A recent study published in Molecules has tested multiple thiazole-based derivatives that appear to activate the sirtuin SIRT1 more than resveratrol [1].
Sirtuins
Resveratrol, commonly found in grape skins and red wine, generated some of the initial interest in sirtuin activators after initial studies showing many therapeutic benefits, such as cancer prevention [2]. Combined with the discovery of the seven human homologs of the yeast Sir2 protein [3], researchers delved into ways to stimulate sirtuin genes.
These sirtuins (Sir2-like proteins) have great relevance to the mechanisms of aging. The seven sirtuin proteins (SIRT1-7) are NAD-dependent enzymes that consume NAD+ to perform their two functions of regulating mono-ADP-ribosylation and performing deacetylation. The NAD+ acts as a cofactor for these functions and has created a whole branch of research around NAD+ precursors, such as NMN and NR, that lead to the stimulation of sirtuin activity.
Sirtuin activators work by increasing the binding affinity to acetylated substrates; for example, MDL-800 increases SIRT6’s binding affinity, and hence activity, 22-fold [4]. Resveratrol greatly activates SIRT1, a cancer-suppressing protein with many other health benefits [5], but it is limited in its bioavailability, leading to impressive results in vitro but subpar in vivo results [6].
Molecular adjustments
These specific compounds had not been previously tested regarding sirtuin activation, but they were similar to other molecules that the research group had tested. The researchers made slight changes to these synthetic molecules, which are based on natural polyphenol activators such as resveratrol, and measured their ability to activate the gene.
These molecular alterations involved the movement of hydroxide groups, and placing these groups at specific places on the ends of the molecule proved useful. Different concentrations of each of the new compounds were tested against a reference treatment of resveratrol (100 µM) in vitro. At least two compounds performed similarly, and one had 116% ± 25.9% SIRT1 activation compared to resveratrol. With lower concentrations of 10 and 30 µM, compounds 8 and 9 showed 140% ± 8% and 155% ± 3%, respectively.
This compound showed higher activation of SIRT1 genes without causing any toxic events in vitro at 10 µM. In vivo tests were performed in a rat model of ischemic heart disease and demonstrated significant positive effects, protecting them against injury.
Conclusion
This new molecule has been shown to activate SIRT1 to a greater extent than resveratrol. In vivo tests of bioavailability have yet to be done, but this is a promising start for a new and potentially superior SIRT1-activating compound. While sirtuins are still not fully understood and overexpression may lead to increased tumor cell migration and lung metastasis [7], this is still a critical discovery of a new class of thiazole-based SIRT1-activating compounds.
Literature
[1] Bononi, G., Citi, V., Lapillo, M., Martelli, A., Poli, G., Tuccinardi, T., Granchi, C., Testai, L., Calderone, V., & Minutolo, F. (2022). Sirtuin 1-Activating Compounds: Discovery of a Class of Thiazole-Based Derivatives. Molecules, 27(19). https://doi.org/10.3390/molecules27196535
[2] Jang, M., Cai, L., Udeani, G. O., Slowing, K. v., Thomas, C. F., Beecher, C. W. W., Fong, H. H. S., Farnsworth, N. R., Kinghorn, A. D., Mehta, R. G., Moon, R. C., & Pezzuto, J. M. (1997). Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science, 275(5297), 218–220. https://doi.org/10.1126/science.275.5297.218
[3] Frye, R. A. (2000). Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochemical and Biophysical Research Communications, 273(2), 793–798. https://doi.org/10.1006/bbrc.2000.3000
[4] Huang, Z., Zhao, J., Deng, W., Chen, Y., Shang, J., Song, K., Zhang, L., Wang, C., Lu, S., Yang, X., He, B., Min, J., Hu, H., Tan, M., Xu, J., Zhang, Q., Zhong, J., Sun, X., Mao, Z., … Zhang, J. (2018). Identification of a cellularly active SIRT6 allosteric activator. Nature Chemical Biology, 14(12), 1118–1126. https://doi.org/10.1038/s41589-018-0150-0
[5] Chen, C., Zhou, M., Ge, Y., & Wang, X. (2020). SIRT1 and aging related signaling pathways. In Mechanisms of Ageing and Development (Vol. 187). Elsevier Ireland Ltd. https://doi.org/10.1016/j.mad.2020.111215
[6] Yu, C., Shin, Y. G., Chow, A., Li, Y., Kosmeder, J. W., Lee, Y. S., Hirschelman, W. H., Pezzuto, J. M., Mehta, R. G., & van Breemen, R. B. (2002). Human, Rat, and Mouse Metabolism of Resveratrol.
[7] Suzuki, K., Hayashi, R., Ichikawa, T., Imanishi, S., Yamada, T., Inomata, M., Miwa, T., Matsui, S., Usui, I., Urakaze, M., Matsuya, Y., Ogawa, H., Sakurai, H., Saiki, I., & Tobe, K. (2012). SRT1720, a SIRT1 activator, promotes tumor cell migration, and lung metastasis of breast cancer in mice. Oncology Reports, 27(6), 1726–1732. https://doi.org/10.3892/or.2012.1750