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, Friedman (1951): Bioisosteres are atoms or molecules that fit Academic Press 1996, pp 203-237. the broadest definition for isosteres and have the same type of biological activity. Definition of Isosterism Thornber (1979): Groups or molecules which have chemical and Langmuir (1919): Compounds or groups of atoms having the physical similarities producing broadly similar biological effects. same number of atoms and electrons - - Examples: N 2 and CO, N 2O and CO 2, N 3 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, pK a, solubility, hydrophobicity, reactivity, stability. Hydride Displacement Law C N O F Ne Na + Bioisosteric replacements: Why? CH NH OH FH - • Greater selectivity CH NH OH FH + 2 2 2 2 • Less side effects + CH 3 NH 3 OH 3 • Decreased toxicity + CH 4 NH 4 • 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 F H to F replacement HN HN E O N Fluorine : similar size with hydrogen O O N S 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 O OH H F Cl CH 3 CF 3 OH CH3 Van der HN HN 1.2 1.35 1.80 2 2 E Waals radius O N O N S 5-Fluorouracil R R Molecular (antineoplastic) 1.03 0.92 6.03 5.65 5.02 Thymidylate Refractivity (DNA synthesis) Inductive - 3.08 2.68 0.00 2.85 E-SH: Thymidylate synthase effect F Resonance 0.00 -0.34 -0.15 -0.13 0.19 effect O NHMe N N Ideal replacement to study the effect of electronegativity change F3C without affecting steric requirements F Fluoxetine Flunarizin (Prozac) (Sibelium) F (or other halogens) can be placed on eacily oxidized positions antidepreessant Ca channel blocker 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 HN Methyl groups often substituted by CF 3 OAc Flufenisal analgesis Ciprofloxacin (Cipro) antibacterial Group Meeting Christos Mitsos Isosteres in Medicinal Chemistry 2/1/2006 -OH to -NH or –SH replacement Van der Waals IC 2 X 50 (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 H NH 1.50 160 Dihydropyrimidine S 1.85 17 calcium channel blockers H2N N N H N N N Halogen replacements H X N CO2H CN and CF 3 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 Ring replacements Replacement of OH with NH 2 can stabilize a different tautomer, 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 OH H 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 R R2 OH OH NHR O 2 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 R R2 N N O 2 O H H H H H N N N N N tetrazole hydroxyisoxazole oxadiazolone N H O H O O R R1 R1 1 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 R S O 2 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 TMSN , DEAD N Ph 3 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 Ph Ph N N HCl N R N N N HN N N- N N J. Med. Chem 2000, 43, 488. N N N Cl Cl PMB CN MeO ClCH C(OEt) N 2 3 N NaN , NH Cl H 3 4 NH N 2 NaN3, AcOH EtO 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 NN 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 F F O O H 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. BF OEt , EtOH 3. DIBAL 3. 2 1. ChxCHPPh3 Chx COOMe CHO CF2Br2, HMPT OAc 2. MeOH, KOH 2. Jone's OO Ph Chx Chx CF2 3. PivCl O OHC O OEt 3. H2, Pd-C OH OTMS OTMS 4. TBSCl TBSO AcO 5. LAH TBSO OAc 6. [O] 1. NaOH 2. n-BuLi, LHMDS2, -90 °C; Chx CF2 + FF ClCOCH2-i-Bu TBSCl, rt; H3O O Chx COOH i-Bu i-Bu Chx Chx O 1. LiNTMS2, MeCHO 2. MsCl O O MeOH, H+ HO 3. Me2CuLi 1. (COCl)2 50 : 50 Me OEt Me O 2. NH3 I2, NaHCO3, TBSO 3. Et OBF FF NH i-Bu 3 4 radical scavenger N Me Me Chx O OEt Chx F 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 2. n-BuNH2 3. PTFA COOEt Me RCOHN NHn-Bu CbzHN COOEt O (78%) CbzHN HO OH i-Bu Me Me O i-Bu 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 CO -t-Bu CO -t-Bu CONH2 CONH2 2 2 1. ClCOOEt, NaBH4 OBn - 2. Bu3P, (PhS)2 OBn 1. DCC, 3,5 Me 3. MCPBA diMe-pyrazole Me 2. LAH 1. DIBAL CbzHN COOH SO2Ph CbzHN Me 3. HWE 2. CH3C(OMe)3 Me CbzHN CO2H CbzHN CO2Et O 1. LDA, ICH2COO-i-Bu 2. LAH Me OHC Aux OTHP 3. DHP Me Me Me 1. OsO4, NMO 4. O3; DMS CO -t-Bu 2 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 + CbzHN OTHP SO2Ph CbzHN CO2-t-Bu 2. Na(Hg), NaH2PO4 CO2-t-Bu Me Me EDCI, Me PheNH2 Me O CO H OBn OBn BocHN 2 BocHN PheNH 1. TFA 2 Jones' 2. NH3 COOH CbzHN OH CbzHN CO2-t-Bu CO2-t-Bu 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..