（R）-四氢噻唑-2-硫酮-4-羧酸的应用研究兼论羧酸金刚烷胺盐的合成及抗肿瘤活性
摘要
手性化合物在医药、农药、工业及许多领域均有重要用途。不对称合成法及外消旋体拆分法是获得手性物质的主要方法。
我们以廉价易得的L-半胱氨酸盐酸盐为手性源合成了(R)-四氢噻唑-2-硫酮-4-羧酸[简称(R)-TTCA],由(R)-TTCA与氢化铝锂反应一步得到一种手性氨基醇((R)-4-(羟甲基)-四氢噻唑-2-硫酮1)催化剂。测定了1的晶体结构,证明它在常态下主要为含有硫羰基的化合物,以1为手性催化剂由苯甲醛与二乙基锌反应得到了手性仲醇其构型为S,探讨了该反应的机理。
以(R)-TTCA为拆分剂对甲砜霉素化学合成过程中的重要中间体D,L-苏式-对-甲砜基苯基丝氨酸乙酯进行动力学拆分,直接得到了L-苏式-对-甲砜基苯基丝氨酸乙酯。
以(R)-TTCA及其它含氮杂环化合物与金刚烷胺反应得到了相应的铵盐,采用MTT法对其进行了体外抗肿瘤活性的筛选,发现烟酸金刚烷胺具有较好的抗肿瘤活性,随后又建立小鼠荷瘤模型对其进行动物体内抗肿瘤作用实验,结果显示最高抑瘤率达51.94%。
在此基础上,我们进一步研究了其它类型的有机酸金刚烷胺盐的体外抗肿瘤活性,发现氯乙酸金刚烷胺对肝癌和胃癌细胞有较好的抑制作用,随后又建立荷瘤动物模型对其体内抗肿瘤活性进行研究。结果证明氯乙酸金刚烷胺对H22小鼠实体瘤的抑制率达44.4%。
以上工作均未见文献报道。
Chiral compounds are widely used in fields of medicine, pesticide, industry, etc. Asymmetric catalytic synthesis and racemic resolution are primary methods to obtain chiral compounds, which highly depend on chiral reagents and chiral resolving agents. Thus, developing new chiral catalysts and resolving agents have been a focus in research of asymmetric synthesis.
In this paper, cheap and commercially available L-cysteine hydrochloride was used as chiral source to synthesize (R)-tetrahydrothiazo-2-thione-4-carboxylic acid [(R)-TTCA], which was used in preparation of chiral reagents for asymmetric catalytic reaction and in racemic resolvent as kinetic resolving reagents. One of the three major treatments for malignant tumor, anticancer drug with high efficiency and low toxicity is a hotspot with chemotherapy in medicine research. To expand application of (R) TTCA, we studied ammonium salts formed in reactions of antivirus adamantanamine with (R) TTCA and with other organic acids , performed research on their in vitro and in vivo anticancer effect, probed products with anticancer effect, and discussed potential influence of organic acid structure on effect of the ammonium salts.
The main content of this paper are as follows:
ⅠThe preparation and application of chiral ligand (R) TTCA.
ⅰWe obtained (R)-4-hydroxymethyl-2-thioxo thiazolidine 1 from (R)TTCA via reduction with LiAlH4 , determined the crystal structure of 1 by X-ray diffraction method, and proved 1 mainly existed in form of thiocarbonyl under normal condition.
But it could be noted by the crystal structure (Figure 1) that there are two kinds of the S-C bonds as shown in figure 1.
The longer bond length of S(1)-C(3) and S(1)-C(1) is 1.810 ? and 1.741 ? respectively, Ascriping to the single bond between S and C atoms.On the other hand one relative short bond 1.675 ? between S(2)-C(1) was found .It suggests one weak double bond (typical C=S double bond distance =1.611 ?) between S(2)-C(1) which may originate from the fact that there is thio group in molecular of 1.The relative short bond lengths of N(1)-C(1) (1.310 ?) also declares the existence of 1b. It is showing that has a tautomer 1 and 1b(Figure 2)
ⅱThe chiral ligand of 1 as catalyst was used to addition of benzaldehyde with diethylzinc and product 3, 90%e.e.was obtained. Interestingly we found the configuration of 3 is S. Although 1-phenyl-1-propyl alchohol with R configuration was obtained under the catalysis of
Scheme 2 Enantioselective addition of diethylzinc to benzaldehyde
ⅲWe studied the reaction mechanism of addition of diethylzinc to benzaldehyde as follow:
Scheme3 A tentative mechanism for enantioselective diethylzinc addition to benzaldehyde in the presence of cat.1
The ethyl group of zinc was attacked to carbonyl of benzaldihyde from Si-face and the product of S-configuration was obtained.
