CN111635418A - Maytansinoid derivative and synthetic method and application thereof - Google Patents
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Abstract
The invention relates to a maytansinoid derivative, a synthetic method and application thereof. The invention constructs an integrated expression vector pSBT11-astC containing an alanylase gene astC and realizes the heterologous expression of the alanylase gene in a precious orange actinosynnema mutant strain. Isolation from crude extract of rare Actinobacillus aurantiaca mutant strain expressing alanylasePurifying a post-alanoylation modified maytansinoid derivative. In vitro antitumor activity test shows that the compound has IC of human cervical cancer cell (HeLa), human colon cancer cell (HCT116) and human breast cancer cell (MDA-MB-231)50The values are 3.1, 9.4 and 10.4nM respectively, so the antibody conjugate can be used for preparing anti-tumor drugs and can be combined with different antibodies and linkers to prepare antibody conjugates.
Description
Technical Field
The invention provides a maytansinoid derivative with tumor inhibition activity, in particular relates to a maytansinoid derivative, and a preparation method and application thereof, and belongs to the technical field of natural pharmaceutical chemistry and medical application.
Background
Maytansinoids belong to ansha class macrolactams, which can be divided into two major classes, plant maytansinoids and bacterial maytansinoids, according to their origin, and both have extremely strong antibacterial and antitumor activities. The research finds that the maytansinoid derivative can be combined with tubulin beta subunit, prevent the formation of microtubule bundle aggregation, and destroy the mitotic process, thereby inhibiting the growth of tumor cells. Due to neurotoxicity, maytansinoid derivatives cannot be used directly in clinic, but can be coupled with specific immunity proteins as 'warheads' to play an anticancer role. In 2013, the first antibody conjugate drug ado-trastuzumab entansine (trade name Kadcyla) against solid tumors was approved by the FDA for the treatment of HER2 positive breast cancer, and the development of maytansinoid antibody conjugate drugs has attracted extensive attention again.
Compared with plant maytansinoids, the bacterial maytansinoids have high yield and simple preparation process, and can provide cheap raw materials for the production of maytansinoid antibody conjugate drugs. However, the bacterial maytansinoid (i.e., ansamitocins) does not have a suitable site for coupling to the linker in its original structure, and requires removal of the C-3 ester group by reduction followed by selective alanylation. The method has the advantages of high cost and low yield, and byproducts which are not easy to separate and remove seriously hinder the research, production and clinical application of the maytansinoid antibody conjugate drug.
The invention aims to efficiently prepare the alanylated maytansinoid derivative with the coupling site through biosynthesis, which can greatly accelerate the research and development process of maytansinoid antibody conjugate drugs, thereby having important significance for finding novel antitumor drugs which have broad-spectrum, high efficiency and independent intellectual property rights.
Disclosure of Invention
Research on the anti-tumor structure-activity relationship of maytansinoid derivatives shows that the C-3 ester side chain plays a key role in the anti-tumor activity (Chem Pharm Bull 2004,52,1-26), and alanyl maytansinol derivatives containing disulfide bonds or sulfydryl at the C-3 position are used for preparing the maytansinoid antibody conjugates. Although the yield of the maytansinoid derivative is high in actinomycetes, a compound having alanyl at the C-3 position cannot be produced.
In view of the disadvantages of the prior art, the present invention provides a maytansinoid derivative which is produced by actinomycetes and has an alanyl group at the C-3 position in the structure. The invention also provides a synthetic method and application of the maytansinoid derivative.
