New Chemistry Method Simplifies Late-Stage Modification of Drug Compounds
November 22, 2017
Chemists at The Scripps Research Institute (TSRI) have invented a technique that overcomes a long-standing problem in organic chemistry and should streamline the process of discovery and development for many new drugs. The technique, known as ligand-accelerated non-directed C H functionalization, is expected to find application not just in the pharmaceutical chemistry industry but also in a wide range of other chemical industries. However, it should be particularly useful for altering complex candidate drug molecules to find versions with optimal therapeutic properties.
One can use this new technology to modify a drug molecule at a late stage of synthesis, to improve the molecule's properties without having to go back to change the synthesis from the beginning, said study senior author Jin-Quan Yu, Ph.D., Frank and Bertha Hupp Professor in the Department of Chemistry at TSRI.
The new method, reported this week in the journal Nature, was developed by Yu's laboratory in collaboration with scientists at Bristol-Myers Squibb, who are already applying the method in their drug development programs.
Yu is known for the many new methods he and his laboratory have devised for achieving a basic molecule-building operation known as C H functionalization. The term refers to the removal of a hydrogen (H) atom from the carbon (C) backbone of an organic molecule and its replacement with a more reactive cluster of atoms known as a functional group. The latter is often the key to the molecule's biological or other properties. C H functionalization frequently involves a metal atom, such as palladium, that catalyzes the initial cleavage of the carbon hydrogen bond.
Most of Yu's recent advances in C H functionalization have involved the use of a special functional group known as a directing group. A directing group becomes a part of the initial organic molecule (substrate) and effectively directs the C H functionalization reaction to occur at the desired carbon hydrogen bond on the substrate.
Directing-group C H functionalizations can't always be used, however. For some substrates, there isn't a suitable directing group, or there isn't one within effective range of the C H bond that is meant to be functionalized, Yu said.
In such cases, there are often no good options. Metal catalysts in the absence of a directing group typically won't interact with the targeted C H bond strongly enough or selectively enough to do the job. The chemist may compensate for the lack of a directing group by using a relatively large amount of substrate molecules to statistically increase the interactions between metal catalyst and substrate molecules thereby enabling the C H activation to proceed, but that is not practical particularly for substrates that are themselves hard to produce in large quantities as only a small portion of the highly valuable substrate will be converted into the desired products.
To overcome this long-standing problem in the field of C H activation, Yu and his team, including first author Peng Wang, a postdoctoral research associate in the Yu Laboratory, sought a special molecule that could serve as a ligand. In metal-catalyzed C H functionalizations, a ligand molecule fastens to the metal atom in a way that enhances its reactivity with a targeted C H bond.
In this case, investigations by Yu's team ultimately led them to a ligand molecule called a 2-pyridone. Using a broad class of substrate molecules called arenes, they found that the 2-pyridone ligand greatly enhances palladium's ability to make non-directed C H functionalizations so much so that the chemists were able to use normal rather than excess quantities of the arene substrate molecules.
Using the technique, Yu's team modified a broad variety of arenes by adding functional groups from the olefin and carboxylic acid families of organic molecules. The products included modified versions of numerous molecules of interest to biologists and medicinal chemists: amino acid derivatives; the beacon molecule fluorescein; the plant-derived stimulant caffeine; the plant-derived antitumor compound camptothecin; and synthetic pharmaceuticals, including fenofibrate, gemfibrozil, diflunisal, viloxazine and betaxolol.
Yu and colleagues found that the use of their 2-pyridone ligand didn't merely accelerate the attachment of functional groups to substrate molecules. In some cases, it also altered the selectivity of these C H functionalizations, favoring some sites on the molecule over others much as a directing group does.
Where these C H functionalizations occur on substrate molecules is mostly dictated by their intrinsic charge properties and geometries, but we have shown here that for a few classes of arenes, the ligand also has the effect of enhancing the site-selectivity of these functionalizations, Yu said.
Yu and his team have begun to study the detailed mechanisms by which the 2-pyridone ligand affects C H functionalizations and hope to expand the application of ligand-accelerated non-directed C H functionalization to other classes of organic molecule beyond arenes.
In addition to co-first authors Yu and Wang, other co-authors of the paper, Ligand-accelerated non-directed C H functionalization of arenes, were Pritha Verma, Guoqin Xia, Jun Shi and Marcus E. Farmer of TSRI; and Jennifer X. Qiao, Shiwei Tao, Peter T. W. Cheng, Michael A. Poss and Kap-Sun Yeung of Bristol-Myers Squibb.
Support for the research came from the National Institutes of Health (grant NIGMS 2R01 GM102265) and Bristol-Myers Squibb.
Chemistry Yu, Jin-Quan
Most recent headlines
05/01/2027
Worlds first 802.15.4ab-UWB chip verified by Calterah and Rohde & Schwarz to be ...
04/08/2026
Dalet, a leading technology and service provider for media-rich organizations, t...
04/07/2026
April 7 2026, 19:00 (PDT) Detective Conan: Fallen Angel of the Highway Opens in...
01/06/2026
January 6 2026, 05:30 (PST) Dolby Sets the New Standard for Premium Entertainment at CES 2026
Throughout the week, Dolby brings to life the latest innovatio...
13/05/2026
New Adobe Premiere Color Grading Mode Accelerated on NVIDIA GPUs
Joel Pennington May 13, 2026
0 Comments
New NVIDIA RTX-accelerated features streamlin...
13/05/2026
Grass Valley announced that dB Broadcast has delivered new IP-based outside broadcast (OB) trucks for Cloudbass, featuring Grass Valley LDX 100 Series cameras a...
