M2 Drug Design Heterochemistry PDF

M2 Drug Design Heterochemistry UE 40 Design & Synthèse 5ème étage aile B [email protected]  SULFUR CHEMISTRY Chalcogenides Bioactif compounds CO2H...

M2 Drug Design Heterochemistry UE 40 Design & Synthèse 5ème étage aile B [email protected]  SULFUR CHEMISTRY Chalcogenides Bioactif compounds CO2H O HS H2N S NH2 OH O Cysteine Taurine H N O O R NH2 N S S S O MeO N N O H H2N O CO2H Sulfanilamide MeO Penicillin omeprazole  Introduction Nomenclature R SH Thiol R R R S Sulfide R S Sulfonium R S R R S Disulfide O R S Sulfinic acid O OH R S Sulfoxide R O R S O Sulfonamide O Sulfone NHR R S O R  Introduction 1.52 A C C Bond lenghts 1.81 A C S 2.05 A S S RSH + NaOH RSNa (PhSH, pKa = 8) pKa = 10 Thiolate Acidity R = aryl ROH + NaOH RONa (PhOH, pKa = 9.9) pKa = 16 RONa R = alkyl NaOH/H2O pka = 14  Reactivity and synthesis Reactivity Nucleophily PhSNa > PhONa O O Electrophily S S S R I R S R S R Cl R Cl O O N SR - + O  Reactivity and synthesis Preparation of thiol: H+/H2O Na2S NaS + R1 X R1 SNa R1 SH R1 X R1 S R1 mixture !  R1 X R1 S R1 R1  Reactivity and synthesis « clean » methodology: from thiourea H2N NH2 NH2 S + R1 X H2N R1 S NH2 R1 S NH2 O OH H NH2 R1 SH O NH2 Reactivity and synthesis Electrophily R Nu S R R + RS S S R NaBH4 / MeOH ex: (PhS)2 PhSH + PhS rt = « room rt temperature » Br2 (PhS)2 2 PhSBr stronger electrophile PhSBr Br Br S SPh (+/-) Ph  Reactivity and synthesis Leaving group R1 Nu S R PhSPh + Nu R R1 ou O O O S Nu R + O R1 O R Nu S R1 O R1 = Ms, Ts, Tf (mesylate, tosylate, triflate) O O O O S S R Cl HO R R1 O R O O O S O O Cl O S < < S H3C Cl F3C Cl H3C + nucleofuge  Reactivity and synthesis Oxidation of thiol: I2 I S SO2H H2O2 D [O] = KMnO4, NaIO4, H2O2, m-CPBA  Reactivity and synthesis Thiocarbonyle ? Lawesson's reagent, solvant  S O R R R R S S P OCH3 aldehyde, ketone, H3CO P S amide S S 2 H3CO P S  Reactivity and synthesis sulfonium ylides R1 R3 R3 R1 R3 R1 R3 R1 base S + I S S S R2 R2 R2 R2 I 0°C stable if T < 5°C sulfoxonium ylides O R3 O R3 O R3 O R3 S base R1 R2 + S S I R1 S R1 R1 R2 0°C R2 R2 I stable if T < 60°C O R3 S R1 Johnson-Corey-Chaykovsky reaction R2 O R3 O S R R R R R1 R1 N if imine S N R R S O R R  Reactivity and synthesis Jonhson-Corey-Chaykovsky reaction R1 R3 S R2 O O or O Addition 1,2 or 1,4 ? O R3 S R1 soft or strong nucleophile ? R2 sulfonium 1,2 Addition epoxide sulfoxonium 1,4 Addition cyclopropane sulfoxonium = soft nucleophile = Michael addition O R3 O O S O R1 O S + DMSO R2 R1 R2 O R3 S R1 R2 O CO2R R1 CO2R O stabilized ylide S ? R2 Base  Reactivity and synthesis b-elimination of sulfoxide: O O SPh [Ox] SPh H SPh  R2 R1 R2 R1 + PhSOH R1 R2 R1 R2 syn-elimination  S-Heterocycle S S S S S N N N N thiophene benzothiophene thiazole benzothiazole imidazothiazole Thiophene: O R R O LR S R R S SH R S S R S R R R R SH H  S-Heterocycle Thiazole: S O S X H2N + HX H2N NH2 R N R H O O H2N S H2N S H2N S H2N S R H R N N N H OH -H2O N H R H H R O ImidazoThiazole: S X S R NH2 N N N R S H S S N NH S N H  O N NH N O H N N Ph -H2O Ph OH H SELENIUM CHEMISTRY Chalcogenides  Introduction Characteristics O Se no sélénone Easier oxidation: R R selenoxide NMR Se 77 Stronger nucleophily:PhSeH > PhSH > PhOH Bioactif compounds O CO2H HSe NH2 Se selenocystéine ebselen anti-oxydant anti-inflammatory  Preparation H3O+ [O] Ph-MgBr + Se PhSeMgBr PhSeH PhSe-SePh nucleophile selenol diselenide (PhSe)2 + X2 PhSeX electrophile  Nucleophily NaBH4/MeOH E+ PhSe-SePh