Derivatives of maytansinoid
A maytansinoid derivative, which has the following chemical structure:
synthesis method of maytansinoid derivatives
The method for synthesizing the maytansinoid derivative is characterized by comprising the following steps of:
(1) carrying out 15L solid fermentation on HGF052+ pJTU824-asm18+ pSBT11-astC of a mutant strain HGF052 of Actinosynnema depressa ssp.autansium ATCC31565 expressing alanylacylase by using YMG culture medium, and culturing for 7-10 days at 28-30 ℃;
(2) cutting the culture into small pieces, soaking and extracting with ethyl acetate/methanol at a volume ratio of 80:20 at room temperature for three times, mixing extractive solutions, concentrating under reduced pressure at 38-40 deg.C to dry to obtain crude extract;
(3) dissolving the crude extract with water, extracting with ethyl acetate, and concentrating the ethyl acetate phase under reduced pressure at 38-40 deg.C to obtain EA extract;
(4) dissolving EA extract in methanol, extracting with petroleum ether for several times, and concentrating under reduced pressure at 38-40 deg.C to obtain methanol extract;
(5) the methanol extract is sequentially subjected to reverse phase silica gel column chromatography separation, thin layer chromatography and preparative HPLC separation, and eluents with the same components are combined to obtain the maytansinoid derivative.
In accordance with a preferred aspect of the present invention,
in the step (1) of the above preparation method, solid fermentation was carried out on HGF052+ pJTU824-asm18+ pSBT11-astC, which is a mutant strain of Actinosynnema presum ATCC31565 expressing alanylacylase, for 10 days at 28 ℃.
In the step (4) of the preparation method, the methanol used for extraction is 95% methanol.
In the step (5) of the preparation method, the reverse phase silica gel column and the preparative HPLC column are filled with C-18, and the gel column is Sephadex LH-20.
In the step (5) of the preparation method, the step of separating the methanol extract comprises the following steps:
separating methanol extract by reverse phase silica gel column chromatography, eluting with water, 30%, 50%, 70%, and 100% methanol sequentially, eluting each component 1L, receiving at 200 mL/part, detecting by TLC, and detecting with CH2Cl2: developing with MeOH 10:1v/v, developing with bismuth potassium iodide, and mixing 70% of elution components; continuously separating by gel column chromatography, eluting with methanol, mixing 25-29 tubes per tube with 5 mL; and (4) continuously separating by using preparative HPLC (high performance liquid chromatography), wherein the mobile phase is acetonitrile with the volume percentage of 38%, and collecting a target peak to obtain the maytansinoid derivative 1.
In the step (1), the preparation method of the actinosynnema aurantiacae mutant HGF052+ pJTU824-asm18+ pSBT11-astC, which expresses alanylacylase, comprises the following steps:
(a) inserting the open reading frame of the alanylase gene astC between the Ned I and EcoR I restriction sites on the plasmid pSBT11 such that the nucleotide sequence is downstream of and under the control of the ermE promoter;
(b) transforming Escherichia coli ET12567/pUZ8002 with the integrative expression vector pSBT11-astC to obtain Escherichia coli-actinomycete conjoint transfer donor bacteria ET12567/pUZ8002/pSBT 11-astC;
(c) and performing joint transfer on the ET12567/pUZ8002/pSBT11-astC and the mycelium of HGF052+ pJTU824-asm18 to obtain mutant HGF052+ pJTU824-asm18+ pSBT11-astC expressing alanylacylase.
The alanine acylase gene astC gene bank accession number KF813023.1 described in the step (a).
The HGF052+ pJTU824-asm18 strain of step (b) was obtained from the literature (Appl Microbiol Biotechnol 2016, 100, 2641-2649).
Application of tri-maytansinoid derivative
Pharmacological test research shows that the compound shows obvious cytotoxic activity and IC on human cervical cancer cells (HeLa), human colon cancer cells (HCT116) and human breast cancer cells (MDA-MB-231)50The values are 3.1, 9.4 and 10.4nM respectively, the invention also provides the pharmaceutical application of the maytansinoid derivative, and the maytansinoid derivative can be used for preparing antitumor drugs. Preferably, the tumor is cervical cancer, colon cancer or breast cancer.
An anti-tumor pharmaceutical composition comprising the maytansinoid derivative of the invention and one or more pharmaceutically acceptable carriers or excipients.
