Sulforaphane and Isothiocyanate Analogues in Cisplatin-Induced Kidney Injury: A Review

The supplied study provides a compact but useful example of how a natural isothiocyanate scaffold can be transformed into a small analogue library to address cisplatin-associated renal cytotoxicity. The modular CS2/Boc2O/DMAP synthetic sequence enabled preparation of 16 sulforaphane-type isothiocyanates, and the resulting SAR demonstrated that side-chain architecture strongly influences cytoprotective activity. SF5 emerged as the most compelling analogue in the reported screen, producing approximately 93% cell survival at 2.5 µM and reducing apoptosis-associated signaling in cisplatin-treated LLC-PK1 cells. [1] From a current perspective, the significance of the work extends beyond the original JNK–p53–caspase-3 observation. Subsequent research has reinforced the importance of NRF2-mediated antioxidant and cytoprotective signaling in cisplatin kidney injury and has continued to support sulforaphane as a promising preclinical renoprotective agent. Accordingly, future sulforaphane analogue development should integrate medicinal chemistry, quantitative SAR, NRF2 pharmacology, stress-kinase biology, pharmacokinetics and tumor-sparing efficacy. SF5 should therefore be regarded as a valuable lead structure for further investigation rather than as a clinically validated nephroprotective drug.

1. Kim, T., Kim, Y.-J., Han, I.-H., Lee, D., Ham, J., Kang, K. S., & Lee, J. W. (2015). The synthesis of sulforaphane analogues and their protection effect against cisplatin induced cytotoxicity in kidney cells. Bioorganic & Medicinal Chemistry Letters, 25, 62–66. https://doi.org/10.1016/j.bmcl.2014.11.014 2. Motwani, S. M., Sandhu Kaur, S., & Kitchlu, A. (2022/2023). Cisplatin nephrotoxicity: Novel insights into mechanisms and preventative strategies. Seminars in Nephrology, 42(6), 151341. https://doi.org/10.1016/j.semnephrol.2023.151341 3. Manohar, S., & Leung, N. (2018). Cisplatin nephrotoxicity: A review of the literature. Journal of Nephrology, 31, 15–25. 4. Dasari, S., & Tchounwou, P. B. (2014). Cisplatin in cancer therapy: Molecular mechanisms of action. European Journal of Pharmacology, 740, 364–378. 5. Guerrero-Beltrán, C. E., Calderón-Oliver, M., Tapia, E., Medina-Campos, O. N., Sánchez-González, D. J., Martínez-Martínez, C. M., Ortiz-Vega, K. M., Franco, M., & Pedraza-Chaverrí, J. (2010). Sulforaphane protects against cisplatin-induced nephrotoxicity. Toxicology Letters, 192(3), 278–285. https://doi.org/10.1016/j.toxlet.2009.11.007 6. Mapuskar, K. A., Pulliam, C. F., Zepeda-Orozco, D., et al. (2023). Redox regulation of Nrf2 in cisplatin-induced kidney injury. Antioxidants, 12(9), 1728. https://doi.org/10.3390/antiox12091728 7. Kensler, T. W., Wakabayashi, N., & Biswal, S. (2007). Cell survival responses to environmental stresses via the Keap1–Nrf2–ARE pathway. Annual Review of Pharmacology and Toxicology, 47, 89–116. 8. Atilano-Roque, A., Wen, X., Aleksunes, L. M., & Joy, M. S. (2016). Nrf2 activators as potential modulators of injury in human kidney cells. Toxicology Reports, 3, 153–159. https://doi.org/10.1016/j.toxrep.2016.01.006 9. Pabla, N., & Dong, Z. (2008). Cisplatin nephrotoxicity: Mechanisms and renoprotective strategies. Kidney International, 73, 994–1007. 10. Monteiro, E. B., Ajackson, M., Stockler-Pinto, M. B., Guebre-Egziabher, F., Daleprane, J. B., & Soulage, C. O. (2023). Sulforaphane exhibits potent renoprotective effects in preclinical models of kidney diseases: A systematic review and meta-analysis. Life Sciences, 322, 121664. https://doi.org/10.1016/j.lfs.2023.121664