The document summarizes the January-March 2010 issue of "The Cutting Edge of Chemistry", a new report from Pharma Matters focusing on recent developments in medicinal chemistry research. The report is organized into sections covering organic synthesis schemes, novel molecular scaffolds, new mechanisms of action, and emerging drug candidates. The featured article describes a total synthesis of the marine natural product Polytheonamide B, which has shown cytotoxic effects against leukemia cells, achieved through a multi-step coupling of peptide fragments using silver-mediated thioligation. The synthesis overcomes prior challenges and provides a platform for further studies on structure-activity relationships and biological function. Overall, the report aims to give chemists insights into cutting-edge research advancing drug

1. Image CopyrIght: REUTERS/Bogdan Cristel
THE CUTTING EDGE
OF CHEMISTRY
A PHARMA MATTERS REPORT.
JANUARY - MARCH 2010
NEW!
Action-packed chemistry review providing insight into the latest
synthesis schemes, scaffolds, mechanisms of actions and new
structures advancing drug discovery and development.

2. The Cutting Edge of Chemistry discloses new ideas and achievements in the
biomedical research field with the chemist’s perspective in mind and is a
recently launched new addition to the Pharma Matters report series. The
report has been organized into sections that delineate essential aspects of
the search for better and safer drugs.
The Organic Synthesis Scheme Showcase presents a selection of cutting-
edge organic syntheses for drugs currently on the market or in development
worldwide and described in premier publications in medicinal chemistry as well
as in the current patent literature. This section provides access to the state-of-
the-art synthetic methods for bioactive compounds, as well as demonstrating
how new synthetic methods lead to interesting intermediates or drugs.
Chemists often start with a novel chemical structure in the drug discovery
process. Molecular scaffolds are the building blocks with which they build
more sophisticated active compounds. Chemists have so far explored only
small regions of the vast molecular universe looking for therapeutic agents,
but are constantly pushing back the frontiers. Scaffolds on the Move relates
efforts in this arena.
Finding new targets to address more selectively is crucial to sustaining a
competitive advantage in pharmaceutical research. Indeed, accurate target
identification and validation processes in the very early stages of any drug
R&D project can make the difference between success and failure in the
clinical application of a new drug as well as a strong intellectual property
strategy. The New Molecular Mechanisms of Action feature highlights this
critical aspect of early-stage research.
The Starting Line includes a series of new molecular entities just entering
the R&D pipeline. Novel, biologically active molecules picked from the
current scientific literature and meetings are revealed in this section. Not
surprisingly, these research projects from industry and academia are the
culmination of the earlier steps in the process: discovery of an original
chemical structure, identification of an appealing new mechanism of action,
and determination of synthetic feasibility.
Thomson Reuters has widely applied in the design of its products and
services the dynamics driving end-user information needs. The Cutting Edge
of Chemistry is the most recent addition to this concept and we expect it
will constitute, together with the existing Pharma Matters reports, a useful
addition to your reading list.
IN THIS ISSUE
1 orgaNIC SyNtheSIS SCheme ShoWCaSe
Marine natural products prove useful as leads repeatedly. A novel
synthetic approach to a rare peptide from a marine sponge opens
the door for evaluating its promising biological activity.
4 SCaFFoLDS oN the moVe
A wide range of new skeletons emphasize the point that novel
chemical scaffolds with biological activity underpin major
advances in medicinal chemistry.
7 NeW moLeCULar meChaNISmS oF aCtIoN
Mechanisms are key to finding ways to improve a given drug
design and also to find still more potent leads with fewer
potential side effects.
9 the StartINg LINe & target FoCUS
Highlighted in this issue, the rise of new molecular entities in the
cancer and CNS R&D arenas.
PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY
A