Has the advantages that:
the maytansinoid derivative with tumor inhibition activity obtained by a biosynthesis method avoids raw material waste and byproducts which are difficult to remove caused by the traditional chemical synthesis method. The invention constructs an integrated expression vector pSBT11-astC containing an alanylase gene astC and realizes the heterologous expression of the alanylase gene in a precious orange actinosynnema mutant strain. A maytansinoid derivative modified after alanylation is isolated and purified from a crude extract of a mutant strain of Actinobacillus aurantiaca which expresses alanylase. In vitro anti-tumor activity tests show that the IC50 values of the compound on human cervical cancer cells (HeLa), human colon cancer cells (HCT116) and human breast cancer cells (MDA-MB-231) are respectively 3.1,
9.4 and 10.4nM, so it can be used to prepare antineoplastic agent, and can be combined with different antibodies and connecting bodies to prepare antibody conjugate.
Detailed Description
The following experimental examples are only for illustrating the technical effects of the present invention, but the experimental examples are not intended to limit the present invention.
The chemical structural formula of maytansinoid derivative 1 (the arabic numerals in the structural formula are the index positions of carbon atoms in the chemical structure) indicated in the following examples:
example 1: biosynthesis and preparation of said Compound 1
1. Construction of mutant strains expressing alanine acylase
1) Construction of expression vectors
A DNA fragment of the alanylacylase gene astC (Genbank accession No. KF813023.1) was amplified and inserted between the Neo I and EcoR I restriction sites of the plasmid pSBT11, so that the nucleotide sequence was located downstream of and regulated by the ermE promoter, resulting in the integrative expression vector pSBT 11-astC.
2) Construction of mutant strains
Coli ET12567/pUZ8002 was transformed with pSBT11-astC to obtain E.coli-actinomycetes conjugative transfer donor strains ET12567/pUZ8002/pSBT 11-astC. And performing joint transfer on ET12567/pUZ8002/pSBT11-astC and mycelium of mutant HGF052+ pJTU824-asm18 of actinosynnema pretiosum ATCC31565 to obtain mutant HGF052+ pJTU824-asm18+ pSBT11-astC expressing alanylacylase.
2. Preparation of Compound 1
1) Solid fermentation (15L) of Actinomyces aurantiacus mutant HGF052+ pJTU824-asm18+ pSBT11-astC was carried out in YMG medium and cultured at 28 ℃ for 10 days.
2) Cutting the culture into small pieces, soaking and extracting with ethyl acetate/methanol (80:20) mixed solvent at room temperature for three times, mixing extractive solutions, concentrating under reduced pressure at 38-40 deg.C to dry to obtain crude extract.
3) The crude extract was dissolved in water, extracted several times with ethyl acetate, and the ethyl acetate phase was concentrated to dryness at 38-40 deg.C under reduced pressure to give EA extract (3.3 g).
4) Dissolving EA extract in 95% methanol, extracting with petroleum ether for several times, and concentrating under reduced pressure at 38-40 deg.C to obtain methanol extract (2.9 g).
5) The methanol extract is first separated by reverse phase silica gel column chromatography (RP-18, 180g column), eluted with water, 30%, 50%, 70%, 100% methanol in sequence, 1L of each fraction eluted, received at 200 mL/portion, detected by TLC, and detected by CH2Cl2: developing with MeOH 10:1, developing with bismuth potassium iodide, and mixing 70% of the elution components; the column chromatography was continued on gel (Sephadex LH-20) eluting with methanol, 5 mL/tube, and 25-29 tubes (39.7mg) were pooled. Separation by preparative HPLC was continued with a mobile phase of 38% acetonitrile and the target peak was collected to give compound 1(5.5 mg).
3. Structural identification of compounds
ESI-MS shows that the peak of the excimer ion of the compound 1 is M/z 648.27[ M + H ]]+。1H and13c NMR showed that compound 1 contained 32 carbon atoms in total (table 1), including 5 methyl groups, 2 methoxy groups, 3 methylene groups, 11 methine groups and 11 quaternary carbons. According to signals of HMQC and HMBC, the compound is determined to be a maytansinoid derivative. The substitution position of alanyl group at O at C-3 position was determined from the remote correlation of proton at C-3 position with C-1', and all NMR spectrum data were assigned to identify a new compound.
