Chemists synthesize guava-derived molecule that halts liver cancer cells in lab

University of Delaware chemists said they have developed a laboratory method to produce a naturally occurring guava compound that halts the growth of human liver cancer cells in petri dishes, a step researchers say could enable development of new targeted therapies for a disease that kills about 30,000 Americans a year.

The team reported the total synthesis of (-)-psiguadial A, a molecule originally isolated from guava plants native to Mexico, Central America, the Caribbean and parts of South America. The researchers said the compound demonstrated potent activity against human liver cancer cells in laboratory tests and that their synthetic route uses common chemicals, making scalable production feasible where extraction from plants would not meet demand.

William Chain, an associate professor in the university’s Department of Chemistry and Biochemistry and senior author of the study, said the advance provides a reproducible “recipe” other chemists can follow to make the molecule in the lab. "The majority of clinically approved medicines are either made from a natural product or are based on one," Chain said. "But there aren't enough natural resources to make enough treatments. Now chemists will be able to take our manuscripts and basically follow our 'recipe' and they can make it themselves."

The researchers described three central technical steps. They first constructed a complex component of the molecule with the precise three-dimensional arrangement required for activity. They then joined that component to another molecular fragment, overcoming a major hurdle because the bonding sites were sterically crowded and buried amid other atoms. Finally, the team triggered a reaction that caused the molecule to cyclize, forming a characteristic ring structure the researchers said is central to the compound’s activity.

Laboratory measurements of (-)-psiguadial A showed potency against human liver cancer cell lines grown in culture. Previous work with crude guava extracts and related molecules suggested anti-cancer effects, and a 2023 international study found that concentrated guava leaf extract prompted apoptosis, or programmed cell death, in liver cancer cells and inhibited growth in a dose-dependent manner. The University of Delaware team said their synthetic product makes it possible to obtain large, pure quantities for more extensive testing.

Researchers cautioned that the compound has not been tested in human patients. The precise mechanism by which (-)-psiguadial A kills cancer cells remains under investigation, and additional work will be needed to optimize the molecule, evaluate safety and efficacy in animals, and conduct clinical trials in people. "We are the first ones to pave that road, and other people can repave it any which way," said Liam O'Grady, a doctoral student in Chain's lab and the article's first author. "Find the shortcuts if they have to. But since we entered into that unknown territory, I think we helped shed light on this unknown pathway that can get us there."

The research team has partnered with the U.S. National Cancer Institute to test the guava-derived molecule against other cancer types and to advance preclinical development. Previous laboratory screening of extracts containing related compounds examined a broad panel of human cancer lines, including breast, lung, prostate and ovarian cancers, but the synthetic compound itself will need systematic evaluation beyond in vitro studies.

Liver cancer incidence and mortality have risen sharply in recent decades. Health estimates cited by the researchers put annual U.S. cases at roughly 42,000 with about 30,000 deaths each year. Incidence rates have more than tripled since 1980, and death rates have more than doubled. Death rates are reported at about 5.3 per 100,000 in women and 10.1 per 100,000 in men. Trends in disease burden have been linked to increases in obesity, diabetes and nonalcoholic fatty liver disease, along with persistent contributions from alcohol use and hepatitis C. Researchers noted that some declines in male cases may reflect lower smoking rates and widespread hepatitis B vaccination.

Prognosis for advanced liver cancer remains poor: fewer than 15 of every 100 patients with advanced disease survive five years, and available treatment options are limited. The researchers said a scalable synthetic route to (-)-psiguadial A could eventually support development of a new class of targeted therapies intended to be more precise and have fewer systemic side effects than traditional chemotherapy, but they warned that translation to patient care is likely years away and will require interdisciplinary collaboration among chemists, pharmacologists and clinicians.

The University of Delaware team said their work demonstrates how chemical synthesis can make scarce natural molecules available for broad study and potential drug development. They described their synthesis and offered the methods to the scientific community so other groups can attempt optimizations, mechanistic studies and preclinical testing that would be required before any human trials.

Further research will seek to define how (-)-psiguadial A affects cancer-cell biology, evaluate its safety profile in animal models, and determine whether analogs or derivatives might improve potency or reduce toxicity. The partnership with the National Cancer Institute is intended to expand testing and accelerate the pathway from laboratory discovery to potential clinical evaluation.