis via p53 mediated apoptotic pathway. Further, ansamitocin P3 was found to bind to purified tubulin in vitro with a dissociation constant (Kd) of 1.3±0.7 µM. The binding of ansamitocin P3 induced conformational changes in tubulin. A docking analysis suggested that ansamitocin P3 may bind partially to vinblastine binding site on tubulin in two different positions. The analysis indicated that the binding of ansamitocin P3 to tubulin is stabilized by hydrogen bonds. In addition, weak interactions such as halogen-oxygen interactions may also contribute to the binding of ansamitocin P3 to tubulin.
In Vivo
The major pathway of ansamitocin P-3 metabolism in human liver microsomes appears to be demethylation at C-10. Oxidation and sequential oxidation/demethylation also occurred, although to a lesser extent. However, the major pathway of maytansine metabolism in human liver microsomes is N-demethylation of the methylamide of the ester moiety. Several minor pathways including O/N-demethylation, oxidation and hydrolysis of the ester bond were also observed. There were no differences in maytansine metabolism between rat and human liver microsomes; however, the rate of metabolism of ansamitocin P-3 was different in rat and human liver microsomes. About 20% of ansamitocin P-3 was converted to its metabolites in rat liver microsomes and about 70% in human liver microsomes under the same conditions. Additionally, 10-O-demethylated ansamitocin P-3 was also detected in the urine after i.v. bolus administration of ansamitocin P-3 to Sprague-Dawley male rats. No metabolites were detected following incubation of maytansine and ansamitocin P-3 with human and rat whole blood and plasma.
Application
ADCs Cytotoxin
Source
Actinosynnema pretoisum
Appearance
White to Off-white Crystalline Solid
Purity
>98%
Shelf Life
≥360 days if stored properly
Shipping
Room temperature, or blue ice upon request.
Storage
Store at 2-8°C
Pictograms
Irritant
Signal Word
Warning
Boiling Point
837.6±65.0°C (Predicted)
1.Process optimization with alternative carbon sources and modulation of secondary metabolism for enhanced ansamitocin P-3 production in Actinosynnema pretiosum.
Fan Y, Gao Y, Zhou J, Wei L, Chen J, Hua Q. J Biotechnol. 2014 Dec 20;192 Pt A:1-10.
Ansamitocin P-3 (AP-3), synthesized by Actinosynnema pretiosum, is a microtubule disruptor with significant antitumor activity. Although efforts have been made for the study of ansamitocin biosynthetic gene clusters and its fermentation improvement, the yield and productivity of AP-3 are still limited. In this study, fructose was found to be more beneficial to AP-3 production than glucose, and the culture condition was optimized via single-factor experiments and response surface method. The AP-3 concentration in the Erlenmeyer flasks reached 144 mg/L with the optimized medium containing fructose 9.36 g/L, glycerol 26.79 g/L and soluble starch 3.03 g/L, increased by ninefold compared with that before optimization. The result of medium optimization showed that fructose was an important element for effective increase in AP-3 production. Transcription of genes involved in primary metabolism and ansamitocin biosynthetic pathway was investigated to elucidate metabolic responses of cell metabolism to the substitution of fructose for glucose.
2.Improvement of ansamitocin P-3 production by Actinosynnema mirum with fructose as the sole carbon source.
Li T1, Fan Y, Nambou K, Hu F, Imanaka T, Wei L, Hua Q. Appl Biochem Biotechnol. 2015 Mar;175(6):2845-56. doi: 10.1007/s12010-014-1445-6. Epub 2015 Jan 7.
Ansamitocin P-3 (AP-3) is an active and potent anti-tumor maytansinoid, which is usually produced by Actinosynnema spp. In this study, the effects of different carbon sources on biomass and AP-3 production by Actinosynnema mirum were investigated. The results showed great biomass production behavior of A. mirum in glucose medium comparatively to other carbon sources. Interestingly, when fructose was used as the sole carbon source, the highest yield of AP-3 was obtained, which was about fourfold than that of strain cultured in glucose after 168 h. Further analysis conducted in regard to better understanding of such observations in glucose and fructose defined media showed that fructose improves AP-3 production through the stimulation of the key genes of the secondary metabolism pathways. It was concluded that fructose could be a potential carbon source for cost-effective production of AP-3 from an industrial point of view.
3.Enhancement of ansamitocin P-3 production in Actinosynnema pretiosum by a synergistic effect of glycerol and glucose.
Gao Y1, Fan Y, Nambou K, Wei L, Liu Z, Imanaka T, Hua Q. J Ind Microbiol Biotechnol. 2014 Jan;41(1):143-52. doi: 10.1007/s10295-013-1374-3. Epub 2013 Oct 31.
Ansamitocin P-3 (AP-3), a secondary metabolite produced by Actinosynnema pretiosum, is well known for its extraordinary antitumor properties and is broadly utilized in clinical research. Through this work, we found, for the first time, that the combination of glucose and glycerol as a mixed carbon source is an appropriate approach for enhancing the production of AP-3 by A. pretiosum. The amount yielded was about threefold that obtained with glucose as the sole carbon source. In order to better understand the mechanisms that channel glycerol metabolism towards AP-3 production, the activities of some key enzymes such as glucose-6-phosphate dehydrogenase, glucose-6-phosphate isomerase, phosphoglucomutase (PGM), and fructose 1,6-bisphosphatase were assessed. The results showed that glycerol affects the production of AP-3 by increasing PGM activity. Furthermore, qRT-PCR analysis revealed that transcriptional levels of structural genes asm14 and asm24, and primary genes amir5189 and amir6327 were up-regulated in medium containing glycerol.
4.Preparation of new alkyne-modified ansamitocins by mutasynthesis.
Harmrolfs K1, Mancuso L1, Drung B1, Sasse F2, Kirschning A1. Beilstein J Org Chem. 2014 Mar 3;10:535-43. doi: 10.3762/bjoc.10.49. eCollection 2014.
The preparation of alkyne-modified ansamitocins by mutasynthetic supplementation of Actinosynnema pretiosum mutants with alkyne-substituted aminobenzoic acids is described. This modification paved the way to introduce a thiol linker by Huisgen-type cycloaddition which can principally be utilized to create tumor targeting conjugates. In bioactivity tests, only those new ansamitocin derivatives showed strong antiproliferative activity that bear an ester side chain at C-3.

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