TABLE 1 NMR data for Compound 1
Example 2: in vitro antitumor Activity assay of the Compound 1
Ansamitocin AP-3: available from mce (medchemexpress).
Cell lines: human cervical cancer cells (HeLa)), human colon cancer cells (HCT116) and human breast cancer cells (MDA-MB-231) were purchased from the Shanghai cell Bank of the Chinese academy of sciences.
The test method comprises the following steps: the inhibition rate of cell growth is determined by using sulforhodamine B (SRB) protein staining method. The method specifically comprises the following steps:
1) tumor cells were cultured to logarithmic growth phase, trypsinized, and cell density adjusted to 3-7 ten thousand/mL with DMEM medium. In a 96-well plate, 100. mu.L of cells per well were placed at 37 ℃ in 5.0% CO2The culture was carried out overnight. Compounding with DMEM MediumThe concentration of the sample was diluted to 2-fold, 100. mu.L of the diluted sample was added to a 96-well plate, and the culture was continued for 72 hours.
2) Carefully blot the medium, add slowly 100. mu.L of pre-cooled 10% TCA solution and stand at 4 ℃ for more than 1 h. The TCA fixative was discarded, washed five times with running water and blotted dry with absorbent paper.
3) Add 100. mu.L of SRB staining solution and incubate for 30 min. The SRB staining solution was discarded and washed five times with 1% glacial acetic acid to remove free SRB dye. The SRB dye was dissolved overnight by air drying at room temperature and adding 100. mu.L of Tris solution (10mM, pH 10.0).
4) OD values of the administration well and the blank well were measured at a wavelength of 570nm using a microplate reader. The cell growth inhibition rate was (1-mean OD value in drug-treated wells/OD value in control wells) × 100%.
And (3) judging and explaining test results: drug concentration IC at half-growth inhibition of cells50And (4) performing conversion according to the dose-effect data. Each experiment was repeated three times with an absorbance difference of less than 5%, IC50The difference is less than 30%. With IC50Less than or equal to 100nM is effective standard.
And (3) test results: as shown in Table 2, maytansinoid derivative 1 of the present invention showed significant cytotoxic activities against human cervical cancer cell (HeLa), human colon cancer cell (HCT116) and human breast cancer cell (MDA-MB-231), and IC thereof50Values were 3.1, 9.4 and 10.4nM, respectively.
And (4) test conclusion: through pharmacological tests, the compound 1 shows obvious cytotoxic activity on human cervical cancer cells (HeLa), human colon cancer cells (HCT116) and human breast cancer cells (MDA-MB-231). Therefore, the compound can be used for preparing antitumor drugs, can be prepared into antitumor drug compositions with other drugs, and can be coupled with different antibodies and linkers to prepare antibody conjugates.
TABLE 2 cytotoxic assay results (IC) of Compound 1 against 3 tumor cell lines50,nM)
Positive control drug
Claims (10)
1. A maytansinoid derivative, having the chemical structure:
2. a method of synthesis of maytansinoid derivatives according to claim 1, comprising the steps of:
(1) carrying out 15L solid fermentation on HGF052+ pJTU824-asm18+ pSBT11-astC of a mutant strain HGF052 of Actinosynnema depressa ssp.autansium ATCC31565 expressing alanylacylase by using YMG culture medium, and culturing for 7-10 days at 28-30 ℃;
(2) cutting the culture into small pieces, soaking and extracting with ethyl acetate/methanol at a volume ratio of 80:20 at room temperature for three times, mixing extractive solutions, concentrating under reduced pressure at 38-40 deg.C to dry to obtain crude extract;
(3) dissolving the crude extract with water, extracting with ethyl acetate, and concentrating the ethyl acetate phase under reduced pressure at 38-40 deg.C to obtain EA extract;
(4) dissolving EA extract in methanol, extracting with petroleum ether for several times, and concentrating under reduced pressure at 38-40 deg.C to obtain methanol extract;
(5) the methanol extract is sequentially subjected to reverse phase silica gel column chromatography separation, thin layer chromatography and preparative HPLC separation, and eluents with the same components are combined to obtain the maytansinoid derivative.
