Texas A&M University chemistry professor Dr. Daniel Romo and his laboratory team have developed a quick and efficient method of creating one type of complex carbon framework commonly found in pharmaceutical drugs and other natural products.
The research, published last month in the journal Nature Chemistry, describes both the construction of complex five-membered rings from two-carbon and three-carbon pieces, and also how to do it with a method that uses relatively cheap commodity chemicals that are and available in large quantities, and as single-mirror images — a feature characteristic of some organic molecules that can dramatically alter their biological properties.
Caption: This image features two basics — Legos and a mirror — in illustrating how Texas A&M chemist Daniel Romo and his team puts together three-carbon and two-carbon atoms to make five-membered rings (a pentagon) and also how they make one of two possible mirror images. (Photo Credit: Mikail Abbasov, graduate student and Romo research group member, Texas A&M Department of Chemistry.)
“Ideally, people will see this method as a very practical, efficient method,” says Dr. Romo in a TAMU release,. “It could potentially be applied to the synthesis of the next generation of drugs, or to make existing drugs more efficiently.”
Chemists have good ways of making six-membered carbocyclic rings, but creating five-membered rings that are found in many drugs is trickier. It’s a dilemma that is of importance in organic synthesis these days, Romo said. “We could just about make any organic compound you could dream up,” Romo said. “But now the question has become, ‘How efficiently can you make that compound?’ This method that we published is a step in that direction. More generally, we’re providing new tools for making useful molecules to probe what’s going on inside a cell.”
The research highlights a shift away from using metal-based catalysts in favor of organic, non-metal-based molecules. The use of organocatalysts is a burgeoning area, Dr. Romo explains, noting that interest in it is partly fueled by the greater emphasis on green chemistry and developing compounds that leave lighter traces of pollution.
The Nature Chemistry paper (Nature Chemistry 5, 1049–1057 (2013) doi:10.1038/nchem.1788)#affil-auth is co-authored by Dr. Romo in collaboration with several graduate students in his Texas A&M laboratory, including Gang Liu (now a research scientist at MD Anderson), Morgan E. Shirley, Khoi N. Van and Rae Lynn McFarlin (now a chemistry teacher at Central High School in San Angelo, Texas). While it represents his commitment to basic science, Dr. Romo also works in the realm of applied, interdisciplinary science that links research and industry.
As a senior in high school, San Antonio native Daniel Romo had an independent study class in which he had free rein to try different experiments he found in the literature. He began his career in academia at Texas A&M as a chemistry major with the goal of becoming an orthodontist, but quickly discovered a knack and passion for organic chemistry and synthesis, in particular found that the innovation and creativity required to make molecules in organic chemistry played right into his interests. He received his B.A. degree in chemistry/biology from Texas A&M in 1986, and “It was all history from there,” he says. Dr. Romo received a Ph.D. in Chemistry from Colorado State University in 1991 as a NSF Graduate Fellow with the late Prof. A. I. Meyers where he worked on cyclopropanations of chiral bicyclic lactams. He studied with Prof. Stuart L. Schreiber at Harvard from 1991-1993 as an American Cancer Society Postdoctoral Fellow and was a team leader in the total synthesis of rapamycin.
Dr. Romo came back to Aggieland in 1993 as an assistant professor in the TAMU Department of Chemistry, moving up the ranks to full professor and earning induction into the College of Science Academy of Distinguished Former Students in 2012. In 2010 he also began serving as director of a project that connects scientists from across the Texas A&M University System and beyond who are interested in natural products research. Called the LalNatural Products LINCHPIN Laboratory — (for “Laboratory for Innovative Chemistry and Natural Products-Based Interdisciplinary Drug Discovery) — the lab is equipped with specialized instrumentation that enables chemical synthesis, derivatization methods, isolation and purification of bioactive natural products and related small molecules.
Research interests of the Romo Lab Group are focused on the chemistry and biology of natural products, compounds isolated from natural sources. These are unique and often structurally complex molecules that appear designed to interact in highly potent and specific ways with various cellular receptors most importantly those found in humans but also human and agricultural parasites. Natural product targets are selected for synthesis are based on compelling and potent biological activity in addition to challenging synthetic hurdles that must be overcome to develop a concise and practical synthesis of the natural product enabling subsequent biological studies. Thus, the Romo group is engaged in developing novel synthetic strategies towards these naturally occurring compounds or derivatives that in turn serve are useful leads for inquiries into protein function and in particular identification of their putative cellular targets.
