Combinatorial & Parallel Synthesis
Combinatorial & Parallel Synthesis CH 405/505
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This 20 page Class Notes was uploaded by Evan Roberts on Friday February 27, 2015. The Class Notes belongs to CH 405/505 at University of Alabama - Tuscaloosa taught by Timothy Snowden in Spring2015. Since its upload, it has received 108 views. For similar materials see Medicinal Chemistry in Chemistry at University of Alabama - Tuscaloosa.
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Date Created: 02/27/15
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has no lou n SuccessRut USU Unl SWQMK 25 Van lc nckl vols 33 0 Df inj 31033 1 kt paidfef Svnmsv 1 Wu coth LL W6 C I39M PHmahm on each lacA Patrick An Introduction to Medicinal Chemistry 5e Chapter 1 Split C Split Combinatorial Synthesis The identities of39 the structures in each vessel are not known Each mixture is tested for activity as the mixture often on bead Inactive mixtures are stored in combinatorial libraries Active mixtures are studied further to identify the active component Mix and split methgd 5957 o Gly gt QGf o Am gt Q Aln lt3w GFw o nl gt Q vm o Snr combine nquot gt Mix and split method a Synthesis of all possible tripeptides using 3 amino acids 34mm C s uni 6 0 Hdwv bcs 2391 l39ripcPH leg in 3 n39alS Mix and split method Synthesis of all possible tripeptides using 3 amino acids Mix and split method Synthesis of all possible tripeptides using 3 amino acids Mix 39and sglit method Synthesis of all possible tripeptides using 3 amino acids Ni Umlg KM sicWM maalvmi PJQ g 6 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Melwwemwr 0L Swath9341111 each Carj ounoIM39V UWU7 g p 05 ve regulL 39 9 umduiackn39 Combivtdac39wA Shruchzre Hm bul iun POOL H V gt r P du 3 C5 FeCuJ BdLL deconvolukm u mamma sgsu m Jahl fr jlek 3 4 warm he CLclwz comPou ad ma as 4392 133 21 Recursive deemnwo lu om oMethod of identifying the active component in a mixture Quicker than separately synthesizing all possible components Need to retain samples b eforeiggchgmix and split stage Emmple Consider all 27 tripeptides synthesized by the mix and split strategy from glycine alanine and valine 0 GL ampGly 0 ap 0 0 Jim s Mix and Split J2 gmn 1 Gly 1 Ala GEGIy Gly to iGly Aln 1 a O Aln Gly Q AIn Mn Ia i aI Gly min M All possible dipeptides in three vessels Retain a sample from each vessel and label by compound just added O Glya lg o Ala Gly O W 1 Gly o GIy Alu o Alu Alu o L t I 0 Gly L o Alal 39l I o l Mix and Split 0 Gly Gly O AIu Gly O a GI 0 GIy mn O Am Mn 0 0 3 a In o Gly Gly Q Mn Gly ou EHGy J GEGly Alu o Alu Aln a An 0 Gly I o Gly Gly Aln Gly O u m Cly o Gly Aln o AIn Aln t 7 In 0 3 Q GIy Gly Gly o Aln GIy Gly l Gly s Gly Gly o GIy AIII Gly GHMn Aln Gly 0 u Irlll Gly Q Gly n Gly o Aln ti Gly 34 i i Gly l VlAla 0 Gly Gly Ala aillil39l Gly A11 0 inE ly Ala o Gly Ala Mn o AIIIM1IMI 0 i m Alu AIII o Gly u gr Mu O AIII r l LII Alquot orlil 1 Val o Gly Gly I cl 9 tlliiI Gy 39I OEVMI ly I H QEGly AIn lv 4 o AIn Alu i ii II III I illi o i il Eli i39InIn quotI gs I o y ii i H All possible tripeptides in three vessels 2 l en mtiw of from enmhinaterial synthesis 21 iquot Hy Gly Gly 0 Alu Gly Gly g GIy Gly o Gly Aln Gly Q Alu Aln Gly 0 iii Aln Gly Q GIy w as Gly r o Mn ivuI Gly L ia iH ad Gly awngive eenvnluti n 0 Gly Gly Mn Alu Gly Ala o F 9 AIquot 0 Gly Alli Ala o AIn Mnzln o i a Aln Aln o Gly GIy h 1 r Li o Aln Aln i 1 o Gw t Mal i ii 3914 I d k r as villi Gly t p G Gly AIn zzmr 9 H AIn s gigv Mixture Inactive Mixture Inactive 399 Possible tripeptides in active mixture All end in valine Add valine to the three retained dipeptide mixtures Mixture Active 39ir onvoln on 21 Rmmrsive 39OGlly Glynwiml I gamm Gly n Q Alu Mn a a J 7 I0 ili iJu n i i Gly i 13 VII AIquotI m a iii Active Requires additional screening but active component narrowed down to one of three possible trip39eptides Synthesize each tripeptide and test 