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CHEM-E4140 Selectivity in Synthesis and Recognition Lecture 11: Bioactive Compounds Jan Deska Laboratory of Organic Chemistry 05.12.2016 structure, b i n d i n g , polysaccharides energy Pri mary B uilding Blocks o f Life § the primary metabolism OH O CO2H pyruvic acid O HO HO HO sugars OH D-glucose HO O O –O SCoA source of acetyl carbon coenzyme A (fats, lipids, citric acid secondary cycle metabolites HO O P O– OH OH D-ribose phosphate global energy storage O ATP NH –O HO2C CO2H HO CO2H citric acid OH m u s c u l a r R CO H 2 tissue, m e s s e n g e r NH2 a m i n e s , . . . L-amino acids –O P O N O O OH OH ribonucleotides O HO pyruvic acid OH D-glucose Pri mary B uilding Blocks o f Life § HO the primary metabolism O O –O HO SCoA citric acid cycle HO2C O P O– OH OH D-ribose phosphate acetyl coenzyme A O ATP NH –O –O CO2H HO CO2H R P O CO2H NH2 citric acid controls N O O O OH OH L-amino acids all chemical reactions in living things OH ribonucleotides controls proteins nucleic acids structure and catalysis store genetic informations N u c l e o b a s e s e n c o d e for Amino a c i d s Structure o f p r o t e i n s § the simple building blocks: proteinogenic amino acids H2N H2N COOH H2N COOH alanine (Ala, A) glycine (Gly, G) H2N COOH valine (Val, V) leucine (Leu, L) S H2N COOH isoleucine (Ile, I) N H COOH proline (Pro, P) COOH H2N COOH methionine (Met, M) Structure o f p r o t e i n s § the simple building blocks: proteinogenic amino acids OH H2N SH OH H2N COOH serine (Ser, S) H2N COOH COOH cysteine (Cys, C) threonine (Thr, T) HO HN H2N COOH phenylalanine (Phe, F) H2N COOH tryptophane (Trp, W) H2N COOH tyrosine (Tyr, Y) Structure o f p r o t e i n s § the simple building blocks: proteinogenic amino acids H2N NH2 O COOH HOOC O H2N H2N COOH asparagine (Asn, N) COOH H2N COOH H2N aspartic acid (Asp, D) glutamine (Gln, Q) H N H2N glutamic acid (Glu, E) NH2 H N NH N H2N COOH histidine (His, H) H2N arginine (Arg, R) COOH COOH H2N COOH lysine (Lys, K) Structure o f p r o t e i n s § primary, secondary and tertiary structures R R R OH H2N N H – H2O O O H N N H O O R R R – H2O § N H O H N N H O R R R O H N N H O R primary structure depicts a virtual linear alignment R O H N N H O R O H N N H O R O Structure o f p r o t e i n s § primary, secondary and tertiary structures § secondary structure describes 3D-objects formed through H-bonding interactions Structure o f p r o t e i n s § primary, secondary and tertiary structures § tertiary structure shows arrangement of subunits to form a complex bulk structure Inhibition o f Protein Functions § proteins as key functional molecules (enzymes and receptors) § the vast majority of protein functions crucial for maintaining a living organism (toxicity vs. pharmaceutical effect) = nothing to mess around with, but... § pharmaceuticals may: o interact with alien proteins (from invading microorganisms, parasites, etc) o modulate enzyme activities to a desired level o mute receptor answers on demand 1 9 t h C e n t u r y Pharmaceutical Chemistry CO2H acetylsalicylic acid O O § analgetic (pain relief) § antipyretic (lowering fever) § anti-inflammatory § anticoagulant § salicylic acid first isolated from willow (Salix) by Löwig, 1838 § industrial synthesis based on Kolbe process, Bayer 1859 CO2 (5 bar) ONa 150 °C O ONa OH 1 9 t h C e n t u r y Pharmaceutical Chemistry CO2H acetylsalicylic acid O O mode of action § selective inhibition of prostaglandine biosynthesis (via cyclooxygenases) § prostaglandins act hormone-like modulating platellet aggregation, neuron sensitizing etc § acetylation of serine blocks entrance for arachidonic acid CO2H CO2H COX-2 2 x O2 O O HOO arachidonic acid prostaglandin G2 Modern B lockbusters Lipitor (Atorvastatin, Pfizer) OH OH O O N OH PhHN Ph F § against athereosclerosis § lowering cholesterol blood levels § prevents cardiovascular diseases (stroke, cardiac arrest,...) best-selling drug ever (>125 billion USD) Cholesterol biosynthesis Lipitor (Atorvastatin, Pfizer) mode of action § selective inhibition of mevalonic acid biosynthesis H N R O O H N S OH O OH O OH HO O mevalonic acid 3-hydroxy-3-methylglutaryl-coenzyme A O P –O –O O P –O –O O O P –O O OH and O P –O –O O O P –O O H H O terpenes H HO H cholesterol H M G -redu ctase CoA S O O NADH OH O H3N HN H3N HO Lys Ser NH2 Arg binding mode for the thioester reduction § lower cholerstrol levels in plasma § lower