From RICE: “Rice lab creates tough, but tender, cancer fighters”

Rice U bloc

Rice University

May 30, 2017
Mike Williams

Variations of anti-tumor agents prove effective in the lab against even drug-resistant cancers

1
This is the structure of one of the analogs of epothilone B, a new compound created in the Rice University lab of synthetic organic chemist K.C. Nicolaou that shows promise as a cancer fighter. Courtesy of the Nicolaou Group.

Rice University scientists have developed and evaluated analogs of potent anti-tumor agents known as epothilones using designs and methods that both improve their biological properties and simplify their manufacture.

The substances introduced by Rice synthetic organic chemist K.C. Nicolaou are similar in their cancer-fighting mechanism to paclitaxel, the drug for which he is best-known, but have superior properties. Some compounds of the dozens of variations the scientists created exhibit potent cytotoxicities against certain cancer cells, including a drug-resistant cell line, Nicolaou said.

The new research study is described this month in the Journal of the American Chemical Society.

Like the family of taxanes (of which paclitaxel is a member), epothilones prevent cancer cells from dividing by interfering with tubulin proteins that form the cells’ skeletal microtubules. Tests with kidney cancer and two human uterine sarcoma cell lines, one with multidrug resistance, showed that 10 of these new compounds were impressively potent against all three cell lines, the researchers reported.

“This is another example of a larger theme in our research, that of the synthesis of complex, rare natural products and their analogs for biological investigations,” Nicolaou said. “Our work is directed toward drug discovery and development in collaboration with biotechnology and pharmaceutical companies, particularly in the cancer area.”

The drugs are variations of epothilone B, a natural product isolated from Sorangium cellulosum, slime bacteria that live in soil. Nicolaou and his colleagues achieved the total synthesis of several of the natural products and related substances in the past, but those compounds proved too toxic to be used as anti-cancer drugs, he said.

“These new results are significant because they represent the discovery of a number of more potent variations of the natural product as cytotoxic agents against cancer cells,” Nicolaou said. “This brings these members of the epothilone class within range of suitability as payloads for antibody-drug conjugates, a new paradigm for targeted cancer therapy.”

2
This is the general structure of the newly synthesized aziridine epothilone B analogs developed at Rice University. The red-colored structural motifs designate the novel functionalities introduced into the epothilone B molecule that led to their enhanced properties as cancer-fighting agents. Courtesy of the Nicolaou Group.

Just as important, he said, is the lab’s ability to add chemical “handles” to the molecules that allow them to be attached to drug-delivery systems like cancer-specific antibodies.

Nicolaou compared the reconfiguration of epothilone B, the starting material for their synthesis, with the transplant of body parts, as he and his team replaced components in the molecule to make the designed analogs more effective.

“The strategy we developed to synthesize them can be described as a kind of chemical surgery,” he said. “The most important structural motif we introduced in these new molecules is the three-membered ring containing a nitrogen atom, a so-called aziridine moiety.” The importance of the aziridine ring is not yet clear, he said, but it could serve as a handle to attach the molecule onto an antibody through a linker.

“The other structural motif, the so-called side chain with a basic nitrogen embedded at a strategic position, was achieved through new extensions and improvements developed in our laboratories of the previously known HWE (Horner–Wadsworth–Emmons) reaction,” Nicolaou said. “The HWE reaction is an important process for making olefinic bonds (carbon-carbon double bonds) stereoselectively.”

He said the new line of research was made possible by the work of Rice colleague László Kürti, who with his team developed a “powerful reaction” that offered a simple, scalable and fast method to synthesize aziridine rings from olefins. That research led by Kürti, then of the University of Texas Southwestern Medical Center, John Falck of Southwestern and Daniel Ess of Brigham Young University was reported in Science in 2014.

Lead authors of the paper are Rice postdoctoral researchers Derek Rhoades and Yanping Wang. Co-authors are scientists Ruoli Bai and Ernest Hamel of the National Cancer Institute and scientist Monette Aujay, research associate Joseph Sandoval and principal scientist Julia Gavrilyuk of AbbVie Stemcentrx, San Francisco.

The National Institutes of Health, the Cancer Prevention and Research Institute of Texas and the Welch Foundation supported the research.

See the full article here .

Please help promote STEM in your local schools.

STEM Icon

Stem Education Coalition

Rice U campus

In his 1912 inaugural address, Rice University president Edgar Odell Lovett set forth an ambitious vision for a great research university in Houston, Texas; one dedicated to excellence across the range of human endeavor. With this bold beginning in mind, and with Rice’s centennial approaching, it is time to ask again what we aspire to in a dynamic and shrinking world in which education and the production of knowledge will play an even greater role. What shall our vision be for Rice as we prepare for its second century, and how ought we to advance over the next decade?

This was the fundamental question posed in the Call to Conversation, a document released to the Rice community in summer 2005. The Call to Conversation asked us to reexamine many aspects of our enterprise, from our fundamental mission and aspirations to the manner in which we define and achieve excellence. It identified the pressures of a constantly changing and increasingly competitive landscape; it asked us to assess honestly Rice’s comparative strengths and weaknesses; and it called on us to define strategic priorities for the future, an effort that will be a focus of the next phase of this process.

Advertisements