PhSe PhSe E diselenide or PhSeCN O O HO NH4Cl ex: PhSe SePh SePh  Electrophily Se Ph Ph Se Nu Ph Se Nu PhSe X Se Ph Ph Ph H H Se Se O OH ex: Ph Ph SePh SePh Ph Ph H2O O O ex: (PhSe)2 SePh I2  Oxidation Riley oxydation SeO2 R OH R  R R [2,3] Wittig R R H O Se O Se OH O Se O HO HO Oxydation into aldehyde O SeO2 O O R R  N SeO2 N CHO ex:   Rearrangment Instability of selenoxydes R [Ox] rt SePh R R SePh O fast H R SePh ox = mCPBA O O NaIO4 H2O Ph Ph OH OH N O ? N O ex: Ph OH mCPBA, rt, DCM 1) secBuLi N O 2) PhSeBr SePh  Biological role preventing damage to important cellular components caused by reactive oxygen species (ROS) Glutathion peroxidase selenium-containing enzymes GSH RO-OH or H2O2 glutathion from oxidative stress glutathionperoxidase GS-SG ROH or H2O GSH = tripeptide with cysteine  Biological role Glutathion oxidation BORE CHEMISTRY  INTRODUCTION Valence Electron: 3 e- B B NMR: 11 B Nomenclature: BH3, BR3 boranes B(OH)3 boric acid R-B (OH)2 boronic acid OR1 boronic ester R B OR1 Medicinal activity: CF3 O F O N B O H B OH OH anticancer anti-trypanosomiasis agent Bortezomib (antitumoral)  Reactivity and synthesis Nu Nucleophilic Addition : B B Nu Hydride transfert : H H B E+ H H O R OH Alkyle transfert : R1 R2 B R R1 base R2 Palladium-catalyzed Cross Coupling (Suzuki-Miyaura) B(OH)2 Ar1 X Pd(Ph3)4 cat Ar2 + Ar2 Ar1 Base  Reactivity and synthesis ex: late-stage of Suzuki-Miyaura coupling N CH3 N 71% N OSO2F Cl Cl Br SO2CH3 Pd(PPh3)4 cat Pd(PPh3)4 cat Etoricoxib NaHCO3 (3 equiv.) KF (3 equiv.) N OSO2F (antiinflammatory) Dioxane,  Dioxane/H2O (1:1) Cl  (HO)2B N CH3 SO2CH3 SO2CH3 63% (HO)2B Chem. Eur. J. 2016, 22, 5692–5697  Reactivity and synthesis Reduction of alkenes : hydroboration R R R B R R B + H B + R1 R2 R R1 R2 R1 R2 syn addition R B H R H R H R B B R R R R R R R B H R  Reactivity and synthesis Reduction of alkynes : hydroboration R NaOH, H2O2 R C CH + H B R CHO R O 2O 2 /H R aOH R2 BR 2 N R 2B H R 1 C C R2 R1 R2 Ac O H R1 R2  Reactivity and synthesis Borane transformation R OH O OH NaOH, R' H R R' H2O2 R Br Base Base Br2 X R B Base R R' R' = Alkyle H+ X R' X R' = Aryle (avec Pd(Ph3)4) R H Base (PhSe)2 I2  Applications for drug H3CO H3CO H3CO H3CO Bioisostere: OCH3 OH OCH3 B(OH)2 OCH3 OCH3 Combrestatine isostere MCF-7 Incresase of tubulin inhibition IC50 = 0.032 m MCF-7 IC50 = 0.017 m Cell Chemical Biology 2005, 12, 1007-1014 Prodrug: active metabolite of Irinotecan Eur. J. Med.Chem., 2016, 116, 84–89 FLUORINATION Permeability (hydrophoby) pKa (electronegativity) potency Hydroxyle/hydrogen Isostere PET (18F)  Known flurorinated drugs O O H2N S F O HN O N N N CF3 H Fluorouracil anticancer O celecoxib antiinflammatory CF3 HN O N O HOH2C OH Trifluridine Antiviral  Nucleophilic Fluorination Diethylaminosulfur trifluoride (DAST) Deoxyfluorination DAST OH F R R F NEt 2 F NEt 2 F S F F S F OH F S N O O F + O S R -HF R R R NEt 2 F R' R' F DAST O F R R  Electrophilic Fluorination Selectfluor NuH + selectfluor NuF O O Exemples: NEt3 O O R OR' R OR' F F N N R' R' Cl F N O N R O R Cl Cl F N N N N H N N H  SuFEx: Sulfonyl Fluorides (RSO2F) New Click Reaction O CLICK O S F + Nu S Nu O O - Ease of preparation - High Stability with H2O - High reactivity with various C, N and O- even under basic or nucleophiles acidic conditions - Thermodynamic Stability fluoride-proton interaction: Stabilization of the fluoride ion in water affords chemistry in aqueous environments. Org. Biomol. Chem., 2017, 15, 1549-1553