Researchers finding ways to rapidly access the “magic methyl” effect

Date

03/24/20
Illustration of a new catalyst replaces a hydrogen atom with a methyl group, which can dramatically increase a drug’s potency. Provided by Kaibo Feng

A breakthrough by an Illinois Chemistry team of researchers could enable medicinal chemists to more easily harness “magic methylation,” a transformation that can significantly boost the potency of some drugs.

M. Christina White, the William H. and Janet G. Lycan Professor of Chemistry, and graduate students Kaibo Feng and Raundi E. Quevedo explain in their paper published in Nature how they use a catalyst to more rapidly and easily achieve this exchange of hydrogen atoms for methyl groups on a variety of drug-like molecules.

The team’s research shows how the exchange can be done from the drug itself, toward the end of the drug building process, using an oxidation catalyst created by the White group along with a reagent, trimethylaluminum.

White said the development of chemical methods to directly change a drug’s properties at late stages is very attractive to medicinal chemists, but very challenging to do.

“A major bottleneck in drug discovery is the optimization of drug leads,” she said.

While that would require only slight changes to bioactive molecules - like swapping a hydrogen atom for a methyl group - often the only way to do that is to remake the molecule from scratch, a costly and time-consuming process.

Chemical methods that directly modify molecules at late stages when the molecule is closest to its form as a drug, White explains, would provide a faster and less expensive way to optimize drug leads.

“The result is that more bioactive molecules would be made and tested and drugs may be discovered faster,” she said.

And more specifically, the exchange of a hydrogen for a methyl group adjacent to heteroatoms, nitrogen and oxygen, is particularly attractive to medicinal chemists but very difficult.

“Switching a hydrogen for a methyl has been shown to dramatically increase a bioactive molecule’s potency, sometimes even up to 2000 folds,” White said. “This is very attractive for medicinal chemists because less of the drug would be required for the same effect, which tends to result in both safer pharmacological profiles and reduction in production costs. Medicinal chemists have called this the ‘magic methyl’ effect, in part because its scope and mechanism haven’t been thoroughly studied due to the difficulties in making methylated analogs of drugs.”

Photo of graduate students Kaibo Feng and Raundi E. Quevedo, and Professor M. Christina White in front of a blackboard with their equation written on it.
Graduate students Kaibo Feng and Raundi E. Quevedo, and Professor M. Christina White

White and her research team demonstrated this oxidative methylation on 41 molecules, including 18 medicinally relevant molecules.

With this discovery medicinal chemists could directly install methyl groups in large numbers of drugs and bioactive molecules that they already have, rather than making each molecule from scratch to install the methyl.

“We anticipate this would facilitate and encourage further studies on the ‘magic methyl’ effect and its application in drug discovery, and also lower cost and side effects for new drugs because of the increased potency,” White said.

Key in this discovery, according to the researchers, was using a novel oxidation platform with very little of the catalyst that still resulted in unprecedented selectivity.

Specifically, we substantially reduced the loading of catalyst, Mn(CF3PDP), which prevented over-oxidation and other side reactions,” White explained. “We paired this with specific alcohol activators that enabled us to transform our oxidized intermediate into the desired methylated product using a very mild methylation reagent, trimethylaluminum.”

Feng also emphasized the importance of discovering they could run the oxidation with a smaller amount of the catalyst yet achieve better results.

“For the first time, we could perform the reaction in molecules containing electron-rich arenes. This allowed us to do the reaction at late stages in complex drugs such as tedizolid,” he said.

In a recent Science article, an organic chemist at the University of Michigan, Tim Cernak, calls the White research group’s paper “stunning.”

Feng said they developed this strategy responding to the call for new methylation methods raised by Cernak and other medicinal chemists.

“I was glad to see their significant interest and eagerness to try this new method. I look forward to seeing it widely used in pharmaceutical research,” Feng said.

Quevedo said it’s very rewarding to see their work completed and published and receiving positive response.

“The impact of this work was evident to us, and it’s fulfilling to see that others agree with our vision,” Quevedo said.

The research was done in collaboration with Pfizer chemists.

“We are excited for medicinal chemists from all over the world to use this platform to rapidly diversify molecules that already exist in drug databases in order to discover new, more potent drugs,” the team said.