A recent project in the Romo Group is the development of selective and concise (2 step) synthetic strategies for conversion of natural products to cellular probes that will contribute to chemical genetics impacting basic cell biology and therapeutic target identification. These methods are being used in numerous local, national, and international collaborations in the Natural Products LINCHPIN Laboratory to perform structure-activity studies of natural products on microscale, ultimately leading to identification of the cellular target of these bioactive natural products
The LINCHPIN Lab’s Web page notes that the lab serves as a central collaboration and idea incubation laboratory for interdisciplinary researchers across the TAMU System campuses and both nation and world-wide that require the derivatization and when warranted chemical synthesis of natural products and derivatives that exert potent biological effects. Assistance with isolation, purification, and structural elucidation is also possible, but of lower priority.Generally, collaborations involve supplying a purified natural product (ideal) or semi-purified extract exhibiting novel and potent bioactivity. Collaborators are typically interested in the derivatization of the natural product for the purpose of performing preliminary structure-activity relationship studies (SAR) to enable synthesis of bioactive biological probes (e.g. biotin, fluorophore, radiolabelled conjugates) to perform cellular localization studies, cellular protein receptor isolation towards elucidating the mechanism of action of novel natural product where this is unknown, or de novo synthesis of the natural product and simplified equipotent derivatives. Data generated at the LINCHPIN Laboratory from these collaborations become important and often essential preliminary results for submission of research grants to support significant, cutting edge interdisciplinary, biological chemistry research with collaborators.
The LINCHPIN brings together diverse researchers with common interests in bioactive natural products and derivatives along with associated proteomics tools (mainly mass spectral analysis both in the LINCHPIN Lab and also through the TAMU Laboratory for Biological Mass Spectrometry) the necessary synergy, established track record (co-publications), and preliminary studies to ultimately develop program projects for major federal funding that will enable the continual mining and enduring potential of natural products as drugs or drug leads.
“We try to do basic research that has a direct practical application, and the LINCHPIN lab is really an expression of my more applied side,” says Dr. Romo. “We’re working with biologists and researchers with an interest in development potential medicines, and we assist in discovering new enzymes and proteins in the body using natural products-based probes that could then be targeted for therapeutics. I was fascinated by the idea of being able to dream up new molecules and the methods to make them. It’s almost like putting a puzzle together. I just always liked the idea of being able to piece together something complex and potentially quite useful.” To view the complete research paper, go to:
Dr. Romo’s awards include a National Science Foundation CAREER award (1995), an Alfred P. Sloan Fellowship (1997), a Zeneca Award for Excellence in Chemistry (1998), the TAMU College of Science Montague Scholar Award (1997-98), a Camille and Henry Dreyfus Teacher-Scholar Award (1999-2004), a Novartis Lectureship (2001-2002), a Pfizer Award for Creativity in Organic Chemistry (2002), an Assoc. of Former Students Distinguished Achievement College Award for Teaching (2009), an Assoc. of Former Students Distinguished Achievement University Award for Research (2009), and he was recently was inducted into the TAMU College of Science Academy of Distinguished Former Students. In 2009, Romo received a NIH Method to Extend Research-In-Time Award (MERIT Award), which ensures 10 years of continuous funding from NIH. He is a regular NSF reviewer and served 4 years on the NIH Med Chem A/Synthesis & Biological Chemistry Study Sections. Romo has 6 issued patents and 2 pending patents focused on novel composition of matter and methods of use of natural products for cancer chemotherapy and diagnostics. In 2008, Romo received an Excellence in Innovation Award by the Office of Technology Commercialization at TAMU.
You can find a previous feature on Dr. Romo’s work with the LINCHPIN lab and the Undergraduate MiniPharma Project he initiated at:
As one of the world’s leading research institutions, Texas A&M is in the vanguard in making significant contributions to the storehouse of knowledge, including that of science and technology. Research conducted at Texas A&M represents annual expenditures of more than $776 million. That research creates new knowledge that provides basic, fundamental and applied contributions resulting in many cases in economic benefits to the state, nation and world. To learn more, visit:
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Natural Products LINCHPIN Laboratory
Mikail Abbasov, Romo research group member, Texas A&M Department of Chemistry