New Chemistry Method Simplifies Late-Stage Modification of Drug Compounds
23/11/2017
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.
About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the worlds largest independent, not-for-profit organizations focusing on research in the b
Most recent headlines
03/06/2024
Dalet and Veritone Reach Agreement to Distribute, Transact and Monetize Media Archives
Dalet, a leading technology and service provider for media-rich organizations, a...
18/03/2024
USC Basketball Star Juju Watkins on Fashion, Film, Friendship Bracelets, and More
Listeners turn to Spotify to connect with their favorites-from artists and album...
18/03/2024
Young professionals successfully complete vocational training at SGL's Meitingen site
Seven young professionals completed their vocational training at SGL Carbon in M...
18/03/2024
Vintage Allure
Released this past January, the music video for Ariana Grande's yes, and? brings a modern approach to vintage allure. The video was directed by Christian ...
18/03/2024
ST Engineering iDirect Unveils Intuition at SATELLITE 2024 Conference and Exhibition
Global satellite communications leader gives market a first look at its next-gen...
18/03/2024
Box to Box Films shares with MediaSilo
Box to Box Films Shares with MediaSilo Amy and Drive to Survive producer updates collaborators simply and securely Boston, MA, March 18, 2024 - Box to Box Fi...
18/03/2024
Telestream Introduces AI-Powered Tools for Rapid Content Delivery at NAB Show 2024
Telestream Introduces AI-Powered Tools for Rapid Content Delivery at NAB Show 20...
18/03/2024
Docufiction Film Bringing Down a Mountain Edited with DaVinci Resolve Studio
Docufiction Film Bringing Down a Mountain Edited with DaVinci Resolve Studio Brie Clayton March 18, 2024 0 Comments Blackmagic Design today announced ...
18/03/2024
FingerWorks Telestrators Releases Enhancements to Computer Vision Live Tracking Software at NAB 2024
FingerWorks Telestrators Releases Enhancements to Computer Vision Live Tracking ...
18/03/2024
DirecTV to Allow Subscribers to Opt Out of Local Stations
DirecTV announced a new feature over the weekend that will allow its subscribers to opt out of their local stations in return for a discount. Customers who ch...
18/03/2024
Logging and reviewing: Moving towards a sustainable workflow
Jane Sung, COO at Cinedeck, explains how broadcasters and content production companies can achieve the goal of moving towards creating a more sustainable, effic...
18/03/2024
Altice Media sold to French shipping tycoon for 1.55 billion
The deal includes BFM TV, one of the country's largest 24-hour news channels, as well as documentary channel RMC D couverte, and RMC Story By Jenny Priestl...
18/03/2024
Meet the CEO and founder
By TVBEurope Staff Published: March 18, 2024 Nick Franco tells TVBEurope how he went from being a master plasterer and refurbishing the ornate plasterwork ...
18/03/2024
Master the Avatar State: Glowing Eyes in Adobe After Effects
Master the Avatar State: Glowing Eyes in Adobe After Effects Levi Borland March 18, 2024 0 Comments In this step-by-step tutorial, learn how to recrea...
18/03/2024
Next Season of Doctor Who' on Disney Plus May 10
The next season of Doctor Who, with Ncuti Gatwa as the 15th Doctor, premieres on Disney Plus and around the world May 10. It is the first season to launch on Di...
18/03/2024
Screen Australia and VicScreen launch new Screen Careers initiative
18 03 2024 - Media release Screen Australia and VicScreen launch new Screen Careers initiative LTR Denise Eriksen, Esther Coleman Hawkins, Caroline Pitcher, K...
18/03/2024
CBC/WRAL Night Helps Bring in Over $26k for PBS NC
Capitol Broadcasting and WRAL-TV continued a decades-long tradition of supporting PBS North Carolina, our state's public television station, to good result ...
18/03/2024
Banglalink Gets Unified Licence to Deliver Superior Digital Services in Bangladesh
18 Mar 2024 Banglalink Gets Unified Licence to Deliver Superior Digital Service...
18/03/2024
Thuraya partners with Niflink to deliver telemedicine and eLearning to users across its network
Abu Dhabi, 18 March, 2024 : Abu Dhabi, 18 March 2024: Thuraya Telecommunication...
18/03/2024
Thuraya partners with Niflink to deliver telemedicine and eLearning to users across its ne...
Abu Dhabi, 18 March, 2024 : Abu Dhabi, 18 March 2024: Thuraya Telecommunication...
18/03/2024
Major League Soccer: IMG on Capturing Fan Rituals and Delivering Consistent Coverage
Major League Soccer: IMG on capturing fan rituals and delivering consistent cove...
18/03/2024
Smashing Padel: Inside Aurora's Innovative Production of the Inaugural Hexagon Cup
Smashing padel: Inside Aurora's innovative production of the inaugural Hexag...
18/03/2024
Airspeeder Teams Up With EMG for World's First Live Broadcast of Flying Car Series
Airspeeder teams up with EMG for world's first live broadcast of flying car ...
18/03/2024
Netflix Announces News About 26 Upcoming Nordic Titles - Including 12 Brand New Titles
Back to All News Netflix Announces News About 26 Upcoming Nordic Titles - Inclu...
18/03/2024
Final sprint in the AS4 market communication
Final Sprint in the AS4 Market Communication: All Arvato Systems Customers Are Ready to Go Customers for market communication AS4-ready Arvato Systems is now...
18/03/2024
Tonight on Uzalo: Nkunzi takes a drastic decision
Tonight on Uzalo: Nkunzi takes a drastic decisionDon't miss Monday, 18 March's riveting episode of South African soapie Uzalo on SABC 1 on DStv channel ...