ⅡResolution of D,L-threo-p-methylsulfonylphenylserine ester, with (R)TTCA as resolving agent.
ⅰR(-)TTCA was used as resolving agent in kinetic resolution of D,L-threo-p-methylsulfonylphenylserine ester, the structure of R(-)TTCA·D -(+)-threo-p-methylsulfonylphenyl -serine ester derived from the reaction was characterized by infrared and NMR. The enantiomeric excess of L-threo-p-MethylsulfonylPhenyl serine ester and D-threo-p-methylsulfonylphenylserine ester obtained were higher than 99 % .
ⅱWe observed the influence of solvents, reaction temperature and dosage of resolving agents on resolution reactions. the R(-)TTCA·D-(+)-threo-p-methylsulfonylphenylserine ester could not yield in solid form from the reaction When water and DMSO were used as solvents. General organic solvents could be used in the reaction. Suitable temperature was between room temperature and 50°C. The reaction could not proceed when temperature was down to 0°C.
ⅲWe determined the molar ratio of resolving agents and the racemic ester that was 1:2.
ⅢAmmonium salts were formed in reactions of adamantanamine with (R) TTCA or other organic acids and studied their anti-tumor activity.
ⅰIn this paper, we prepared 17 kinds of ammonium salts of adamantanamine with (R) TTCA and with organic acids for the first time and determined their structure with IR, element analysis and NMR.
ⅱThe anti-tumor effect of these ammonium salts were studied by the method of MTT in vitro. Nicotinic acid adamantanamine salt, chloroacetic acid adamantanamine salt and oxalic acid adamantanamine salt showed better anti-tumor effect to human hepatoma cell SMMC-7721 and human gastric cancer cell SGC-7901, and lower toxicity to normal cells.
ⅲwe investigated the anti-tumor effect of nicotinic acid adamantanamine salt, by animal model of transplanted tumor in mice
(i) The anti-tumor activity and side effects of nicotinic acid adamant -anamine salt were studied by using mice model bearing hepatoma H22. The results of this experiment indicated that nicotinic acid adamantanamine salt could inhibit the growth of transplanted tumor H22 in mice with a highest tumor inhibition rate of 51.49%; No toxicity to white cell of peripheral blood and no side effects as lowering weight of spleen and thymus were noted. In medium dosage group, nicotinic acid adamantanamine salt promoted proliferation of T Lymphocy in spleen.
(ii) Using mice bearing transplanted hepatoma H22 and 5-fluorouracil as positive control drug, we observed influence of chloroacetic acid adamantanamine salt on tumor inhibition ratio, organ index, peripheral leukocytes, bone marrow nucleated cells, bone marrow DNA, catalase and malondialdehyde. The results indicated chloroacetic acid adamantanamine salt could effectively inhibit growth of hepatoma H22 in mice with a highest inhibition rate of 44.4% and showed dose dependent. In all three groups, leukocyte count in blood, weight of spleen and thymus were increased. No inhibition of hematopoietic function of bone marrow was noted in medium and high dosage group. MDA level in mice bearing hepatoma were lowered to some extent. Less side effects like bone marrow inhibition and immune system inhibition were caused compared with by positive control drug. No damage to immune function, hematopoietic function and antioxidation ability was exhibited.
ⅳWe discussed the relationship between the structure of the organic acids which formed ammonium salts with adamantanamine and anti-tumor activity that electron-atracting group(electronegativity) ofα-position of carbosylic acid showed better anti-tumor activity.
Compared structur of nicotinic adamantanamine salt isonicotinic adamantanamine salt that stereoscopic place of carboxy group have demonstrated a different effect of antitumor activity.
