Biochemical

已经设计并合成了一种化合物，该化合物可以靶向表达雌激素受体（ER）的细胞，并在这些细胞中主要产生3-MeA加合物。该化合物在与小牛胸腺DNA反应时主要产生3-MeA加合物，并以51%的相对结合亲和力（雌二醇=100%）与ER结合。该化合物对表达ER的MCF-7乳腺癌症细胞是有毒的，用ER拮抗剂氟维司琼预处理消除了毒性。用netropsin预处理MCF-7细胞，可以抑制化合物N3腺嘌呤甲基化，使毒性降低三倍。这些结果证明了该策略在靶细胞中生产3-MeA加合物的可行性[1]。

Absorption, Distribution and Excretion
In rats, approximately 30% of the radioactivity injected as (14)CH3 methyl methanesulfonate was exhaled as (14)CO2 within 30 hr, and an additional 20% was recovered from urine. In mice given a single ip dose ... approximately 34% ... was recovered from urine and 27% as (14)CO2.
In mice and rats methyl methanesulfonate is rapidly distributed throughout the body, including the CNS. In pregnant rats (21st day of gestation), transplacental passage into fetuses occurred within 2 min after iv injection. Following iv injection of 100 mg/kg body weight to rats, no detectable amount of methyl methanesulfonate were found in blood serum after 2 hr.
... If administered intraperitoneally, it reaches the excretion mechanism readily in activated form.

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Metabolism / Metabolites
Various urinary metabolites (methylmercapturic acid sulfoxide, 2-hydroxy-3-methylsulfinylpropionic acid, methylsulfinylacetic acid and a mixture of methylmercapturic acid and N-(methylthioacetyl)glycine) were identified in rats after iv administration of (14)CH3-methyl methansulfonate during the first 16 hr. About 80% of the excreted radioactivity was accounted for by these metabolites, resulting from an initial methylation of cysteine residues by methyl methanesulfonate.

Interactions
The combined effects of methyl methanesulfonate and ethyl methanesulfonate on the induction of 6-thioguanine resistant mutants and chromosome aberrations were examined in Chinese hamster V79 cells. Cells were simultaneously treated with ethylmethanesulfonate at a concentration of D20 /SRP: D20 = concentration required to reduce cell survival to 20%/ and methyl methanesulfonate at various concentrations for 3, 6 or 9 hr. In other experiments cells were simultaneously treated with methyl methanesulfonate at a concentration of D20 and ethyl methanesulfonate at various concentrations for 3, 6 or 9 hr. The mathematical analysis of the combined effects of both chemicals for cell killing (cytotoxicity) and 6-thioguanine resistant mutations indicates that synergistic interactions were observed for both cell killing and mutations induced by methyl methanesulfonate and ethyl methanesulfonate. The frequency of chromosome aberrations induced by simultaneous treatment with methyl methanesulfonate at a concentration of D20 and ethyl methanesulfonate at various concentrations for 3 hr was additive. However, the frequency of chromosome aberrations induced by ethyl methanesulfonate at a concentration of D20 and methyl methanesulfonate at various concentrations for 3 hr was not significantly different from those induced by methyl methanesulfonate alone.
Ethanol itself did not induce any apparent chromosome aberrations in Chinese hamster ovary cells. However, post-treatment with ethanol potentiated the chromosome aberrations induced by ... methyl methanesulfonate. ... Chromatid exchanges were predominantly increased in cultures treated with ... methyl methanesulfonate ... and then with ethanol. ... Post-treatment with acetaldehyde, the major metabolite of ethanol, also potentiated the chromosome aberrations induced by ... methyl methanesulfonate. ... The main types of aberrations potentiated by posttreatment with acetaldehyde were similar to those by posttreatment with ethanol. /Methyl methanesulfonate/

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Non-Human Toxicity Values
LD50 Rat oral 225 mg/kg
LD50 Rat ip 140 mg/kg
LD50 Rat sc 125 mg/kg
LD50 Rat iv 175 mg/kg

[1]. Bioorg Med Chem. 2011 Sep 1;19(17):5093-102.

