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Synthesis of 1-(4-hydroxy-3-methoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid derivatives as mast cell stabilizers
Medicinal Chemistry Research ( IF 2.6 ) Pub Date : 2020-05-12 , DOI: 10.1007/s00044-020-02555-y
Karan Saini , Jatinder Singh , Ramanpreet Shah , Jaspreet Kaur , Dhandeep Singh , Nirmal Singh , Amteshwar Singh Jaggi , Dimple Sethi Chopra , Ram Sarup Singh

The role of mast cells can be protective or harmful; depending upon the physiological/pathological condition in which they get activated. The latter role is due to mast cell degranulation and release of an array of incendiary mediators. Mast cells have a well-established role in diseases like allergy, eczema, anaphylactic shock, mastocytosis, and other miscellaneous mast cell diseases. Previously, we have shown that spiro-β-carboline alkylated analogs have mast cells stabilization activity. Recently, tryptophan has been reported to suppress the mast cell activation. Indeed, vanillin analogs were reported to inhibit degranulation. Hence, it is worthwhile to synthesize 21 constrained analogs of tryptophan with vanillin which are derivatives of 2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid and their evaluation for ex-vivo inhibition of the compound 48/80 induced mast degranulation activity. By comparing IC50 (µM) values with standard drug cromolyn sodium (IC50 = 0.486 ± 0.003 µM), the bulky group compounds like tri-substituted isopropyl (compound 7; cis-1-(4-Isopropoxy-3-methoxyphenyl)-2,9-diisopropyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid; IC50 = 0.389 ± 0.015 µM) and tri-substituted octyl (compound 17; cis-1-(3’-Methoxy-4’-(octyloxy)phenyl)-2,9-dioctyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid; IC50 = 0.237 ± 0.031 µM) were found to be equipotent. Furthermore, the polar group SO2 containing compound tosyl derivative (compound 21; cis-1-(4’-hydroxy-3’-methoxyphenyl)-2-tosyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid; IC50 = 1.16 ± 0.080 µM) also showed marked potency. This is an important study of β-carboline derivatives showing mast cell stabilization having a wider scope in mast cell research, although their mechanism remains to be unknown.


中文翻译:

肥大细胞稳定剂1-(4-羟基-3-甲氧基苯基)-2,3,4,9-四氢-1H-β-咔啉-3-羧酸衍生物的合成

肥大细胞的作用可以是保护性的或有害的;取决于它们被激活的生理/病理状况。后者的作用是由于肥大细胞脱粒和一系列燃烧介质的释放。肥大细胞在诸如变态反应,湿疹,过敏性休克,肥大细胞增多症以及其他各种肥大细胞疾病中具有公认的作用。以前,我们已经证明螺-β-咔啉烷基化类似物具有肥大细胞稳定活性。最近,色氨酸被报道抑制肥大细胞的活化。实际上,据报道香兰素类似物抑制脱粒。因此,值得合成21个色氨酸与香草醛的受限类似物,它们是2,3,4,9-四氢-β-咔啉-3-羧酸的衍生物,并对其进行离体评估抑制化合物48/80诱导的肥大脱粒活性。通过将IC 50(µM)值与标准药物克罗莫林钠(IC 50  = 0.486±0.003 µM)进行比较,可得到大体积的基团化合物,如三取代异丙基(化合物7;顺式-1-(4-异丙氧基-3-甲氧基苯基)- 2,9-二异丙基-2,3,4,9-四氢-1 H -β-咔啉-3-羧酸; IC 50  = 0.389±0.015 µM)和三取代辛基(化合物17;-1-( 3'-甲氧基-4'-(辛氧基)苯基)-2,9-二辛基-2,3,4,9-四氢-1 H -β-咔啉-3-羧酸; IC 50  = 0.237±0.031 µM)被发现是等势的。此外,极性基团SO 2含有化合物甲苯磺酰基衍生物(化合物21;顺式-1-(4'-羟基-3'-甲氧基苯基)-2-甲苯磺酰基-2,3,4,9-四氢-1 H -β-咔啉-3-羧酸; IC 50  = 1.16±0.080 µM)也显示出明显的效价。这是一项重要的β-咔啉衍生物研究,显示肥大细胞稳定在肥大细胞研究中具有更广泛的范围,尽管其机理尚不清楚。
更新日期:2020-05-12
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