3. ORGANIC SYNTHESIS SCHEME
SHOWCASE: SoakINg up
polyTheoNaMIDe B SyNTheSIS
polytheonamides a and B (pa and pB) were first isolated from
the coral reef sponge Theonella swinhoei, a well-known source of
novel natural products with physiological activity. What makes
pB particularly interesting is that it can stimulate an ion flux
across cell membranes and quickly kill cells. The compound has
been investigated for a potential role in treating leukemia as it is
cytotoxic against a strain of mouse leukemia p388 cells.
Researchers have assumed that a symbiotic microorganism
present in T. swinhoei is responsible for the biosynthesis of pB.
as such, the total synthesis of pB has represented a challenge.
Masayuki Inoue of the graduate School of pharmaceutical
Sciences, The university of Tokyo, and colleagues have now
obtained good yields in a laboratory synthesis involving a
coupling reaction between appropriate segments of pB using
thioligation with silver ions [1].
In detail, the team uses a four-stage synthesis. The first
step is the synthesis of the required amino acids, which are
not commonly found in proteins. The second stage is the
preparation of the required peptide fragments by solid-phase
assembly of the protected amino acids over a Wang resin. after
derivatization of the three fragments into thioesters, they are
inter-connected, in the third stage, by means of silver ions in
processes with yields of about 85%. The fourth and final step
involves global deprotection.
The researchers add that the stereoselective synthesis of the
sulfoxide from the sulfide precursor and its stereochemical
assignment were not simple tasks, primarily because chiral
reagents for sulfide oxidation do not exhibit diastereoselectivity.
however, by turning to katsuki conditions the team was able to
promote a highly diastereoselective oxidation to the final product.
This invaluable approach to peptide disconnections and
protecting-group strategy not only has made it much more
straightforward to synthesize such a significant compound as
pB, but could allow chemists to construct other polypeptide
drugs for testing against a range of disorders. Inoue and
colleagues also point out, “The synthetic material now available
will allow studies of the relationships between its conformational
properties, channel functions and cytotoxicity.”
Indeed, Inoue and colleagues conclude, “This attempt to gain
precise atom-by-atom control of the structure will provide the
first chemical basis for systematically correlating its molecular
structure and biological function.”
INTEGRITY ENTRY NUMBER: 691631
PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 1

4. Synthesis scheme for Polytheonamide B (Part 1)
O O O O O O
H H H H H
N N N Ile N N
E tO S L T le Fmoc
H H
N N
H 3C C H3 HO C H3 C H3
OH
O O
(I)
HOOBt, AgNO 3 , DIEA
N
N O O O O O
H H H H H
N N N N Ile N N
O L T le Fmoc
H H
O N N
H 3C C H3 HO C H3 C H3
OH
O O
O (II)
Ile NH 2
H
N
C H3 O
O T rt
O O O O N
H H H H
HN Val N Ala N Val D Ser N N O
H H H
N C H3 H N
N C H3 H 3C C H3 O
t BuO C H3 + C H3
NH S
O O O
O
O
HO Thr(tBu) D Thr(tBu) G ln(T rt) NH H 3 C C H 3
O
Pip
NH
T rt
(III)
O O O O
H H H H
Ile N G ly N N Ile N G ly NH 2
L T le
H H H
N N N
C H 3 H 3C C H3 HO C H3 C H3 O
OH
O O O T rt
O O O O N
H H H H
HN Val N Ala N Val D Ser N O
N
H H H
N C H3 H N
N C H3 H 3C C H3 O
t BuO C H3 + C H3
NH S
O O O
O
O
HO Thr(tBu) D Thr(tBu) G ln(T rt) NH H 3 C C H 3
O
C H3
H 3C C H3 NH
T rt
L Tle
OH
H 2N (IV)
Synthesis scheme for Polytheonamide B (Part 2)
O
O O O O
continued H H H H
Ile N G ly N N Ile N G ly NH 2
L T le
H H H
N N N
C H 3 H 3C C H3 HO C H3 C H3 O
OH
O O O T rt
O O O O N
H H H H
continues HN Val N Ala N Val D Ser N O
N
H H H
N C H3 H N
N C H3 H 3C C H3 O
t BuO C H3 + C H3
NH S
O O
O
O
OH O
H 3C C H3 O C H3
O HO Thr(tBu) D Thr(tBu) G ln(T rt) NH H C
H H 3
O N Ala D T le N
N Fmoc O
H
O C H3
O NH 2 NH
HN T rt
C H3 H 3C O
O O
H H H
N N
G ly Ala G ly L T le N Ala G ly S OE t (IV)
H
H O
N H 3C C H3
C H3 OH
O
(V) 1) HOOBt, AgNO3 , DIEA
2) Pip
OH
H 3C C H3
O
H
O N Ala D T le Ala NH
2
N
H
O
O NH 2
HN
C H3 H 3C
O O
H H H
N N Ala
G ly Ala G ly L T le N
H
H O
N H 3C C H3
C H3 OH G ly
O
O O O O
H H H H
Ile N G ly N N Ile N G ly
L T le
H H H
N N N
C H 3 H 3C C H3 HO C H3 C H3 O
OH
O O O T rt
O O O O N
H H H
H O
HN Val N Ala N Val D Ser N
N
H H H
N C H3 H N
N C H3 H 3C C H3 O C H3
t BuO C H3 +
NH S
O O
O O
O
HO Thr(tBu) D Thr(tBu) G ln(T rt) NH H 3 C C H 3
O
C H3 NH
H 3C C H3 T rt
D Tle
OH (VI) continues
H 2N
O
2 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY

