新型钙拮抗剂——二氢嘧啶酮甲磺酸及其配合物的合成与生物活性研究

Since the physiological activities and the pharmaceutical activities of dihydropyrimidinones (DHPMs), such as calcium antagonistic activity, hypotensive activity, α-1a-antagonistic activity, antifungal activity, anti-hepatitis b virus activity and anticancer activity, have aroused great interest, the research on synthesizing DHPMs, in recent years, has become one of the hot spots in the field of study on organic heterocyclic compounds. Most DHPMs have low water solubility or alcohol solubility, influencing their bioavailability and the rate of showing effect. Therefore, this project is about the following aspects:(1) studying the sulfonation of DHPMs and synthesizing new compounds of dihydropyrimidinonyl methylene sulfonic acids (DHPMMSAs) and their sodium, potassium, magnesium and calsium complexes; (2) determining their impact on coronary flow and left ventricular systolic pressure of SD rats during myocardial ischemia/reperfusion, as well as their impact on Na+-K+-ATPas, Ca2+-Mg2+-ATPase, lactate dehydrogenase, glutathione peroxidase creatine kinase and superoxide dismutase in the myocardial tissue of SD rats; (3) investigating the correlation between bioactivity and molecular structure of these compounds and analyzing the mechanisms of pharmaceutical activities; (4) researching on their stability and toxicity; (5) inquiring into the theoretical value and the practical significance of them for developing new type of calcium antagonists.

二氢嘧啶酮类化合物的钙拮抗、降压、α-1a-拮、抗真菌、抗乙肝病毒、抗癌等多种生理和药理活性引起了人们极大的研究兴趣，近年来对它的合成已成为生物活性有机杂环化合物研究领域的热点之一。由于大多数二氢嘧啶酮类化合物水溶性或醇溶性较低，药用时会影响其生物利用度和显效速率,因此本项目研究二氢嘧啶酮类化合物的磺化改性，合成一类未见文献报道的二氢嘧啶酮甲磺酸及其钠、钾、镁和钙配合物；研究它们对SD大鼠心脏缺血／再灌注时冠脉流量及左心室收缩压的影响，对心肌组织中钠钾ATP酶、钙镁ATP酶、乳酸脱氢酶、谷胱甘肽过氧化物酶、肌酸激酶和超氧化物歧化酶活性的影响；探讨其生物活性与分子结构的关联性、药效分子作用机理以及稳定性和急性毒性；研究其对开发新型的钙拮抗剂的理论价值和现实意义。

二氢嘧啶酮类化合物的钙拮抗、降压、α-1a-拮、抗真菌、抗乙肝病毒、抗癌等多种生理和药理活性引起了人们极大的研究兴趣，近年来对它的合成研究已成为生物活性有机杂环化合物研究领域的热点之一。本项目利用biginelli反应，合成了23种不同取代的二氢嘧啶酮化合物，利用这些化合物作原料进行磺化反应，首次合成了5种不同取代的二氢嘧啶酮甲磺酸及其钠、钾、镁、钙、锌或锰等金属的10个配合物，研究了其中4种金属配合物的热稳定性和荧光性质。对(6-苯基-5-乙氧羰基-1,6-二氢嘧啶-2(3H)-酮-4-基)甲磺酸和(6-甲基-5-乙氧羰基-1,6-二氢嘧啶-2(3H)-酮-4-基)甲磺酸在水或乙醇中的溶解性进行了测定，结果表明：将磺酸基引入不同取代的二氢嘧啶酮分子中能不同程度的改善其在水或乙醇中的溶解性；对外消旋(6-苯基-5-乙氧羰基-1,6-二氢嘧啶-2(3H)-酮-4-基)甲磺酸进行了拆分试验；对SD大鼠心肌组织用(6-苯基-5-乙氧羰基-1,6-二氢嘧啶-2(3H)-酮-4-基)甲磺酸或其钠盐处理后进行了生化指标的测定，结果表明：该化合物能提高超氧化物歧化酶(SOD)、肌酸激酶(CK)、 Na+-K+-ATP酶、以及Ca2+-Mg2+-ATP酶的活性，降低丙二醛的含量，而对乳酸脱氢酶(LDH)、谷胱甘肽过氧化物酶(GSH-Px)、过氧化氢酶(CAT)、总一氧化氮合酶(TNOS)、诱导型一氧化氮合酶(iNOS)、内皮细胞性一氧化氮合酶(eNOS)的活性无明显影响。该化合物能够对SD大鼠心肌缺血再灌注损伤起保护作用；对(6-苯基-5-乙氧羰基-1,6-二氢嘧啶-2(3H)-酮-4-基)甲磺酸钠、(6-苯基-5-乙氧羰基-1,6-二氢嘧啶-2(3H)-酮-4-基)甲磺酸钾、(6-(对-氟苯基)-5-乙氧羰基-1,6-二氢嘧啶-2(3H)-酮-4-基)甲磺酸钠、(5-乙氧羰基-1,6-二氢嘧啶-2(3H)-酮-4-基)甲磺酸钾和(6-甲基-5-乙氧羰基-1,6-二氢嘧啶-2(3H)-酮-4-基)甲磺酸钾等5个化合物进行了抑制肿瘤细胞生长的试验，结果表明：该5个化合物对HeLa和Bel-7402细胞生长的抑制效果较阳性对照药物5-氟尿嘧啶的效果差。