combinatorial chemistry online

Work on extending this concept in binding to three sites including the active and secondary sites on PTP1B has A library of 104 compounds based on the general struc-ture i was synthesise

Combinatorial Chemistry Online Volume 7, Issue 3, March 2005

N K Terrett Pfizer Global R&D, Cambridge, MA 02139, USA

1 Current literature highlights

1.1 Protein tyrosine phosphatase inhibitors

Protein tyrosine phosphatases (PTPases) andkinases

regulate tyrosine phosphorylation in proteins, andserve

as key mechanisms for controlling intracellular signal

transduction pathways Unregulated activity of

example, the PTP-a andCdc25 phosphatases are

impli-catedin the development of cancer PTP-a activates the

Src-family of kinases while Cdc25B activates the

cyclin-dependent kinases

Since PTPases are important to a wide variety of

biolog-ical processes, there is current interest in these enzymes

as targets for diverse therapeutic intervention Much

effort is being directed toward the development of potent

andspecific PTPase inhibitors that also show

goodbio-availability One challenging aspect to the design of

PTPase inhibitors is the ability of these compounds to

achieve selectivity as all PTPases share a common

cata-lytic mechanism

The active site of PTPases is selective for binding

phos-photyrosine, but phosphotyrosine by itself has a low

affinity for the enzyme So it appears that regions of

the active site cleft beyondthe catalytic residues are

sub-strates Several groups have taken advantage of this

finding to develop bidentate ligands that bind to PTP1B

Work on extending this concept in binding to three sites

(including the active and secondary sites) on PTP1B has

A library of 104 compounds based on the general

struc-ture (i) was synthesisedin solution, andthese

com-pounds were screened initially in unpurified form against Yersinia PTPase andPTP1B Following the ini-tial screen, four of the most potent analogues were selectedfor re-synthesis andthis time purifiedbefore screening against Yersinia PTPase, PTP1B, LAR, CD45 andTCPTP One of the most active compounds

of 590 nM, excellent selectivity over LAR, 10-foldselec-tivity over CD45 andless than 2-foldselec10-foldselec-tivity over TCPTP This work has demonstrated the rapid synthesis

of a range of inhibitors against PTP1B and, importantly

in this area of research, demonstrated some selectivities against relatedenzymes

O

O

O

O

HO2C

CO2H

O

O

O NH

O

O

HO2C

CO2H (i)

(ii)

1.2 Dopamine transporter binding and reuptake inhibitors The power of combinatorial chemistry arises from its ability to synthesise large numbers of compounds in a time efficient manner The effectiveness of this technique

is often weighedagainst whether the library synthesis

doi:10.1016/j.comche.2005.02.001

E-mail: nick.terrett@pfizer.com

Combinatorial Chemistry - An Online Journal 7 (2005) 9–13

protocol is sufficiently reliable androbust enough to

re-place the traditional ÔwetÕ synthesis of single compounds,

andwhether the ÔrightÕ compounds are synthesised in the

first place reducing the need for the synthesis of

biolog-ically inactive entities Thus, any methodthat permits

the reliable generation of compounds for biological

screening will be in demand

Multicomponent Grignardreagents can be made

andre-actedwith several different electrophiles to generate

uni-form mixtures of alkylatedproducts in a library uni-format

Using this approach, the identification of biologically

active library members would normally require

individ-ual re-synthesis or so-calleddeletion synthesis To avoid

the unnecessary synthesis of scores of inactive

com-pounds, a method has recently been reported that allows

easy identification of active compounds from libraries

In essence, the methodworks by applying alternative

ways of mixing Grignardreagents to give the desired

compounds would be prepared and each product

(Grignardreagent) wouldbe assigneda coordinate x,

y, where x is the library number and y the number of

the member If the synthesis is now repeatedwith the

identities of x and y reversed, (so that y depicts a library

number, etc.), n new libraries will result containing the

By screening the 2n libraries, library members with

the display of activity in any of their coordinate

libraries

analogues were selected 3-Phenyl tropanes (iii) are

dopamine transport inhibitors and can be made by a

1,4-conjugate addition of Grignard reagents to methyl

ecgonidine (iv) In this fashion by varying reagent

solution

Compounds were screened against the monoamine transporters hDAT, hSERT andhNET in a competitive binding assay One of the most potent compounds

binding of 19 nM to hDAT This work is of interest as the methodology allows for the rapid preparation and screening of homologous compounds