5. Synthesis scheme for Polytheonamide B (Part 3)
continued
OH
H 3C C H3
O
H
O N Ala D T le Ala NH
2
N
H
O
O NH 2
HN
C H3 H 3C
O O C H3 O O
H H H H 3C H
N N Ala G ly N G ly L T le D T le L T le D Ala
G ly Ala G ly L T le N H 3C
H
O O
H H 3C C H3 CH
N CH 3 L T le
C H3 OH G ly C H3 3
O E tO S
G ly Ala D T le
O O O O
H H H H O
Ile N G ly N N Ile N G ly
L T le
H H H (VII)
N N N
C H 3 H 3C C H3 HO C H3 C H3 O
OH
O O O T rt
O O O O N
H H H
H O
HN Val N Ala N Val D Ser N
N
H H H
N C H3 H N
N C H3 H 3C C H3 O C H3
t BuO C H3 +
NH S
O O
O O
O 1) HOOBt, AgNO 3, DIEA
NH H 3 C C H3 2) TFA
HO Thr(tBu) D Thr(tBu) G ln(T rt)
O
NH
T rt
(VI)
C H3 O O
H 3C H
G ly N G ly L T le D T le L T le D Ala
H 3C
O
C H3
C H3
C H3 L T le
OH
H 3C C H3
O
H
O N Ala D T le Ala G ly Ala D T le
N
H
O O NH 2
HN H 3C
C H3 O O
H H H
N N Ala
G ly Ala G ly L T le N
H
H O
N H 3C C H3 G ly
C H3 OH
O
O O O O
H H H H
Ile N G ly N N Ile N G ly
L T le
H H H
N N N
C H 3 H 3C C H3 HO C H3 C H3
OH
O O O
O O O
H H
HN Val N Ala N Val D Ser Val D Asn
H H H
N N N
C H3 HO C H3 C H3
O O O O
C OOH Thr D Thr G ln D Asn NH
O
H 3C S
+
C H3
H 3C
Diastereoselective oxidation of sulfide to sulfoxide (Katsuki conditions)
H 3C H 3C +
O
S S
C H3 1) H 2NCONH 2.H 2O 2, C H3
C H3 di-µ-oxo Ti(salen) C H3
Fmoc O Fmoc OH
N t-Bu N
H 2) TFA H
O O
PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 3

6. SCAFFOLDS ON THE MOVE
Novel chemical scaffolds with biological activity underpin major
advances in medicinal chemistry. In this issue, a wide range of
new skeletons emphasize this point once again. For instance,
a series of 2-arylbenzoxazoles from Merck & Co. offers hope in
treating lipid disorders and atherosclerosis, while arthritis is the
target of almirall’s new dihydroorotate dehydrogenase inhibitors.
a promising skeleton, carene, from Novartis also features in this
issue and offers a new lead for treating transplant rejection.
BENZOXAZOLE BLOCKS CHOLESTEROL TRANSFER
Merck scientists have developed a series of 2-arylbenzoxazoles that block
cholesteryl ester transfer protein (CeTp) and so might be useful in treating
lipoprotein disorders and disorders of the coronary arteries as well as
atherosclerosis. Their structure-activity studies on the impact of varying
the substitution of the benzoxazole moiety suggest that substitution at
the 5- and 7-positions is beneficial to CeTp inhibition. The most potent
compound of the series has an IC50 of 28 nM.
NC N THERAPEUTIC GROUP: SOURCE:
O C H3 Treatment of lipoprotein Disorders; Smith, C.J.; ali, a.; Chen, l.;
O
C H3
O Treatment of Coronary arteries and hammond, M.l.; et al.
N
HO H atherosclerosis Disorders 2-arylbenzoxazoles as CeTp
C H3
STUDIED MECHANISM OF ACTION: inhibitors: Substitution of the
Cholesteryl ester Transfer protein benzoxazole moiety.
(CeTp) Inhibitors Bioorg Med Chem Lett 2010, 20(1):
346.
ORGANIZATION: INTEGRITY ENTRY NUMBER:
Merck & Co. 684173
O OH ANTI-INFLAMMATORY AMINO(ISO)NICOTINIC ACIDS
F
H arthritis is the focus of novel, patented dihydroorotate dehydrogenase
N
(DhoDh) inhibitors from almirall, that are orally active and could be suitable
N O F for treating autoimmune conditions, such as rheumatoid arthritis. The potent
F
F amino(iso)nicotinic acid derivatives represent a new scaffold for DhoDh
C H3 F
inhibitors, one biaryl derivative showing an IC50 of 6 nM against human
DhoDh (featured molecule). Structure-activity studies and optimization of
the series led to one particular compound (chemical structure undisclosed)
with potent in vitro activity against human, rat and mouse DhoDh (IC50
values of 0.037, 0.034 and 0.07 µM, respectively) compared with that of
teriflunomide (respective IC50 values of 1.5, 0.033 and 1.1 µM). The compound
also inhibits proliferation of human peripheral blood mononuclear cells
more effectively and has demonstrated efficacy in reducing inflammation, as
measured by paw volume, in a rat model.
THERAPEUTIC GROUP: SOURCE:
antiarthritic Drugs erra, M.; Sanahuja, J.; Fonquerna,
STUDIED MECHANISM OF ACTION: S.; Navarro, e.; et al.
Dihydroorotate Dehydrogenase Best in class DhoDh inhibitors:
(DhoDh) Inhibitors evolution of clinical compounds.
239th aCS Natl Meet (March 21-25,
San Francisco) 2010, abst MeDI 461.
ORGANIZATION: almirall INTEGRITY ENTRY NUMBER:
691251
4 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY

7. IMIDAZO[1,2-a] PYRAZINE ANTICANCER DRUGS
H
aurora-a (aRk1) kinase and aurora-B (aRk2) kinase are two enzymes N N
over-expressed in tumors. Belonging to a family of three Ser/Thr kinases,
they are critical regulators of mitosis, abundant in tumors, and so have
H 3C
been longstanding targets for anticancer compounds. Merck has recently N
disclosed novel dual inhibitors of aurora kinases a and B based on an N
N
H 3C C H3
imidazo[1,2-a] pyrazine scaffold. lead optimization allowed for the
HN OH
identification of progression candidates, albeit they showed poor oral N
bioavailability. The sites of metabolism were identified by studying the S N
metabolic profile of a particular compound of the series. C H3
THERAPEUTIC GROUP: SOURCE:
oncolytic Drugs kerekes, a.D.; esposite, S.J.; Doll,
STUDIED MECHANISM OF ACTION: R.J.; yu, T.; et al.
aurora-a (aRk1) kinase Inhibitors; aurora kinase inhibitors based
aurora-B (aRk2) kinase Inhibitors on the imidazolopyrazine core:
Fluorine incorporation improves
oral absorption and exposure.
239th aCS Natl Meet (March 21-25,
San Francisco) 2010, abst MeDI 146.
yu, T.; Tagat, J.R.; Zhang, y.; Xiao,
y.; et al.
Discovery of aurora kinase inhibitors
based on 3,6,8-trisubstituted
imidazo[1,2-a] pyrazine scaffold.
239th aCS Nat Meet (March 21-25,
San Francisco) 2010, abst MeDI 145.
ORGANIZATION: INTEGRITY ENTRY NUMBER:
Merck & Co. 689948
PYRAZOLES AVOID REJECTION
H 3C C H3
employing a high-throughput screening and hit-to-lead optimization
H 3C
approach, Novartis has come out with a new carene scaffold displaying
N
selective S1p1 agonist properties. Furthermore, the key structural requisites N
for potent agonism were also outlined by building up a pharmacophore NH
model for the S1p1 receptor, a biological target for immunosuppression O
and the treatment of transplant rejection.
THERAPEUTIC GROUP: SOURCE:
Immunosuppressants; Treatment of Zécri, F.J.; albert, R.; landrum, g.;
Transplant Rejection hinterding, k.; et al.
STUDIED MECHANISM OF ACTION: pyrazole derived from (+)-3-carene;
lysophospholipid edg1 (S1p1) a novel potent, selective scaffold
Receptor agonists for sphingosine-1-phosphate (S1p1)
receptor agonists.
Bioorg Med Chem Lett 2010, 20(1): 35.
Zécri, F.J.; albert, R.; Baenteli, R.;
landrum, g.; et al.
Discovery and optimization of
multiple scaffolds of selective S1p1
receptor agonists.
239th aCS Natl Meet (March 21-25,
San Francisco) 2010, abst MeDI 31.
ORGANIZATION: INTEGRITY ENTRY NUMBER:
Novartis 369046
PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 5