We have been requesting patent of antitumor activity of nicotinic, chloroacetic acid and oxalic acid adamantanamine salts.
我们以廉价易得的L-半胱氨酸盐酸盐为手性源合成了(R)-四氢噻唑-2-硫酮-4-羧酸[简称(R)-TTCA],由(R)-TTCA与氢化铝锂反应一步得到一种手性氨基醇((R)-4-(羟甲基)-四氢噻唑-2-硫酮1)催化剂。测定了1的晶体结构,证明它在常态下主要为含有硫羰基的化合物,以1为手性催化剂由苯甲醛与二乙基锌反应得到了手性仲醇其构型为S,探讨了该反应的机理。
以(R)-TTCA为拆分剂对甲砜霉素化学合成过程中的重要中间体D,L-苏式-对-甲砜基苯基丝氨酸乙酯进行动力学拆分,直接得到了L-苏式-对-甲砜基苯基丝氨酸乙酯。
以(R)-TTCA及其它含氮杂环化合物与金刚烷胺反应得到了相应的铵盐,采用MTT法对其进行了体外抗肿瘤活性的筛选,发现烟酸金刚烷胺具有较好的抗肿瘤活性,随后又建立小鼠荷瘤模型对其进行动物体内抗肿瘤作用实验,结果显示最高抑瘤率达51.94%。
在此基础上,我们进一步研究了其它类型的有机酸金刚烷胺盐的体外抗肿瘤活性,发现氯乙酸金刚烷胺对肝癌和胃癌细胞有较好的抑制作用,随后又建立荷瘤动物模型对其体内抗肿瘤活性进行研究。结果证明氯乙酸金刚烷胺对H22小鼠实体瘤的抑制率达44.4%。
以上工作均未见文献报道。
Chiral compounds are widely used in fields of medicine, pesticide, industry, etc. Asymmetric catalytic synthesis and racemic resolution are primary methods to obtain chiral compounds, which highly depend on chiral reagents and chiral resolving agents. Thus, developing new chiral catalysts and resolving agents have been a focus in research of asymmetric synthesis.
In this paper, cheap and commercially available L-cysteine hydrochloride was used as chiral source to synthesize (R)-tetrahydrothiazo-2-thione-4-carboxylic acid [(R)-TTCA], which was used in preparation of chiral reagents for asymmetric catalytic reaction and in racemic resolvent as kinetic resolving reagents. One of the three major treatments for malignant tumor, anticancer drug with high efficiency and low toxicity is a hotspot with chemotherapy in medicine research. To expand application of (R) TTCA, we studied ammonium salts formed in reactions of antivirus adamantanamine with (R) TTCA and with other organic acids , performed research on their in vitro and in vivo anticancer effect, probed products with anticancer effect, and discussed potential influence of organic acid structure on effect of the ammonium salts.
The main content of this paper are as follows:
ⅠThe preparation and application of chiral ligand (R) TTCA.
ⅰWe obtained (R)-4-hydroxymethyl-2-thioxo thiazolidine 1 from (R)TTCA via reduction with LiAlH4 , determined the crystal structure of 1 by X-ray diffraction method, and proved 1 mainly existed in form of thiocarbonyl under normal condition.
But it could be noted by the crystal structure (Figure 1) that there are two kinds of the S-C bonds as shown in figure 1.
The longer bond length of S(1)-C(3) and S(1)-C(1) is 1.810 ? and 1.741 ? respectively, Ascriping to the single bond between S and C atoms.On the other hand one relative short bond 1.675 ? between S(2)-C(1) was found .It suggests one weak double bond (typical C=S double bond distance =1.611 ?) between S(2)-C(1) which may originate from the fact that there is thio group in molecular of 1.The relative short bond lengths of N(1)-C(1) (1.310 ?) also declares the existence of 1b. It is showing that has a tautomer 1 and 1b(Figure 2)
ⅱThe chiral ligand of 1 as catalyst was used to addition of benzaldehyde with diethylzinc and product 3, 90%e.e.was obtained. Interestingly we found the configuration of 3 is S. Although 1-phenyl-1-propyl alchohol with R configuration was obtained under the catalysis of
Scheme 2 Enantioselective addition of diethylzinc to benzaldehyde
ⅲWe studied the reaction mechanism of addition of diethylzinc to benzaldehyde as follow:
Scheme3 A tentative mechanism for enantioselective diethylzinc addition to benzaldehyde in the presence of cat.1
The ethyl group of zinc was attacked to carbonyl of benzaldihyde from Si-face and the product of S-configuration was obtained.
