Department of Biotechnology, University of Rijeka, Radmile Matejčić 2, Rijeka, 51000, Croatia.
Medical Faculty, Juraj Dobrila University of Pula, Zagrebačka 30, 52100, Pula, Croatia.
Curr Med Chem. 2024;31(25):3997-4021. doi: 10.2174/0109298673272687231226111132.
While granulatamides A and B have been previously isolated, their biological activities have been only partially examined. The aim of this study was to synthesize granulatamide B (4b), a tryptamine-derivative naturally occurring in coral species, using the well-known procedure of Sun and Fürstner and its 12 structural analogues by modifying the side chain, which differs in length, degree of saturation as well as number and conjugation of double bonds.
The prepared library of compounds underwent comprehensive assessment for their biological activities, encompassing antioxidative, antiproliferative, and antibacterial properties, in addition to toxicity evaluation using a Zebrafish model. Compound 4i, which consists of a retinoic acid moiety, exhibited the strongest scavenging activity against ABTS radicals (IC = 36 ± 2 μM). In addition, 4b and some of the analogues (4a, 4c and 4i), mostly containing an unsaturated chain and conjugated double bonds, showed moderate but non-selective activity with certain IC values in the range of 20-40 μM.
In contrast, the analogue 4l, a derivative of alpha-linolenic acid, was the least toxic towards normal cell lines. Moreover, 4b was also highly active against Gram-positive with an MIC of 125 μM. Nevertheless, both 4b and 4i, known for the best-observed effects, caused remarkable developmental abnormalities in the zebrafish model .
Since modification of the side chain did not significantly alter the change in biological activities compared to the parent compound, granulatamide B (4b), the substitution of the indole ring needs to be considered. Our group is currently carrying out new syntheses focusing on the functionalization of the indole core.
虽然 previously isolated 已经分离出 granulatamides A 和 B，但它们的生物活性仅部分得到了研究。本研究的目的是使用 Sun 和 Fürstner 已知的方法合成 granulatamide B（4b），这是一种在珊瑚物种中天然存在的色胺衍生物，并通过修饰侧链来合成 12 个结构类似物，该侧链在长度、饱和度以及双键的数量和共轭上有所不同。
对合成的化合物库进行了全面评估，包括抗氧化、抗增殖和抗菌活性，以及使用斑马鱼模型进行毒性评估。含有视黄酸部分的化合物 4i 对 ABTS 自由基的清除活性最强（IC = 36 ± 2 μM）。此外，4b 和一些类似物（4a、4c 和 4i）主要含有不饱和链和共轭双键，具有中等但非选择性的活性，某些 IC 值在 20-40 μM 范围内。
相比之下，类似物 4l 是 alpha-亚麻酸的衍生物，对正常细胞系的毒性最小。此外，4b 对革兰氏阳性菌也具有高度活性，MIC 为 125 μM。然而，4b 和 4i 都表现出最好的观察效果，在斑马鱼模型中引起了显著的发育异常。
由于与母体化合物相比，侧链的修饰并没有显著改变生物活性的变化，因此需要考虑对 granulatamide B（4b）进行取代。我们的小组目前正在进行新的合成，重点是吲哚环的功能化。