2 A summary of the papers in this month’s issue 2.1 Solid-phase synthesis

A library of 16 dihydropyrido[2,3-d]pyrimidines has been synthesisedin high yields (82–92%) by a three com-ponent reaction on solidsupport using microwave

Convenient methods for regioselective solid-phase syn-theses of Methotrexate derivatives have been described andthese showedhigher efficiency than liquidphase

Ôresin-to-resin transfer reactionÕ (RRTR) concept Two fragments, one containing the halide moiety and the sec-ondone incorporating the alkyne functionality, were anchored on different solid supports using allyl and/or Wang-type linkages Treatment with Pd(0) cleaves the

2.2 Solution-phase synthesis Rhodium (II) acetate catalysed reactions of various substituted3-diazopiperidin-2-ones with a range of aro-matic amines, indoles, and benzotriazole yield exclu-sively the corresponding N–H insertion products despite competing C-H or O-H insertions This strategy provides an example of a facile chemoselective N–H insertion reaction delivering a library of 3-arylamino and 3-heteroarylpiperidin-2-one derivatives in high

-diaminotriphenylmethanes under microwave irradia-tion, suitable for parallel library syntheses have been

R1,1MgBr

R1,2MgBr

R1,3MgBr

Electrophile (E)

R1,2MgBr

R2,2MgBr

R3,2MgBr

Electrophile (E)

E-R1,1 E-R1,2 E-R1,3 E-R2,1 E-R2,2 E-R2,3 E-R3,1 E-R3,2 E-R3,3

Scheme 1 Synthesis of nine compounds in two dimensions using

variable mixing Six three-component Grignardreagents are reacted

with an electrophile (E) to give six libraries Screening of libraries 1,x

andx,2 will show whether compoundE-R1,2 is significantly more

active than the background.

N

CO 2 Me

N

CO2Me Ph

N

CO2Me

PhMgBr, Et 2 O, -40 o C

(v)

10 N K Terrett / Combinatorial Chemistry - An Online Journal 7 (2005) 9–13

By combining a Staudinger/aza-Wittig and an Ugi

three-component reaction in a one-pot process (SAWU-3CR),

a new andefficient multicomponent reaction has

been developed, and the versatility of this methodology

demonstrated by the construction of a molecular

2.3 Scaffolds for combinatorial libraries

No papers this month

2.4 Solid-phase supported reagents

A series of ionic polymers preparedby quaternisation of

several alkylating agents, including short-length PEG

mesylate have been usedas polymeric supports to

Isocyanate resins are usedin polymer

assistedsolution-phase synthesis However, their use is limitedby their

high cost andoften unfavourable reaction profiles A

route to prepare efficient supportedisocyanate resins

from aminomethyl resin andinexpensive diisocyanates

has been reportedandcomparedto commercially

The BINOL moieties have been successfully

immobi-lisedon the surface of a micelle-derivedpolymer

Ti-BINOLate complexes preparedfrom the polymer with

PS–Et, andTentaGel supporting

levels of enantioselectivity (up to 99% ee) in

2.5 Novel resins, linkers and techniques

A multi-parallel enzyme screen has been usedto identify

potential catalysts for the selective hydrolysis of

diaste-reomeric esters andthen subsequently appliedto their

A rapidandeasy route to formamides by microwave

as-sisted N-formylation of primary andsecondary amines

has been described Using an insoluble polymer or an

inorganic solid-supported reagent as a formylating

agent, microwave irradiation gave the corresponding

formamides in high yields, with reduced reaction time

Oxabicyclo[2.2.1]norbornenes constitute a convenient

and readily thermally-cleaved linker for solid-phase

organic synthesis A simple andinexpensive

furfuryl-substitutedresin has been shown to capture andrelease

maleimide dienophiles under conditions compatible with

Hydrolytic yields as high as 80% have been obtained by using penicillin G amidase (PGA) on substrates anchoredon optimisedpositively chargedPEGA poly-mers The effect of different amounts of charges on polymer swelling andprotein retention inside the poly-mer was investigatedandcorrelatedto the enzyme effi-ciency demonstrating that electrostatic interactions predominate over swelling properties in determining

