在侧链具有ω-羧基烷氧基或ω-羧基-1-炔基取代的吡利曲辛及其他二氨基嘧啶二氢叶酸还原酶抑制剂新类似物的设计、合成及抗叶酸活性
Design, synthesis, and antifolate activity of new analogues of piritrexim and other diaminopyrimidine dihydrofolate reductase inhibitors with omega-carboxyalkoxy or omega-carboxy-1-alkynyl substitution in the side chain.
作者信息
Chan David C M, Fu Hongning, Forsch Ronald A, Queener Sherry F, Rosowsky Andre
机构信息
Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
出版信息
J Med Chem. 2005 Jun 30;48(13):4420-31. doi: 10.1021/jm0581718.
As part of a search for dihydrofolate reductase (DHFR) inhibitors combining the high potency of piritrexim (PTX) with the high antiparasitic vs mammalian selectivity of trimethoprim (TMP), the heretofore undescribed 2,4-diamino-6-(2',5'-disubstituted benzyl)pyrido[2,3-d]pyrimidines 6-14 with O-(omega-carboxyalkyl) or omega-carboxy-1-alkynyl groups on the benzyl moiety were synthesized and tested against Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium DHFR vs rat DHFR. Three N-(2,4-diaminopteridin-6-yl)methyl)-2'-(omega-carboxy-1-alkynyl)dibenz[b,f]azepines (19-21) were also synthesized and tested. The pyridopyrimidine with the best combination of potency and selectivity was 2,4-diamino-5-methyl-6-[2'-(5-carboxy-1-butynyl)-5'-methoxy]benzyl]pyrimidine (13), with an IC(50) value of 0.65 nM against P. carinii DHFR, 0.57 nM against M. avium DHFR, and 55 nM against rat DHFR. The potency of 13 against P. carinii DHFR was 20-fold greater than that of PTX (IC(50) = 13 nM), and its selectivity index (SI) relative to rat DHFR was 85, whereas PTX was nonselective. The activity of 13 against P. carinii DHFR was 20 000 times greater than that of TMP, with an SI of 96, whereas that of TMP was only 14. However 13 was no more potent than PTX against M. avium DHFR, and its SI was no better than that of TMP. Molecular modeling dynamics studies using compounds 10 and 13 indicated a slight binding preference for the latter, in qualitative agreement with the IC(50) data. Among the pteridines, the most potent against P. carinii DHFR and M. avium DHFR was the 2'-(5-carboxy-1-butynyl)dibenz[b,f]azepinyl derivative 20 (IC(50) = 2.9 nM), whereas the most selective was the 2'-(5-carboxy-1-pentynyl) analogue 21, with SI values of >100 against both P. carinii and M. avium DHFR relative to rat DHFR. The final compound, 2,4-diamino-5-[3'-(4-carboxy-1-butynyl)-4'-bromo-5'-methoxybenzyl]pyrimidine (22), was both potent and selective against M. avium DHFR (IC(50) = 0.47 nM, SI = 1300) but was not potent or selective against either P. carinii or T. gondii DHFR.
作为寻找二氢叶酸还原酶（DHFR）抑制剂的一部分工作，旨在将吡利霉素（PTX）的高效能与甲氧苄啶（TMP）对寄生虫相对于哺乳动物的高选择性相结合，合成了迄今未描述的2,4 - 二氨基 - 6 -（2',5'-二取代苄基）吡啶并[2,3 - d]嘧啶6 - 14，其苄基部分带有O -（ω - 羧基烷基）或ω - 羧基 - 1 - 炔基，并针对卡氏肺孢子虫、刚地弓形虫以及鸟分枝杆菌的DHFR与大鼠DHFR进行了测试。还合成并测试了三种N -（2,4 - 二氨基蝶啶 - 6 - 基）甲基）-2'-（ω - 羧基 - 1 - 炔基）二苯并[b,f]氮杂卓（19 - 21）。效能和选择性最佳组合的吡啶并嘧啶是2,4 - 二氨基 - 5 - 甲基 - 6 - [2' -（5 - 羧基 - 1 - 丁炔基）-5'-甲氧基]苄基]嘧啶（13），其对卡氏肺孢子虫DHFR的IC(50)值为0.65 nM，对鸟分枝杆菌DHFR的IC(50)值为0.57 nM，对大鼠DHFR的IC(50)值为55 nM。13对卡氏肺孢子虫DHFR的效能比PTX（IC(50) = 13 nM）高20倍，其相对于大鼠DHFR的选择性指数（SI）为85，而PTX没有选择性。13对卡氏肺孢子虫DHFR的活性比TMP高20000倍，SI为96，而TMP的SI仅为14。然而，13对鸟分枝杆菌DHFR的效能并不比PTX高，其SI也不比TMP好。使用化合物10和13进行的分子模拟动力学研究表明，后者具有轻微的结合偏好，这与IC(50)数据定性一致。在蝶啶类化合物中，对卡氏肺孢子虫DHFR和鸟分枝杆菌DHFR最有效的是2' -（5 - 羧基 - 1 - 丁炔基）二苯并[b,f]氮杂卓基衍生物20（IC(50) = 2.9 nM），而最具选择性的是2' -（5 - 羧基 - 1 - 戊炔基）类似物21，相对于大鼠DHFR，其对卡氏肺孢子虫和鸟分枝杆菌DHFR的SI值均>100。最后一种化合物，2,4 - 二氨基 - 5 - [3' -（4 - 羧基 - 1 - 丁炔基）-4'-溴 - 5'-甲氧基苄基]嘧啶（22），对鸟分枝杆菌DHFR既有效又有选择性（IC(50) = 0.47 nM，SI = 1300），但对卡氏肺孢子虫或刚地弓形虫DHFR既无效能也无选择性。
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