Paper Spotlight: ASDRP students publish anticancer small molecule study

Earlier this month, students from Dr. Njoo, Dr. Chen, and Dr. Zhang’s research groups published a collaborative paper in the journal Bioorganic and Medicinal Chemistry Letters - “Synthesis, antiproliferative activity, and biological profiling of C-19 trityl and silyl ether andrographolide analogs in colon cancer and breast cancer cells”, which is now published online - (DOI: https://doi.org/10.1016/j.bmcl.2025.130163). This project, headed by senior Tiffany Gu (Harker ‘25), junior Rushika Raval (Irvington ‘26), senior Carina Zhou (MSJHS ‘25), senior Sanghyuk Ko (Homestead ‘25), senior Natalie Kong (American ‘25) and alumni Zachary Bashkin (UC Berkeley ‘27) together with over a dozen other students. Junior Rushika Raval recalls, “Throughout this publication process, I was introduced to cell-culture and learned how to conduct complex biological experiments, assessing the activity of synthesized natural product analogs. Facing multiple challenges, especially under the time constraints of peer review, taught me far more than just troubleshooting technical and experimental failures. Beyond the technical skills I learned, the challenges pushed us to become more resourceful, adaptable, and thoughtful in how we prioritize our efforts. These are all skills I will take with me in my future academic career.”

The Paper Spotlight - The project details the synthetic derivatization of a natural product called andrographolide, which is the bioactive substituent from the plant Andrographis paniculata, whose extracts have been utilized for several millennia in traditional herbal medicine in Ayurvedic medicine across ancient India, Sri Lanka, and other peoples in southeast Asia. This paper is one of several from our chemistry department in developing natural product analogs with altered biological properties that may provide leads for the development of future therapeutics (for representative papers from ASDRP, see Lu, et al. Natural Product Research 2024; Somani, et al. bioRxiv 2025; Zhou, et al. J. Emerg. Inv. 2022; Gutti, et al. bioRxiv 2025). 

The project that is now published was initiated in January of 2023, and was inspired by prior work from other groups whose research suggested that modifications at a key hydroxyl group on andrographolide leads to potent anticancer activity through modulation of the Wnt1/β-catenin signaling pathway, which is dysregulated in many cancer types including colorectal cancer. 

The Njoo lab team, including now-alumni Anushree Marimuthu (U of Washington), Srishti Venkatesan (MIT), Alice Tao (UC Berkeley), Emily Shu (UC Berkeley), Lorelei Xia (Purdue), completed chemical synthesis of the first eight analogs of andrographolide by September of 2023, and passed the compound library to collaborators in the Zhang lab and Chen lab for further biological evaluation, at which point a clear pattern began to emerge in several compounds of this series exhibiting unique selectivity for human colon cancer over breast cancer cell lines. By early 2024, more detailed biological evaluation was passed back to the Njoo lab; led by senior Natalie Kong, the team conducted immunofluorescence imaging to track intracellular β-catenin localization using our powerful fluorescence microscopes in our bioengineering laboratory, and led by junior Rushika Raval, the team employed a series of reporter cells that are specially engineered to provide a colorimetric readout for the activation of the NF-κB and Wnt1 signaling pathways when cells are treated with each compound. Collectively, these assays provide a precise and quantitative way to understand how these compounds exert their activity in cancer cells. From this study, the team identified a potent new analog of andrographolide with a 4-chlorobutyldimethyl silicon group that has several orders of magnitude greater potency than the natural product in targeting human breast and colon cancer cells, and highlights the potential for synthetic chemistry to develop non-natural derivatives of biologically active natural compounds as new therapeutic leads for the treatment of cancer.

The team submitted the initial manuscript to Bioorganic and Medicinal Chemistry Letters for peer review in October of 2024, and received the first round of reviews in early December. The three peer reviewers, one of whom was an expert in medicinal chemistry and another who was an expert in signaling transduction pathways in cancer, requested several validation experiments, and after three rounds of peer review, the manuscript was accepted for publication in January of 2025. When asked about what advice they would give about publishing to other students at ASDRP, Raval states, “To those who wish to publish their research, my biggest piece of advice would be to embrace the inevitable setbacks, and recognize that the journey is not bound to be smooth. And generally, those are the times that spark meaningful growth — both personally and scientifically.”