Group Meeting

Christos Mitsos Isosteres in Medicinal Chemistry 2/1/2006

Reviews Definition of Bioisosterism

G. A Patani, E. J. LaVoie, Chem Rev. 1996, 3147-3176.
C. G. Wermuth, in The Practice of Medicinal Chemistry,
Academic Press 1996, pp 203-237.
Definition of Isosterism
Langmuir (1919): Compounds or groups of atoms having the
same number of atoms and electrons
Friedman (1951): Bioisosteres are atoms or molecules that fit
the broadest definition for isosteres and have the same type of
biological activity.
Thornber (1979): Groups or molecules which have chemical and
physical similarities producing broadly similar biological effects.

Examples: N2 and CO, N2O and CO2, N3- and NCO-

Grimm (1925): “Hydride Displacement Law” addition of Parameters affected with bioisosteric replacements
hydride to an atom gives to the resulting pseudoatom' the
properties of the atom with the next highest atomic number. Size, conformation, inductive and mesomeric effects,
polarizability, H-bond formation capacity, pKa, solubility,
hydrophobicity, reactivity, stability.
Hydride Displacement Law
C N O F Ne Na+
Bioisosteric replacements: Why?
CH NH OH FH -
• Greater selectivity
CH2 NH2 OH2 FH2+
• Less side effects
CH3 NH3 OH3+ • Decreased toxicity
CH4 NH4+ • Improved pharmacokinetics (solubility-hydrophobicity)
• Increased stability
Erlenmeyer (1932): atoms, ions or molecules in which the • Simplified synthesis
peripheral layers of electrons can be consider identical.
•Patented lead compounds
Examples: atoms in the same column of the periodic table, Cl
and CN and SCN (despite having different number of atoms)
 Group Meeting
Christos Mitsos Isosteres in Medicinal Chemistry 2/1/2006

OH O
H to F replacement HN
F HN
E O N
O N S
Fluorine: similar size with hydrogen O
R
F E-SH R
most electronegative halogen HN 2'-deoxyuridylic
C-F bond very stable
O N E-SH
O
-O O
P
-O O
H F Cl CH3 CF3 O OH
OH CH3
HN HN
Van der
1.2 1.35 1.80 2 2 E
Waals radius O N O N S
5-Fluorouracil
R R
(antineoplastic)
Molecular Thymidylate
1.03 0.92 6.03 5.65 5.02 (DNA synthesis)
Refractivity
Inductive E-SH: Thymidylate synthase
- 3.08 2.68 0.00 2.85
effect
F
Resonance
0.00 -0.34 -0.15 -0.13 0.19
effect
O NHMe N N

F3C
Ideal replacement to study the effect of electronegativity change
F
without affecting steric requirements Fluoxetine Flunarizin
(Prozac) (Sibelium)
antidepreessant Ca channel blocker
F (or other halogens) can be placed on eacily oxidized positions
to increase stability during metabolic processes
O
F F CO2H
Thus, F (or other halogens when size is not critical) are
CO2H
frequently place on easily oxidized aromatics N N
Methyl groups often substituted by CF3 OAc
HN

Flufenisal
analgesis Ciprofloxacin
(Cipro)
antibacterial
 Group Meeting
Christos Mitsos Isosteres in Medicinal Chemistry 2/1/2006

-OH to -NH2 or –SH replacement Van der Waals IC50

X
(also C=O to C=NH or C=S) radius (Å) (nm)
MeO2C CO2Et
O and NH have similar sizes (but not SH) N O 1.40 140
All three bear H-bonding donor and acceptor capacities X N Me NH 1.50 160
H

Dihydropyrimidine
S 1.85 17
calcium channel blockers
H2N N N
H
N
N
N Halogen replacements
H
X N CO2H
CN and CF3 may be used as alternative electron-withdrawing
O CO2H groups instead of halogens.

X = NH2, Aminopterin (Methotrexate) The two groups have comparable effects on electronics, but CN
(an antimetabolite anticancer)
will increase the overall hydrophilicity.
X = OH, Folic acid

Replacement of OH with NH2 can stabilize a different tautomer, Ring replacements

especially in the case of heterocyclic systems
Sulfonamide antebacterials: phenyl group may be replaced by
many heterocycclic aromatics to give active compounds

N O N OH O O N
H S Ar
N Ar =
more stable H N N
H2N
Sulfapyridine Sulfapyrazine

S N
N NH N NH2
H N N
more stable
Sulfathiazole Sulfapyrimidine
 Group Meeting
Christos Mitsos Isosteres in Medicinal Chemistry 2/1/2006

COOH replacements
Peptide surrogates
O O O O O Peptides are characterized by diminished bioavailability
O OH CN S
N N N R when administered orally.
H H H
OH Replacement of the sensitive amide bond by various groups
hydroxamic acylcyanamide sulfonimide
can increase their stability.
(strong chelating
agents) (similar acidities)

O O O O O
P OH S S R2 R2
OH OH NHR O O
H H
N N
phosphonate sulfonate sulfonamide O N
(more acidic; (less acidic) O R O
ionized at physiological pH) R1 R1
Ester N-alkylation

N N O N N O
N OH O R2 R2
N R2 O
N O H
H H H H
N N N N
N N
tetrazole hydroxyisoxazole oxadiazolone H
O H O
R1 O R1
R1
Amide to double bond Azapeptide
Carboxyl group may be replaced in order to alter acidity, or modify
lipophilicity without affecting pKa
Tetrazoles have comparable pK’s with carboxylic acids, but greater R2 R2
S O
lipophilicity H H
N N
N N
H H
O O
Cl R1 R1
N Thioamide Dehydroaminoacid
HO
N N N
HN N Losartan
(antihypypertensive)
CH3
 Group Meeting
Christos Mitsos Isosteres in Medicinal Chemistry 2/1/2006

Preparation of tetrazoles
BocHN BocHN
H
N TMSN3, DEAD N
Ph Ph
R O PPh3, THF O
N CN Ph3P CN
N
-N N
N HN3 R N BocHN BocHN
CN NaOH;
N N N
R base, ∆ HN N Ph Ph
N HCl N
R N N HN N
N
N-
N N J. Med. Chem 2000, 43, 488.