3. The method for synthesizing maytansinoid derivatives of claim 2, wherein in step (1), said actinomyces aurantiacae mutant HGF052+ pJTU824-asm18+ pSBT11-astC, which expresses alanylacylase, is prepared by the steps of:
(a) inserting the open reading frame of the alanylase gene astC between the Ned I and EcoR I restriction sites on the plasmid pSBT11 such that the nucleotide sequence is downstream of and under the control of the ermE promoter;
(b) transforming Escherichia coli ET12567/pUZ8002 with the integrative expression vector pSBT11-astC to obtain Escherichia coli-actinomycete conjoint transfer donor bacteria ET12567/pUZ8002/pSBT 11-astC;
(c) and performing joint transfer on the ET12567/pUZ8002/pSBT11-astC and the mycelium of HGF052+ pJTU824-asm18 to obtain mutant HGF052+ pJTU824-asm18+ pSBT11-astC expressing alanylacylase.
4. The method for synthesizing maytansinoid derivatives of claim 2, wherein step (1) comprises subjecting HGF052+ pJTU824-asm18+ pSBT11-astC, a mutant strain of Actinosynnema spp (ATCC 31565) expressing alanylacylase, to solid fermentation at 28 ℃ for 10 days.
5. The method for synthesizing maytansinoid derivatives of claim 2, wherein in step (4), the methanol used for the extraction is 95% methanol.
6. The method for synthesizing the maytansinoid derivative of claim 2, wherein in step (5), the reverse phase silica gel column and preparative HPLC column packing are C-18, and the gel column is Sephadex LH-20.
7. The method for synthesizing maytansinoid derivatives of claim 2, wherein the step of separating the methanol extract in step (5) comprises:
separating methanol extract by reverse phase silica gel column chromatography, eluting with water, 30%, 50%, 70%, and 100% methanol sequentially, eluting each component 1L, receiving at 200 mL/part, detecting by TLC, and detecting with CH2Cl2: developing with MeOH 10:1v/v, developing with bismuth potassium iodide, and mixing 70% of elution components; continuously separating by gel column chromatography, eluting with methanol, mixing 25-29 tubes per tube with 5 mL; and (4) continuously separating by using preparative HPLC (high performance liquid chromatography), wherein the mobile phase is acetonitrile with the volume percentage of 38%, and collecting a target peak to obtain the maytansinoid derivative 1.
8. Use of the maytansinoid derivative of claim 1 for the preparation of an antitumor agent.
9. The use of maytansinoid derivatives according to claim 8, wherein the neoplasm is cervical cancer, colon cancer or breast cancer.
10. An anti-tumor pharmaceutical composition comprising the maytansinoid derivative of claim 1 and one or more pharmaceutically acceptable carriers or excipients.
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| CN113461708A (en) * | 2021-07-22 | 2021-10-01 | 深圳市泰尔康生物医药科技有限公司 | Ansamitocin P-3 derivative and application thereof in preparation of drugs for treating gastric cancer |
| WO2021253794A1 (en) * | 2020-06-17 | 2021-12-23 | 山东大学 | Maytansine derivative, synthesis method therefor and use thereof |
| CN114805391A (en) * | 2021-01-18 | 2022-07-29 | 复旦大学 | Natural maytansine compound and application thereof in pharmacy |
| CN114875095A (en) * | 2022-05-30 | 2022-08-09 | 山东大学 | Alanyl maytansinol and synthetic method and application thereof |
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| CN116199695B (en) * | 2022-08-30 | 2024-05-28 | 浙江大学 | Citrinin derivative, and preparation method and application thereof |
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| WO2021253794A1 (en) | 2021-12-23 |
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