2.6 Library applications

A new diversity-oriented approach to the bengamides, a new class of antitumour natural products of marine ori-gin, has been reportedfrom epoxyamides, preparedby reaction of aldehydes with sulphur ylides The combina-tion of cross olefin metathesis, introduccombina-tion of different nucleophiles by the oxirane ring opening andthe intro-duction of different amines via amide bond formation,

A Ôfragment approachÕ andsolidphase synthesis has

Through compoundlibrary screening, using an HCV NS5B RNA-dependent RNA polymerase enzymatic

15 lM was identified Parallel synthesis allowed SAR studies to focus on the different groups at the 6- and 7-positions, substitutions at the 4-position,

A convenient one-pot synthetic route was developed for the preparation of asymmetric 1,3-dialkyl-1,3,5-triazine-2,4,6-triones from readily available alkyl- or aryl-isocy-anates, primary amines and N-chlorocarbonyl isocya-nates Subsequent alkylation with N-protectedamino alcohols afforded the desired 1,3,5-triazine-2,4,6-triones

in good yields This methodology was applied to the synthesis of a chemical library acting as antagonists of

Two series of potent andselective allosteric Akt kinase inhibitors that display an unprecedented level of selec-tivity for either Akt1, Akt2 or both Akt1/Akt2 have been developed An iterative analogue library synthesis approach quickly provided a highly selective Akt1/ Akt2 inhibitor that induced apoptosis in tumour cells

combinatorial approach, phenylglycine amide tissue fac-tor/factor VIIa inhibitors with low nanomolar affinity andgoodselectivity against other serine proteases of the coagulation cascade have been designed, using the guidance of X-ray structural analysis and molecular

A library of 256 neomycin–dipeptide conjugates has been constructed on TentaGel beads using a split-and-pool combinatorial synthesis Five conjugates were selectedafter screening the library as ligands for Rev

N K Terrett / Combinatorial Chemistry - An Online Journal 7 (2005) 9–13 11

responsive element (RRE) RNA, andthey were

identi-fiedafter sequencing by MALDI-TOF mass

A structure–activity study on a benzylpiperidine has

been accomplishedby utilising high-throughput

synthe-sis Three focusedlibraries were

an MCH receptor R1 antagonist with over 400-fold

improvement in biological activity over the original

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Further reading

Papers on combinatorial chemistry or solid-phase synthesis from

other journals

Gouault, N.; Pinel, B.; Cupif, J.-F.; Depince, A.;

Martin-Chouly, C A E.; Belleguic, C.; David, M Synthesis and

potential anti-inflammatory activity of some tetrahydroph-thalazinones Journal of Enzyme Inhibition and Medicinal Chemistry 2004, 19 (6), 475–480

Lelais, G.; Micuch, P.; Josien-Lefebvre, D.; Rossi, F.; Seebach,

D Preparation of protected and b3-homocysteine, b2-and b3-homohistidine, b2-and b2-homoserine for solid-phase syntheses Helvetica Chimica Acta 2004, 87 (12), 3131– 3159

Sheela, M S.; Sreekumar, K Epoxidation and oxidation reactions using 1,4-butanediol dimethacrylate crosslinked polystyrene-supported tertiary butyl hydroperoxide Jour-nal of Chemical Sciences (Bangalore, India) 2004, 116 (6), 319–324

Albrecht, M.; Janser, I.; Runsink, J.; Raabe, G.; Weis, P.; Froehlich, R Selecting different complexes from a dynamic combinatorial library of coordination compounds Ange-wandte Chemie, International Edition 2004, 43 (48), 6662–6666