2 Identi cation of sh oUse a coding or encryption method employing a triplet code Three tags AC can be used to represent up to seven reagents for the rst stage of a synthesis 49 from combinatorial synthesis Reagent Tagging molecule 1 A B C AB AC BC ABC qamamu Identi cation of from synthesis Three different tags DF can be used for up to seven reagents used in the second stage of the synthesis Tags DF are chosen to have a Ivon gfenletengollime on a gas chromatograph com ared to tags AC 39 L z I p L Lm PQYi hri 40 furKt I ageigmmj 2 co m u39uTutohck Reagent Tagging molecule 91an3 33 mg a 3 a Lia0 1 D S fmiwergyl on 2115 E F DE DF EF 39 DEF IGUIBUJN lden ea o of slimetug Ear ending from combinatorial synthesis Tags are linked to bead by a photocleavable bond Irradiation removes all the tags at the same time Mixture is passed through a gas chromatograph quot1 r 1 59 quotTr if 43quot 5quot HM S fW l W306 u Tags are identified by their retention time 1 mg in Fla Vt 39 39 E 391 39Erl n39 fa 1mm quot 7 gt7 uquotquot Mar I MEL I w39 i If r I 7 3quot59 15 We Ligr i w WW if m m r v V t 7 7 E or 7 frim a r F39 e 5 oAbsence or presence of tags Identi es reagents used at di erent stages of the quot 39 quot 2 M39 2 gm lamb star a lifltnw synthesns a I 1quot h 39u39wf r h m iz 39 i Identifies the product assuming reaction goes as predicted L 615k Snowman quotnow Wg Cg ice uric O Sunk I ma 0v 6 Frog 7 Ftorq cm lQ tf39b in 31 ii a n r I 4 mullme QM i x 9mm wamw b E a gi Q Vania 553 61 f a i D I ESP as o f n 2 Identi cation of 22 v Gas chromatogram Retention i i 7 l time 1 O 1 l 1 Barcode Y T l L Y 1 lst reagent 2nd reagent 3rd reagent A B C D E F G H l Molecularja 0 l l jquot F lrra mal Design Sorafenib Nexavar by BayerOnyx a General kinase inhibitor Treatment for kidney liver and thyroid cancers Promotes autophagy degradation of cell components through the action of lysosomes 5 Only combinatorial drug to make it to market as of 2014 Pkgc liM raPW A MadL 6g SoUd Surpor f IAKHn amp on H Tear U1 Mole a 1665 parHan gr each r mcn a quot7 394 53321 ArenaL 39 j CchHon 09 399 i bicuks bind m 5 S jm ktsift Hu 6 masks Jv HQ 39 each szk 0 lijl39 anh39 Hm deprokclt an F Plak 1 3 7 0 39HM SuPPq 3 lo33 gr a Seed 39clNSHcJI39Q Phuk abile P th 5 Stem 1S CoutafCA H39K whack exfoseds 6 diffecem t a1 a Emmaa 00 i 3999 run reach on quot 039 h lg fkolrapt y id S upporI 5 tcgc at Back 15k bk noh39eKPo z is Prokckd 9mm requiem ckmb msuMI OP radiuiSo rc u Wadi m as alktmlng mm rk gust ncor Kt39nau 115 L 5 lukb 3mm Tkucs CLJ39ZH JHM H wll P08 Problem Sc39t39 dur ins Wkn he 30 5ch m4er L or 1246 C i mphquot165 Thquot c e emulator 3roupgtPam1e quMSh 3 ImpNLud39 me 39 2 125 tack armless gr aeRIi 39lit39o 1 S Rt mn a39nj IntroGian 7 NM 350 Rmuzuo Hsb 1 quot a 39 M 39 r MH iann ning Pi in rii i m resin ih fl 39 cm mmiuu 0 NHFmoc M F XOH or coan 939 Fmocprotectlng group 39 HFmoc NH 1 Base Piperidine AcOH 2 Rquot deprotection Cycnsation Alkyla m l TFAHzOMezS 39 gt Cleavage quot M lmllr mun 7 397 h Iu llr1H rlnfu lIzllhll F r quot1quot g L 1quotr39 vnI L39 739 Iu 1 ramp iiiL l IquotJ i 39 i I I l I i i ll mm mm PMquot quot39quot Mquot I quotlm39m quot391 v I E Scoring functlon 7 639 I v39 quot r 2 r Pharmacophm mapping I 39 I 7 Vlrtual Ilbu dulgn Molaullrllmlllrlty PMWH39PW alomtion 003307322 6419 V a 063343332 6405 r a Mme rmly CurHon ol I virtual Ganmm of IIIfCOlInDMIn anllnl docking by Ranklng and llbmy ol alutrophllu and quotand conformation minimum umplln manual uhcllon Nature Chemical Biology 2014 10 1066 4 Stirring Sbind EintTASTorva a1 Eel a2 Ehb 3 Ehp a4 Esf Where va Eel Ebb Ehp and Esf are van der Waals electrostatic hydrogen bonding and nonpolar and polar atom solvation energy differences between bound and unbound states respectively Eint is the39 ligand internal strain ASTOr is its conformational entropy loss upon binding and T 300 K Cell Death and Disease 2014 5 el293
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