Methyl Methanesulfonate can cause cancer according to an independent committee of scientific and health experts.
Methyl methanesulfonate is a colorless to amber liquid. (NTP, 1992)
Methyl methanesulfonate is a methanesulfonate ester resulting from the formal condensation of methanesulfonic acid with methanol. It has a role as an alkylating agent, a genotoxin, a carcinogenic agent, a mutagen and an apoptosis inducer.
Methyl Methanesulfonate is a stable, colorless, combustible liquid that emits toxic fumes of sulfoxide when heated to decomposition. Methyl methanesulfonate is used for laboratory purposes as a catalyst in chemical synthesis and has been tested clinically as a cancer chemotherapeutic agent. This substance is an alkylating agent and acts as a mutagen by altering and damaging DNA and is reasonably anticipated to be a human carcinogen. (NCI05)
An alkylating agent in cancer therapy that may also act as a mutagen by interfering with and causing damage to DNA.

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Mechanism of Action
Monofunctional, methylating agents, such as methyl methanesulfonate, produce primarily 7-methyl-guanine, an adduct that is believed to be innocuous due to its inability to block nucleic acid synthesis or cause misincorporation of bases in newly synthesized DNA. This altered base, however, has been postulated to be indirectly deleterious to cells due to the increased lability of the /glycosyl/ bond, leading to the formation of noninstructive apurinic sites in the DNA template. Another abundant lesion formed is 3-methyladenine. This product has been shown to block nucleic acid synthesis, but direct evidence that it is a lethal moiety in mammalian cells is lacking. The primary promutagenic lesions formed by methylating agents are O6-methylguanine and O-4-methylthymine, both of which can cause base transitions in newly synthesized DNA. O-Methylguanine is formed to a higher extent than O-4-methylthymine, and it has been demonstrated that guanines preceded at 5' by adenine are twice as likely to be methylated at the O6 position as those preceded by thymine, indicating the existence of base sequence effects on adduct formation. Another lesion formed by methylating agents is the methylphosphotriester. This persistent adduct clearly slows nucleic acid synthesis in cell-free systems, but its effect on gene expression or mutagenesis in cells is not clear. ... Longer chain alkylating agents produce similar spectra of damage, but the relative proportions of the adducts formed are significantly different. The lesions formed in the greatest quantities are the alkylphosphotriesters, which represent more than 50% of the total damage to the DNA. The promutagenic lesion that becomes increasingly important with these agents is O4-alkylthymine. It is produced in amounts five- to tenfold greater than occur with methylating agents, and, although it is slowly removed from DNA, its half-life is significantly longer than that for O6-alkylguanine, making it potentially more important in causing point mutations following DNA synthesis.

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Drug Warnings
Therapeutic application of total doses of between 2.8-800 mg/kg bw over period of up to 350 days to 13 cancer patients led to significant GI and hepatic toxic effects.

C2H6O3S

110.13

110.003

66-27-3

Methyl methanesulfonate-d3;91419-94-2

4156

Colorless to light yellow liquid

1.2±0.1 g/cm3

202.1±9.0 °C at 760 mmHg

20ºC

104.4±0.0 °C

0.4±0.4 mmHg at 25°C

1.406

-0.57

51.75

0

3

1

6

105

0

S(C([H])([H])[H])(=O)(=O)OC([H])([H])[H]

MBABOKRGFJTBAE-UHFFFAOYSA-N

InChI=1S/C2H6O3S/c1-5-6(2,3)4/h1-2H3

methyl methanesulfonate

METHYL METHANESULFONATE; 66-27-3; Methyl mesylate; Methanesulfonic acid methyl ester; Methylmethanesulfonate; methylmethane sulfonate; Methanesulfonic acid, methyl ester; Methyl methanesulphonate;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 100 mg/mL (908.02 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (22.70 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (22.70 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (22.70 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。