 

Related People

mcwhite7

Directory

scheelinAlexander
Scheeline
bjmccallBenjamin
McCall
r-gennisRobert
Gennis
j-gerltJohn
Gerlt
sgranickSteve
Granick
mgruebelMartin
Gruebele
hergenroPaul
Hergenrother
huangRaven
Huang
mlkraftMary
Kraft
leckbandDeborah
Leckband
yi-luYi
Lu
martinisSusan
Martinis
snairSatish
Nair
eoldfielEric
Oldfield
cmsCharles
Schroeder
zanZaida
Luthey-Schulten
selvinPaul
Selvin
sksScott
Silverman
s-sligarStephen
Sligar
tajkhorsEmad
Tajkhorshid
zhao5Huimin
Zhao
pbraunPaul
Braun
mdburkeMartin
Burke
jeffchanJefferson
Chan
sdenmarkScott
Denmark
dlottDana
Dlott
foutAlison
Fout
agewirthAndrew
Gewirth
ggirolamGregory
Girolami
sohirataSo
Hirata
jainPrashant
Jain
jkatzeneJohn
Katzenellenbogen
nmakriNancy
Makri
douglasmDouglas
Mitchell
jsmooreJeffrey
Moore
murphycjCatherine
Murphy
r-nuzzoRalph
Nuzzo
dimerPhilip
Phillips
rauchfuzThomas
Rauchfuss
joaquinrJoaquín
Rodríguez-López
sarlahDavid
Sarlah
kschweizKenneth
Schweizer
jsweedleJonathan
Sweedler
vddonkWilfred
van der Donk
renskeRenske
van der Veen
vuraweisJosh
Vura-Weis
mcwhite7M.
White
sczimmerSteven
Zimmerman
beakPeter
Beak
wklemperWalter
Klemperer
jdmcdonaJ.
McDonald
pogoreloTaras
Pogorelov
mshen233Mei
Shen
dewoonDavid
Woon
wboulangWilliam
Boulanger
rxbRohit
Bhargava
qchen20Qian
Chen
jianjuncJianjun
Cheng
hy66Hong
Yang
andinomaJosé
Andino Martinez
decosteDonald
DeCoste
thhuangTina
Huang
tjhummelThomas
Hummel
dkellDavid
Kell
doctorkMichael
Koerner
marvilleKelly
Marville
crrayChristian
Ray
tlbrownTheodore
Brown
rmcoatesRobert
Coates
thdjrThom
Dunning
dykstraClifford
Dykstra
j-jonasJiri
Jonas
j-lisyJames
Lisy
shapleyJohn
Shapley
pshapleyPatricia
Shapley
zumdahl2Steven
Zumdahl
ksuslickKenneth
Suslick
jcoxJenny
Cox
sqdSean
Drummond
sheeleySarah
Sheeley
jsmaddenJoseph
Madden
cknight4Connie
Knight
schulzeHeather
Schulze
kbaumgarKeena
Finney
adkssnBeatrice
Adkisson
trabari1Katie
Trabaris
metclfKara
Metcalf
ljohnso2Lori
Johnson
lchenoweLeslie
Chenoweth
wdedoWolali
Dedo
spinnerDavid
Spinner
plblumPatricia
Simpson
stevens2Chad
Stevens
lsagekarLori
Sage-Karlson
bertholdDeborah
Berthold
kecarlsoKathryn
Carlson
sdesmondSerenity
Desmond
axelson2Jordan
Axelson
scbakerStephanie
Baker
pflotschPriscila
Falagan Lotsch
dgrayDanielle
Gray
thennes2Tom
Hennessey
holdaNancy
Holda
aibarrAlejandro
Ibarra
kimshSung Hoon
Kim
kocherg2Nikolai
Kocherginsky
philipk2Philip
Kocheril
legare2Stephanie
Legare
alewandoAgnieszka
Lewandowska
smccombiStuart
McCombie
jdm5Justin
McGlauchlen
egmooreEdwin
Moore
myerscouKathleen
Myerscough
snalla2Siva
Nalla
romanovaElena
Romanova
roubakhiStanislav
Rubakhin
shvedalxAlexander
Shved
asoudaAlexander
Soudakov
xywangXiying
Wang
kwilhelKaren
Wilhelmsen
wilkeyRandy
Wilkey
silongSilong
Zhang
schlembaMary
Schlembach
trimmellAshley
Trimmell
emccarr2Elise
McCarren
cmercierChristen
Mercier
atimpermAaron
Timperman
niesShuming
Nie
hshanHee-Sun
Han
mmgMutha
Gunasekera
kknightsKatriena
Knights
lisawLisa
Williamson
keinckKatie
Einck
kneef1Kate
Neef
txiang4Tiange
Xiang
j-hummelJohn
Hummel
i-paulIain
Paul
munjanjaLloyd
Munjanja
glnGayle
Nelsen
agerardAnna
Gerard
powerskaKimberly
Powers
lolshansLisa
Olshansky
miricaLiviu
Mirica
qingcao2Qing
Cao
lisa3Lisa
Johnson
tinalambTina
Lamb
baronpBaron
Peters
bransle2Sarah
Bransley
dylanmh2Dylan
Hamilton
raegansRaegan
Smith
apm8Angad
Mehta
leverittJohn
Leveritt
xingwXing
Wang
emillrEva
Miller
jmill24Jacqueline
Miller
jlbass2Julia
Bass
ramonarRamona
Rudzinski
tlcraneTracy
Crane
cejohnstCelia
Johnston
adlAmber
LaBau
cnsolomoCandice
Solomon-Strutz
mikaelbMikael
Backlund
jacksonnNick
Jackson