Wallner, F K.; Norberg, H A.; Johansson, A I.; Mogemark, M.; Elofsson, M Solid-phase synthesis of serine-based glycosphingolipidanalogues for preparation of glycocon-jugate arrays Organic & Biomolecular Chemistry 2005,

3 (2), 309–315

Sheng, S.-R.; Zhou, W.; Sang, X.-Y.; Liu, X.-L.; Wang, Q.-Y Solid-phase synthesis of acrylamides with polymer-bound 2-sulfonylpropanoic acid Journal of Chemical Research

2004 (9), 626–627

Bae, S.; Hahn, H.-G.; Nam, K D.; Mah, H Solid-phase synthesis of fungitoxic 2-imino-1,3-thiazolines Journal of Combinatorial Chemistry 2005, 7 (1), 7–9

Hulliger, J.; Awan, M A ÔSingle sample conceptÕ: theoretical model for a combinatorial approach to solid-state inorganic materials Journal of Combinatorial Chemistry 2005, 7 (1), 73–77

Kappe, C O Synthetic methods Controlled microwave heating in modern organic synthesis Angewandte Chemie, International Edition 2004, 43 (46), 6250–6284

Lavrador, K.; Murphy, B.; Saunders, J.; Struthers, S.; Wang, X.; Williams, J A screening library for peptide activated G-protein coupledreceptors 1 The test set Journal of Medicinal Chemistry 2004, 47 (27), 6864–6874

Braese, S.; Dahmen, S.; Popescu, C.; Schroen, M.; Wortmann, F.-J The structural influence in the stability of

2004, 10 (21), 5285–5296

Roy, K Topological descriptors in drug design and modeling studies Molecular Diversity 2004, 8 (4), 321–323

Kautz, R A.; Goetzinger, W K.; Karger, B L High-throughput microcoil NMR of compoundlibraries using zero-dispersion segmented flow analysis Journal of Combi-natorial Chemistry 2005, 7 (1), 14–20

Picard, S.; Le Roch, M.; Renault, J.; Uriac, P Parallel

Organic Letters 2004, 6 (25), 4711–4714

Sivakumar, K.; Xie, F.; Cash, B M.; Long, S.; Barnhill, H N.; Wang, Q A fluorogenic 1,3-dipolar cycloaddition reaction

of 3-azidocoumarins and acetylenes Organic Letters 2004,

6 (24), 4603–4606

Lysek, R.; Grzeszczyk, B.; Furman, B.; Chmielewski, M [2 + 2]-cycloaddition of chlorosulfonyl isocyanate to (Z)-propenyl ethers boundto polystyrene resins by alkylsulfo-nyl linkers European Journal of Organic Chemistry

2004 (20), 4177–4187

Roberts, R S ROMPgel Beads in IRORI Format: Acylations Revisited Journal of Combinatorial Chemistry 2005, 7 (1), 21–32

Carranco, I.; Diaz, J L.; Jimenez, O.; Vendrell, M.; Albericio, F.; Royo, M.; Lavilla, R Multicomponent reactions with dihydroazines: efficient synthesis of a diverse set of

pyrido-12 N K Terrett / Combinatorial Chemistry - An Online Journal 7 (2005) 9–13

fusedtetrahydroquinolines Journal of Combinatorial

Chemistry 2005, 7 (1), 33–41

Agarkov, A.; Greenfield, S J.; Ohishi, T.; Collibee, S E.;

Gilbertson, S R Catalysis with phosphine-containing

amino acids in various turn motifs Journal of Organic

Chemistry 2004, 69 (23), 8077–8085

Saha, B.; Srivastava, G K.; Kundu, B Solid phase synthesis of

triazadibenzoazulenone Synlett 2004 (12), 2242–2244

Rosse, G.; Strickler, J.; Patek, M Efficient solid-phase synthesis of disubstituted 1,3-dihydro-imidazol-2-ones Synlett 2004 (12), 2167–2168

Ruhland, T.; Torang, J.; Pedersen, H.; Madsen, J C.; Bang, K S Traceless solidphase synthesis with

2323–2328

N K Terrett / Combinatorial Chemistry - An Online Journal 7 (2005) 9–13 13