risk for plaque § lower risk for blocked arteries Lipitor bound irreversibly inside active site C e r i v a s t a t i n – a failed competitor Lipobay (Cerivastatin, Bayer) OH OH O N O What has happened? OH F § approval in 1997 § 1998-1999: several deaths related to Lipobay treatment § § statins often combined with lipid lowering drugs (fibrates) § mutual inhibition of degradation mechanisms ("statin" + "fibrate") ü 5-fold increased statin levels ü inflammation and degradation of muscle tissue ü kidney failure 2001: withdrawl from market N u c l e i c a c i d s a s Ta r g e t –O –O P O –O base O –O O P O ribonucleotide deoxyribonucleotide O NH2 N N N N N adenine NH2 cytosine NH N guanine O N N O OH H OH OH N base O NH2 O NH O N O NH N O thymine uracil DNA only RNA only Base Pairing thymine/ uracil R O H N N adenine N H H N N O N N N O guanine N H cytosine N N N N H N H O N H H R e l a t i o n s h i p DNA - RNA - p r o t e i n s replication x2 single nucleotides § DNA-targeting drugs can interfere with either the replication or transcription § affect in principle all cells (cytostatika) § but: applicable fighting against rapidly growing/replicating systems ü anti-tumor drugs ü anti-virals Fluorouracil O F NH N H O § cytostatic suicide inhibitor § on the list of the most important medication in basic health systems § widely applied against various types of cancer (stomach, breast, colorectal, skin,...) acts as... § so-called anti-metabolite § irreversible inhibitor of thymidylate synthase § thymineless death of rapidly dividing cells Fluorouracil § transformation of deoxyuracil to deoxythymidine required to provide DNA building blocks for replication O Me+ NH 2–O 3PO O N O thymidylate synthase 3PO Me NH Enz 2–O Enz O O– 2–O S O SH N O – Enz OH 3PO O NH N O SH OH OH deoxyuracil monophosphate § deoxythymidin monophosphate deoxyfluorouracil not capable of methylation Me+ Enz OPO32– O– F NH S O OH N O Tr o j a n H o r s e s § fake nucleotides affect all cells § using tumor- or virus-specific activation for selective drug recognition O NH O N HO O N NH N Aciclovir anti-herpes § NH2 N HO O N O NH2 HO N3 AZT (azidothymidine) anti-HIV manipulated nucleosides show high selectivity as anti-virals (herpes, HIV, ...) N (R)-cytallene anti-hepatitis O Tr o j a n H o r s e s § rapid replication of virus-infected cells due to sloppy kinase enzymes § kinase-catalyzed phosphorylation renders active DNA-building block ü incorporation results in unfunctional DNA ü cell death only of the infected cells O N HO O N NH N NH2 O viral kinase –O –O P O N O O N NH N Aciclovir inactive active unfunctional DNA NH2 Groove Binders § interaction of non-DNA related molecules to the DNA's grooves renders it unreadable ü DNA binders selectively inhibit transscription § organometallics as anti-cancer drugs (cisplatin, carboplatin, oxaliplatin,...) ü cross-linking of DNA via purine bases Cl NH3 Pt Cl NH3 O O cisplatin NH3 Pt O NH3 O carboplatin Groove Binders § interaction of non-DNA related molecules to the DNA's grooves renders it unreadable ü DNA binders selectively inhibit transscription § pyrrole amidine antibiotics § based on netropsin, isolated from Streptomyces netropsis (1951) § binds selectively to the minor groove of AT rich DNA NH H2N O N N H NH O Netropsin O N N H N H2N NH2 Groove Binders § interaction of non-DNA related molecules to the DNA's grooves renders it unreadable ü DNA binders selectively inhibit transscription § pyrrole amidine antibiotics § modulation of the pyrrole pattern allows for selective interactions with particular nucleobases O N N N H O HN NH N O N O N HN NH3+ HN CO2 – O H N O N+ N N H N NH O N O N H N O in clincal trials against prostate cancer Selectivity in Transport § selective transport of a drug to the desired organ crucial for effect § unfavorable polarity, rapid degradation etc. pose problems ü masking of the pharmaceutical motif = pro-drugs OH HO H N OH H N H N HO adrenaline ephedrine amphetamine highly polar highly unpolar peripheral effect acts in brain hypertensive effect intoxicative effect Selectivity in Drug D e l i v e r y § selective transport of a drug to the desired organ crucial for effect § unfavorable polarity, rapid degradation etc. pose problems ü masking of the pharmaceutical motif = pro-drugs O N O H2N O O N NH N O NH2 O C13H27 Cl Val-Aciclovir slow hydrolytic release O2N HN Cl O Chloramphenicol palmitate selective enzymatic hydrolysis in dudenal guts