13/05/2026
Ikegami will exhibit the latest additions to its wide range of broadcast production cameras, control units, viewfinders and monitors on stand 5D3-1 at Broadcast...
13/05/2026
FISE, working with the founding members of the XR Sports Alliance (XRSA), Accedo, Qualcomm Technologies, Inc. and HBS, have collaborated to develop an immersive...
13/05/2026
Canon Unveils New EOS R6 V Full-Frame EOS Camera and RF20-50mm F4 L IS USM PZ Bu...
13/05/2026
Boston Conservatory at Berklee Honors Beth Morrison and Moses Pendleton at Comme...
13/05/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
13/05/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
13/05/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
13/05/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
13/05/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
13/05/2026
Creative software developer Foundry today announced the latest developments on Nuke Stage. A purpose-built application for end-to-end virtual production and in-...
13/05/2026
A definitive portrait of one of Ireland's most influential musicians
New TV documentary airs Monday 18 May on RT One and RT Player at 9.35pm
Watch the...
13/05/2026
Agentic AI is changing the way users get work done. Following the success of OpenClaw, the community is embracing new open source agentic frameworks. The latest...
13/05/2026
Reinforcement-learning agents - AI systems that learn by trial and error - can c...
12/05/2026
Beyond the Hype: A Strategic Post-Hoc Analysis of NAB 2026 If NAB Show 2026 had an underlying theme, it was a quiet, industry-wide pivot from the high-energy sp...
12/05/2026
Guntermann and Drunck (G&D), a Panoptec Technologies Group company, and CT Square, led by Chandresh Shah, have announced a joint venture to distribute G&D and V...
12/05/2026
With 30 days until the start of the FIFA World Cup 2026, Telemundo, the exclusive Spanish-language home of the tournament in the United States, has announced th...
12/05/2026
The NHL has announced the return of Stanley Pup for its third consecutive year, a 90-minute special featuring adoptable rescue dogs competing on a miniature rin...
12/05/2026
NBCUniversal presented its 2026 Upfront to advertisers at Radio City Music Hall, detailing upcoming programming across NBC, Peacock, Bravo, and Versant properti...
12/05/2026
FOX Sports has announced funding for the Fandom and Social Connection Initiative at Harvard Kennedy School's Shorenstein Center on Media, Politics, and Publ...
12/05/2026
TNDV and Live Media, both divisions of Live Media Group, supported live broadcast coverage around NCAA Final Four weekend in Indianapolis, including the March M...
12/05/2026
The European Football Alliance (EFA) has announced a content distribution agreement with Fubo Sports Network, the free ad-supported streaming TV (FAST) channel ...
12/05/2026
For the first time, Spanish-speaking fans in the U.S. will have two separate tel...
12/05/2026
CP Communications led a comprehensive spectrum management initiative on behalf of Churchill Downs during Kentucky Derby week, coordinating RF assets across the ...
12/05/2026
LiveU has announced a strategic partnership with DRONERESPONDERS, a 501(c)3 non-...
12/05/2026
Open Broadcast Systems has announced that BMC TV, a specialist in IP transport of broadcast content, has selected the Open Broadcast Systems 5G Flyaway solution...
12/05/2026
NEP Europe, part of NEP Group, has announced it will deliver broadcast solutions...
12/05/2026
Grass Valley has announced continued collaboration with Ravensbourne University ...
12/05/2026
Stats Perform has announced the launch of Opta Pulse, an AI-assisted video creation and distribution platform for leagues, rights holders, and broadcasters. The...
12/05/2026
FOX Sports has announced a collaboration with Sesame Workshop to integrate Sesame Street characters into FOX Sports' FIFA World Cup 2026 programming. Conten...
12/05/2026
To date, NHL Productions has produced 19 broadcasts with commentary in American Sign Language
NHL in ASL (American Sign Language) may be just one show, but the...
12/05/2026
Google's Brian Albert: creators, athletes, highlights, nostalgia, second-scr...
12/05/2026
A still from Past Lives by Celine Song, an official selection of the Premieres program at the 2023 Sundance Film Festival. (Courtesy of Sundance Institute | p...
12/05/2026
Spotify is where fans and artists come together, turning discovery into somethin...
12/05/2026
Features patented Marco-MMC clocking technology
Black Lion Audio's latest release combines the company's expertise in clocking with their renowned p...
12/05/2026
New Track Panel, sequencer upgrades & more
Following their recent public beta release, Reason Studios have announced the full release of Reason 14. With the...
12/05/2026
One month to go! SBS reveals expansive FIFA World Cup 2026 lineup beyond the pi...
12/05/2026
Rohde & Schwarz presents its advanced solutions for power electronics testing at...
12/05/2026
aconnic AG (ISIN: DE000A0LBKW6), Munich, has developed a modified fund raising p...
12/05/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
12/05/2026
Tyrell Corporation, specialists in high-end live sports and entertainment broadcasts, was tasked with delivering compelling broadcast coverage of premier equest...
12/05/2026
Registration is now open for IBC2026 as the global media, entertainment and technology community prepares to converge on the RAI Amsterdam from 11 14 September ...
12/05/2026
Ross Video, a global leader in live video production technology, will present its latest innovations and integrated production workflows at BroadcastAsia 2026, ...
12/05/2026
500 selected leaders from around the world across start-ups, corporates, and venture capital. Over 50bn in assets under management among attending investors, a...
New Chemistry Method Simplifies Late-Stage Modification of Drug Compounds 