N N
N Cl PMB
CN MeO Cl
N ClCH2C(OEt)3
H N
NaN3, NH4Cl
NH2 NaN3, AcOH EtO N N
N N
PMB
DMF, 90 oC
PhtHN CO2Me PhtHN CO2Me
Tet Lett 1998, 39, 3367.

O CO2H O OSiR3 N N
SiCl4, NaN3 N
O N NH2 N N
H MeCN, reflux SiR3
SiR3
HN N

N N NH H2O
N N
Tomudex analogues
N N
N
Tet Lett 1997, 38, 1257. N
J. Med. Chem. 1999, 42, 3809. H
 Group Meeting
Christos Mitsos Isosteres in Medicinal Chemistry 2/1/2006

Peptide (amide) repalcements

Amide to alpha-difluoroketone
Amide to hydroxyethyl

H F F
O O
H N COOEt COOEt
N CbzHN CbzHN
BocHN N BocHN N
H H O i-Bu O i-Bu
O HO
Me Me Me Me

1. H2, Rh-C
2. TMSCN
1. BF3.OEt2, EtOH 1. ChxCHPPh3 Chx 3. DIBAL CF2Br2, HMPT
OAc COOMe CHO
2. MeOH, KOH 2. Jone's Ph Chx Chx CF2
O O
O 3. PivCl OHC O OEt 3. H2, Pd-C OTMS
OH OTMS
4. TBSCl TBSO
AcO 5. LAH TBSO
OAc 6. [O] 1. NaOH
2. n-BuLi, LHMDS2, -90 °C; F F
ClCOCH2-i-Bu Chx CF2 TBSCl, rt; H3O+
O Chx COOH
i-Bu
Chx O i-Bu
1. LiNTMS2, MeCHO Chx
2. MsCl O O
3. Me2CuLi MeOH, H+ HO 1. (COCl)2 OEt
Me 50 : 50 Me 2. NH3
O NH I2, NaHCO3,
TBSO 3. Et3OBF4 F F radical scavenger i-Bu
Me Chx N
Me O F
OEt Chx
equilibrate with LHMDS i-Bu F
I

Chx 1. RCOOH, Chx Chx

1. DEAD, DPPA O 1. H3O+ Chx
DPPCN 2. CbzCl F F Moffatt F F
2. H2, Pd-C H2N COOEt
2. n-BuNH2 RCOHN NHn-Bu
3. PTFA COOEt
Me CbzHN
O HO (78%) CbzHN
OH i-Bu O i-Bu
Me Me
Me
O

Damon, D. B.; Hoover, D. J. J. Am. Chem. Soc. 1990, 112, 6439-6442.

Shiozaki, et.al. Tetrahedron Lett. 1989, 30, 3669-3670.
 Group Meeting
Christos Mitsos Isosteres in Medicinal Chemistry 2/1/2006

Peptide (amide) repalcements

Amide to alkene
Amide to alkene
Me Me
BnO BnO Me O Me O
H H
N COOH COOH N
CbzHN CbzHN BocHN Phe-NH2 BocHN Phe-NH2
O O
CONH2 CONH2 CO2-t-Bu CO2-t-Bu

1. ClCOOEt, NaBH4
OBn 2. Bu3P, (PhS)2 OBn 1. DCC, 3,5-
3. MCPBA Me diMe-pyrazole Me 1. DIBAL
SO2Ph 2. LAH
CbzHN COOH CbzHN Me 3. HWE 2. CH3C(OMe)3
Me
CbzHN CO2H
CbzHN CO2Et

O 1. LDA, ICH2COO-i-Bu
2. LAH OHC
Me OTHP
Aux
3. DHP Me Me 1. OsO4, NMO
Me 4. O3; DMS CO2-t-Bu 1. NaOH 2. NaIO4
Me 2. DCC, t-BuOH Me 3. Jones'
3. (Boc)2O Cbz 4. NaOH
CbzHN N
OBn Boc
OBn OHC 1. MeLi COOMe CO2-t-Bu
OTHP MeOAl(i-Bu)2
SO2Ph + CbzHN OTHP
CbzHN CO2-t-Bu 2. Na(Hg),
NaH2PO4 CO2-t-Bu
Me Me
EDCI,
Me PheNH2 Me O
CO2H
OBn OBn BocHN BocHN PheNH2
1. TFA
2. NH3 Jones'
COOH CO2-t-Bu CO2-t-Bu
CbzHN OH CbzHN

CONH2 CONH2 Separate by Flash Chromatography

de Gaeta, et.al. J. Org. Chem. 1989, 54, 4004-4005. Shue, et.al. Tetrahedron Lett. 1988, 29, 4041-4044.
Spaltenstein, et.al. J. Org. Chem. 1987, 52, 3759-3766.