The Rice lab of synthetic chemist K.C. Nicolaou announced this month it had streamlined the total synthesis of uncialamycin to make it simpler to create novel variations of the molecule. Such variations could allow the substance, which is too toxic in its original form, to be made into useful drugs to fight cancer.
The new work by Nicolaou and colleagues appears in the Journal of the American Chemical Society.
Nicolaou’s lab specializes in the synthesis of molecules found in nature with medicinal properties, but in amounts too small for testing or clinical use. The new process is scalable for bulk production, he said.
Uncialamycin is an enediyne, compounds defined by the presence of nine- and 10-member atomic rings in their structures. Two other enediynes, neocarzinostatin and calicheamicin, are or have been used as chemotherapy agents to treat leukemia and cancers of the liver and the brain.
“The 10-member ring is like the warhead of the molecule,” Nicolaou said. “The ring undergoes the Bergman reaction, producing radicals that cut both strands of the DNA, rendering it difficult to repair by the cell. It’s a Trojan horse that gets inside the cell and causes havoc.”
The payoff has been a long time coming for Nicolaou and his colleagues who began investigating uncialamycin after it was isolated from a strain of streptomycete related to Streptomyces cyanogenus, a marine bacterium, in 2005. The lab reported the total synthesis of the molecule in 2007 and followed up in 2008 with a report on new synthetic versions and demonstration of its DNA-cleaving, antibiotic and cytotoxic capabilities.
He said the newly developed synthetic strategies and methods make it possible to synthesize a series of designed analogs of the molecule for biological evaluation. As part of the new study, the lab synthesized not only pure synthetic uncialamycin but also 13 variants of the molecule, with handles for attachment to cancer-cell-associated antibodies and other drug-delivery systems.
These were tested for their potency against lung, gastric, ovarian and multidrug-resistant cancer cell lines. Three of the variants showed “remarkably high potency against the tested cell lines,” the researchers reported.
Nicolaou said the analogs proved stable enough to be used as payloads in antibody drug conjugates that combine a delivery system – an antibody capable of recognizing and targeting cancer cells – with the anti-cancer drug through a chemical linker that joins the two until they reach the target.
Co-authors of the paper are Rice postdoctoral fellow Yanping Wang, graduate student Ruocheng Yu and former postdoctoral fellow Akshay Shah, now a senior scientist at Pfizer; Min Lu, now a senior scientist at Merck, Debashis Mandal and postdoctoral fellow Manas Pattanayak of Rice and the Scripps Research Institute, La Jolla, Calif.; Jason Chen, Hongjun Zhang, James Crawford and Laxman Pasunoori of the Scripps Institute; Yam Poudel, Naidu Chowdari, Chin Pan, Ayesha Nazeer and Sanjeev Gangwar of Bristol-Myers Squibb Research and Development, Redwood City, Calif., Gregory Vite of Bristol-Myers Squibb Research and Development, Princeton, N.J., and Emmanuel Pitsinos of the National Centre of Scientific Research, Greece.
The National Institutes of Health, the Skaggs Institute for Research, the Cancer Prevention and Research Institute of Texas, the Welch Foundation, Bristol-Myers Squibb and the U.S.-U.K. Fulbright Commission supported the research.