Lab creates tough, yet tender, cancer fighters

Structure of one of the analogs of epothilone B, a fresh compound created from the Rice University lab of synthetic organic chemist K.C. Nicolaou in which shows promise as a cancer fighter. Credit: Nicolaou Group/Rice University

Rice University scientists have developed along with evaluated analogs of potent anti-tumor agents known as epothilones using designs along with methods in which both improve their biological properties along with 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 will be best-known, yet 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 fresh research study will be described This specific month from the Journal of the American Chemical Society.

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

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

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

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 in which led to their enhanced properties as cancer-fighting agents. Credit: Nicolaou Group/Rice University

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

Just as important, he said, will be the lab’s ability to add chemical “handles” to the molecules in which 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 along with his team replaced components from 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 fresh molecules will be the three-membered ring containing a nitrogen atom, a so-called aziridine moiety.” The importance of the aziridine ring will be not yet clear, he said, yet the item could serve as a handle to attach the molecule onto an antibody through a linker.

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

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

Explore further:
Rice scientists synthesize anti-cancer agent

More information:
K. C. Nicolaou et al, 12,13-Aziridinyl Epothilones. Stereoselective Synthesis of Trisubstituted Olefinic Bonds by Methyl Ketones along with Heteroaromatic Phosphonates along with Design, Synthesis, along with Biological Evaluation of Potent Antitumor Agents, Journal of the American Chemical Society (2017). DOI: 10.1021/jacs.7b02655

Lab creates tough, yet tender, cancer fighters

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