ⅡResolution of D,L-threo-p-methylsulfonylphenylserine ester, with (R)TTCA as resolving agent.
ⅰR(-)TTCA was used as resolving agent in kinetic resolution of D,L-threo-p-methylsulfonylphenylserine ester, the structure of R(-)TTCA·D -(+)-threo-p-methylsulfonylphenyl -serine ester derived from the reaction was characterized by infrared and NMR. The enantiomeric excess of L-threo-p-MethylsulfonylPhenyl serine ester and D-threo-p-methylsulfonylphenylserine ester obtained were higher than 99 % .
ⅱWe observed the influence of solvents, reaction temperature and dosage of resolving agents on resolution reactions. the R(-)TTCA·D-(+)-threo-p-methylsulfonylphenylserine ester could not yield in solid form from the reaction When water and DMSO were used as solvents. General organic solvents could be used in the reaction. Suitable temperature was between room temperature and 50°C. The reaction could not proceed when temperature was down to 0°C.
ⅲWe determined the molar ratio of resolving agents and the racemic ester that was 1:2.
ⅢAmmonium salts were formed in reactions of adamantanamine with (R) TTCA or other organic acids and studied their anti-tumor activity.
ⅰIn this paper, we prepared 17 kinds of ammonium salts of adamantanamine with (R) TTCA and with organic acids for the first time and determined their structure with IR, element analysis and NMR.
ⅱThe anti-tumor effect of these ammonium salts were studied by the method of MTT in vitro. Nicotinic acid adamantanamine salt, chloroacetic acid adamantanamine salt and oxalic acid adamantanamine salt showed better anti-tumor effect to human hepatoma cell SMMC-7721 and human gastric cancer cell SGC-7901, and lower toxicity to normal cells.
ⅲwe investigated the anti-tumor effect of nicotinic acid adamantanamine salt, by animal model of transplanted tumor in mice
(i) The anti-tumor activity and side effects of nicotinic acid adamant -anamine salt were studied by using mice model bearing hepatoma H22. The results of this experiment indicated that nicotinic acid adamantanamine salt could inhibit the growth of transplanted tumor H22 in mice with a highest tumor inhibition rate of 51.49%; No toxicity to white cell of peripheral blood and no side effects as lowering weight of spleen and thymus were noted. In medium dosage group, nicotinic acid adamantanamine salt promoted proliferation of T Lymphocy in spleen.
(ii) Using mice bearing transplanted hepatoma H22 and 5-fluorouracil as positive control drug, we observed influence of chloroacetic acid adamantanamine salt on tumor inhibition ratio, organ index, peripheral leukocytes, bone marrow nucleated cells, bone marrow DNA, catalase and malondialdehyde. The results indicated chloroacetic acid adamantanamine salt could effectively inhibit growth of hepatoma H22 in mice with a highest inhibition rate of 44.4% and showed dose dependent. In all three groups, leukocyte count in blood, weight of spleen and thymus were increased. No inhibition of hematopoietic function of bone marrow was noted in medium and high dosage group. MDA level in mice bearing hepatoma were lowered to some extent. Less side effects like bone marrow inhibition and immune system inhibition were caused compared with by positive control drug. No damage to immune function, hematopoietic function and antioxidation ability was exhibited.
ⅳWe discussed the relationship between the structure of the organic acids which formed ammonium salts with adamantanamine and anti-tumor activity that electron-atracting group(electronegativity) ofα-position of carbosylic acid showed better anti-tumor activity.
Compared structur of nicotinic adamantanamine salt isonicotinic adamantanamine salt that stereoscopic place of carboxy group have demonstrated a different effect of antitumor activity.
We have been requesting patent of antitumor activity of nicotinic, chloroacetic acid and oxalic acid adamantanamine salts.
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