18/03/2024
Thales to modernize Montreal Mtro blue Line,improving passengers' punctuality and train reliability
Facebook Twitter LinkedIn Following a call for tenders, the Soci t de tra...
18/03/2024
Streaming today: Vida the Vet' on Netflix - 18 March 2024
Streaming today: Vida the Vet' on Netflix - 18 March 2024Looking for something to watch tonight? Check out all the new streaming releases from all your fav...
18/03/2024
Skeem Saam': Is Tobias Maswahla Evelyn's son?
Skeem Saam': Is Tobias Maswahla Evelyn's son?Is actor Sicelo Buthelezi's character Tobias Maswahla related to Deputy Principal Evelyn Maswahla in S...
18/03/2024
Tonight on Generations: Khensani tries to mend his friendship with Sphe
Tonight on Generations: Khensani tries to mend his friendship with SpheDon't miss Monday, 18 March's riveting episode of South African soapie Generation...
18/03/2024
Question: Did George Lucas rip off Dune?
Question: Did George Lucas rip off Dune?Miles Phillips explores Dune's Legacy and its echo in Star Wars, claiming that the former is among the best science ...
18/03/2024
Tonight on Skeem Saam: Jacobeth kicks Bullet to the curb
Tonight on Skeem Saam: Jacobeth kicks Bullet to the curbDon't miss Monday, 16 March's riveting episode of South African soapie Skeem Saam on SABC 1 on D...
18/03/2024
Tonight on Muvhango: Matshidiso finds incriminating information on Nkele
Tonight on Muvhango: Matshidiso finds incriminating information on NkeleDon't miss Monday, 18 March's riveting episode of South African soapie Muvhango ...
18/03/2024
Tonight on Smoke and Mirrors: In a haze of alcohol, Sakhile knocks down Fanyana
Tonight on Smoke and Mirrors: In a haze of alcohol, Sakhile knocks down FanyanaDon't miss Monday, 18 March's riveting episode of South African soapie Sm...
18/03/2024
Tonight on Scandal: Jojo's bad PR costs him more than he can afford
Tonight on Scandal: Jojo's bad PR costs him more than he can affordDon't miss Monday, 18 March's riveting episode of South African soapie Scandal! o...
18/03/2024
Tonight on Champions: Lebo's family are tearing him apart
Tonight on Champions: Lebo's family are tearing him apartDon't miss Monday, 18 March's riveting episode of South African soapie Champions on Mzansi ...
18/03/2024
Tonight on Gqeberha: Msimelelo lays down the rules at the Tshisa Nyama
Tonight on Gqeberha: Msimelelo lays down the rules at the Tshisa NyamaDon't miss Monday, 18 March's riveting episode of South African soapie Gqeberha: T...
18/03/2024
Tonight on Umkhokha: Zisebenzele makes a bet with Khululiwe that Siphamandla will do it within a week
Tonight on Umkhokha: Zisebenzele makes a bet with Khululiwe that Siphamandla wil...
18/03/2024
Cyberani and Thales enter a strategic alliance to strengthen the Kingdom's cybersecurity
Facebook Twitter LinkedIn Mr. Saeed Al Saeed, CEO of Cyberani, and Mr. Pie...
18/03/2024
Thales to equip Cibao International Airport in Dominican Republic with new Air Traffic Control Radar System
Facebook Twitter LinkedIn Instituto Dominicano de Aviaci n Civil (IDAC) se...
17/03/2024
WATCH: Highlights from the 2024 Cape Town Carnival [video]
WATCH: Highlights from the 2024 Cape Town Carnival [video]The Mother City's biggest annual street parade returned to Green Point on Saturday with the Cape T...
17/03/2024
WATCH: Highlights from the 2024 Cape Town Carnival
WATCH: Highlights from the 2024 Cape Town CarnivalThe Mother City's biggest annual street parade returned to Green Point on Saturday with the Cape Town Carn...
17/03/2024
Young Papi leaves Big Brother Mzansi'
Young Papi leaves Big Brother Mzansi'Young Papi was the thirteenth housemate to get evicted from the Big Brother Mzansi' reality TV show on Sunday, 17...
17/03/2024
Smoke and Mirrors': Why Thandiswa might dump Caesar
Smoke and Mirrors': Why Thandiswa might dump Caesar Smoke and Mirrors' spoilers reveal that Caesar will propose marriage to Thandiswa. Will she stay wit...
16/03/2024
Josh Brolin Drama Outer Range' Returns To Prime Video May 16
Western drama Outer Range is back with season two on Prime Video May 16. Josh Brolin stars and executive produces. He also directs the season's penultimate ...
16/03/2024
Kristen Wiig Lined Up to Host SNL' for Fifth Time
Kristen Wiig hosts Saturday Night Live for the fifth time on April 6. Wiig stars in and executive produces Palm Royale, which premieres March 20 on Apple TV Plu...
16/03/2024
Magnite, Mediaocean Join To Make Buying CTV Campaigns Easier
Media buyers using Mediaocean's Prisma platform will be able to plan, execute and reconcile ad campaigns on connected TV directly from programmers who work ...
16/03/2024
Bitmovin, Yospace Combine To Insert Ads Into Live Streams
Streaming infrastructure company Bitmovin is teaming up with ad-insertion vendor Yospace to enable broadcasters to put commercials in live-streaming programming...
16/03/2024
Bumble Engages Peacock's The Traitors' To Promote Dating Deception Detector'
Bumble, the dating service, has tapped into Peacock's murder-mystery competi...
16/03/2024
Gerald Levin, Former Time Warner CEO, Has Died
Gerald Levin, former CEO of Time Warner, died March 13. He was 84 and had battled Parkinson's disease....